STRUCTURE,
CHEMICAL PROPERTIES OF HETEROCYCLIC COMPOUNDS. STRUCTURE,
COMPOSITION AND PROPERTIES OF NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS.
STRUCTURE,
COMPOSITION AND PROPERTIES NUCLEIC ACIDS. HETEROCYCLIC COMPOUNDS. COMPARISON WITH CARBOCYCLIC
COMPOUNDS
n Heterocyclic
compounds are cyclic
compounds in which one or more ring atoms are not carbon (that is hetero
atoms).
As hetero atom
can be N, О, S, В, Al, Si, P, Sn, As, Cu. But common is
N, О, or S.
Heterocycles are conveniently
grouped into two classes, nonaromatic and aromatic
n
By
size of ring
Three-membered
Four-membered
Five-membered
Six-membered
The molecules of organic chemical compounds are
built up from a framework or backbone of carbon atoms to which are attached
hydrogen (H), oxygen, or other heteroatoms. Carbon atoms have the unique
property of being able to link with one another to form chains of atoms. When
the ends of the chains are joined together into a ring, cyclic compounds
result; such substances often are referred to as carbocyclic or alicyclic
compounds. Substitution of one or more of the ring carbon atoms in the
molecules of a carbocyclic compound with a heteroatom gives a heterocyclic
compound.
Five - membered
heterocyclic compounds with one heteroatom.
The
structures of these three heterocyclic would suggest that they have highly
reactive diene character.
These heterocyclic have
characteristics associated with aromaticity.
A typical carbocyclic
compound is cyclopentane (C5H10), the molecular structure
of which is indicated by the formula
in which the chemical symbols
represent atoms of the elements and the lines represent bonds (see covalent
bond) between the atoms. For convenience such formulas are often written in
simplified polygonal form, such as
for cyclopentane, in which each
corner of the polygon represents a carbon atom (it being understood that
hydrogen atoms are joined to the carbon atoms as required).
When one of the carbon atoms of cyclopentane is
replaced with an atom of nitrogen, the compound pyrrolidine, a chemical
relative of pyrrole, is produced. The structural formula of pyrrolidine is
written:
Other heterocyclic compounds can be envisioned
similarly as derivatives of cyclopentane by substitution with other heteroatoms
or of other carbocyclic compounds by substitution with nitrogen or other
heteroatoms.
The simplest organic compounds are the hydrocarbons, compounds of carbon
and hydrogen only. Hydrocarbons are classified as saturated if all four
possible bonds of every carbon atom are joined singly to another carbon atom or
to a hydrogen atom. They are classified as unsaturated if they contain a double
or triple bond between any two of the carbon atoms, and they are classed as
aromatic if they contain at least one ring, all atoms of which are joined by
alternating double and single bonds. Nonaromatic unsaturated compounds are
highly reactive—that is, they readily undergo additions of atoms or groups of
atoms to the carbon atoms of their double bonds, giving each carbon four substituents.
Aromatic compounds, though having double bonds, are extremely stable and do not
readily undergo the addition reactions characteristic of other unsaturated
compounds. The stability and unreactivity of, for instance, a six-membered
aromatic ring are associated with the presence of three pairs of electrons,
called pi (π) electrons, associated with the three double bonds of the
ring. Together these electrons, constituting the so-called aromatic sextet,
form an unusually stable structure associated with the aromatic ring as a whole
rather than with the individual pairs of atoms.
Heterocycles too may be classified as saturated,
unsaturated, or aromatic. Thus, as shown in the following structural formulas,
pyrrolidine is a saturated heterocyclic compound containing no double bond; 4,5-dihydrofuran is an unsaturated heterocyclic compound; and
pyridine is a typical heterocyclic aromatic, or heteroaromatic, substance. In
the two structural formulas given for pyridine, the first shows the double
bonds, whereas the second represents the aromatic sextet with a circle.
This classification relates the chemistry of
heterocycles directly with that of carbocyclic derivatives, which are usually
better known. In general, synthetic methods and physical and chemical properties
of the saturated and the partly unsaturated heterocyclic compounds closely
resemble those for their acyclic (noncyclic, or open-chain) analogs. Thus,
pyrrolidine may be considered as a cyclic secondary amine and has much in
common with the corresponding acyclic amine, diethylamine, which is represented
by the formula:
Similarly, 4,5-dihydrofuran mirrors many of the
properties of the corresponding unsaturated ether, ethyl vinyl ether, which has
the formula:
Nomenclature of
heterocyclic compounds
Naming heterocyclic compounds is complicated
because of the existence of many common names in addition to the
internationally agreed-upon systematic nomenclature. (A brief account of
systematic nomenclature is given here; for more information, see below Major
classes of heterocyclic compounds.)
The types of heteroatoms present in a ring are
indicated by prefixes; in particular, oxa-, thia-, and aza- denote oxygen,
sulfur, and nitrogen atoms, respectively. The numbers of heteroatoms of a
particular kind are indicated by number prefixes joined to the heteroatom
prefixes, as dioxa- and triaza-. The presence of different kinds of heteroatoms
is indicated by combining the above prefixes, using the following order of
preference: oxa- first, followed by thia- and then aza-.
In addition, partially saturated rings are indicated by the prefixes
dihydro-, tetrahydro-, and so on, according to the number of “extra” hydrogen
atoms bonded to the ring atoms. The positions of heteroatoms, extra hydrogen
atoms, and substituents are indicated by Arabic numerals, for which the
numbering starts at an oxygen atom, if one is present, or at a sulfur or
nitrogen atom and continues in such a way that the heteroatoms are assigned the
lowest possible numbers. Other things being equal, numbering starts at a
nitrogen atom that carries a substituent rather than at a
multiply bonded nitrogen. In compounds with maximum unsaturation, if the
double bonds can be arranged in more than one way, their positions are defined
by indicating the nitrogen or carbon atoms that are not multiply bonded and
that consequently carry an extra hydrogen atom (or substituent), as follows:
1H-, 2H-, and so on.
Physical
properties of heterocyclic compounds
Physical properties are important as criteria for
judging the purity of heterocycles just as for other organic compounds. Organic
compounds generally show great regularity in their physical properties, and
heterocycles are no exception.
The melting point was once a widely used criterion for purity, but it
has been increasingly superseded by optical spectra, based on light absorption;
mass spectra, based on relative masses of molecular fragments; and magnetic
resonance spectra, based on nuclear properties (see spectroscopy).
Nevertheless, knowledge of melting and boiling points is still helpful for
judging the purity of a compound.
Introduction to Heterocyclic
Compounds
Heterocyclic compounds are cyclic compounds that contain atoms other
than carbon in their ring. The figure above shows just a few single-ring heterocyclic
compounds. The ones shown are simply 5 and 6 membered rings. There are smaller
and larger rings and there are also multiple ring heterocycles.
Heterocyclic compounds play a big role in organic chemistry and because
they have different electron configurations from carbon, they react differently
from carbon rings and differently from each other. Later in this book we will
discuss several specific heterocyclic compounds that are very commonly used in
organic chemistry and we'll discuss their individual characteristics.
For now, it's simply important to know what a heterocyclic compound is.
Chemical
properties of organic compounds
Chemical properties of furan, pyrrole, thiophene
The typical reaction of furan,
pyrrole, and thiophene is electrophilic substitution. All three
heterocycles are much more reactive than benzene. The reactivity order being
is:
To give some idea of the
magnitude of this reactivity order, partial rate factors (activities related to
benzene) for tritium exchange with fluoroacetic acid.
Reciprocal
transformation of furan, pyrrole, thiophene
(Yurie`s cycle reactions)
1. Interaction with dilute
mineral acids
Pyrroles are polymerized by even dilute acids by a mechanism
such as the following .
2. Reactions of electrophilic
substitution:
This orientation is understandable in terms of the mechanism
of electrophilic aromatic substitution. The a/b ratio is determined by the relative
energies of the transition states leading to the two isomers. As in the case of
substituted benzenes, we may estimate the relative energies of these two
transition states by considering the actual reaction intermediates produced by
attack at the a-or b-positions.
Nitration
Sulfonation
Acylation
Of these structures, the most important are the
two with the positive charge on sulfur because, in these two sulfonium cation
structures, all atoms have octets of electrons. Nevertheless, as the sets of
resonance structures show, the charge on the cation resulting from attack at
the a-position is
more extensively delocalized than that for the cation resulting from attack at
the b-position. The following examples
demonstrate the generality of a-attack.
Halogenation
Reactions of
oxidation
Properties
For identification of pyrrole and furan used the
method coloring of a pine chip. Couples of pyrrole painted a pine chip soaked
in hydrochloric acid in the red colour and furan - in the green colour.
Qualitative reaction on thiophene is indophenin`s reaction: a mixture of
izathine with concentrated sulfuric acid painted in the blue colour.
The chemical reactivity of the saturated members
of this class of heterocycles: tetrahydropyran, thiane and piperidine, resemble
that of acyclic ethers, sulfides, and 2º-amines, and will not be described
here. 1,3-Dioxanes and dithianes are cyclic acetals
and thioacetals. These units are commonly used as protective groups for
aldehydes and ketones, as well as synthetic intermediates, and may be hydrolyzed
by the action of aqueous acid. The reactivity of partially unsaturated
compounds depends on the relationship of the double bond and the heteroatom
(e.g. 3,4-dihydro-2H-pyran is an enol ether).
Fully unsaturated six-membered nitrogen heterocycles, such as pyridine,
pyrazine, pyrimidine and pyridazine, have stable aromatic rings. Oxygen and
sulfur analogs are necessarily positively charged, as in the case of 2,4,6-triphenylpyrylium tetrafluoroborate.
From heat of combustion measurements, the aromatic stabilization energy
of pyridine is 21 kcal/mole. The resonance description
drawn at the top of the following diagram includes charge separated structures
not normally considered for benzene. The greater electronegativity of nitrogen
(relative to carbon) suggests that such canonical forms may contribute to a
significant degree. Indeed, the larger dipole moment of pyridine compared with
piperidine supports this view. Pyridine and its derivatives are weak bases,
reflecting the sp2 hybridization of the nitrogen. From the polar canonical
forms shown here, it should be apparent that electron donating substituents
will increase the basicity of a pyridine, and that
substituents on the 2 and 4-positions will influence this basicity more than an
equivalent 3-substituent. The pKa values given in the table illustrate a few of
these substituent effects. Methyl substituted derivatives have the common names
picoline (methyl pyridines), lutidine (dimethyl pyridines) and collidine
(trimethyl pyridines). The influence of 2-substituents is complex, consisting
of steric hindrance and electrostatic components. 4-Dimethylaminopyridine is a
useful catalyst for acylation reactions carried out in pyridine as a solvent.
At first glance, the sp3 hybridized nitrogen might appear to be the stronger
base, but it should be remembered that N,N-dimethylaniline
has a pKa slightly lower than that of pyridine itself. Consequently, the sp2
ring nitrogen is the site at which protonation occurs.
Nucleotides
Nucleotides consist of two parts: A base and a
sugar, linked together by an N-glycosidic bond. The base can take two major
forms, that of a purine or of a pyrimidine:
The numbering will be important later, and it follows the numbering
scheme of heterocycles. There are 5 major bases that we will see. These are
adenine, (A), guanine (G), cytosine (C), thymine (T), and uracil (U):
As most heterocyclic compounds, bases are pretty funky molecules.
Although there are many natural sources for similar bases (xanthines), they are
made from scratch by the organisms that use them. This means that these
molecules connect all organisms in the very early stages of evolution. The same
goes for DNA and RNA - They are the same in all organisms, so they link all
evolution at a certain point in time - Everything came from a primordial bug
that already made DNA and RNA. Pretty spooky.
In any case, the bases are highly congujated rings. If you analyze them,
you will recognize that almost all the carbons are in sp2 hybridization, and
form part of congujated systems. Even those that are sp3 (like the N9 in
purines) are sharing their electron to form aromatic systems. Other nitrogens
are either sp2 or form part of amide bonds (partial sp2 character). This means
that this molecules will absorb UV-visible radiation, will be flat or almost
flat, and they are pretty non-polar (except for the exocyclic amines in A and
C).
Furthermore, since they have clouds of p-electrons, they will form
favourable p-p stacking interactions with one another. This, as we will see
later on, is a very important force that stabilizes polynucleotides like DNA
and RNA. The bases will place on top of one another due to the favourable p-p
stacking interactions, increasing the stability of the molecules they form part
of.
Finally, the functional groups of the bases, carbonyls (C=O) and amines
(-NH2) and amides (NH-CO), will participate in h-bonds. These h-bonds can be to
water, or more importantly, between them - The second important interaction in
molecules like DNA or RNA:
As we will see later, h-bonding will be between A and T or U, and G and
C. Another property of the bases is they can form tautomers (not the same as
resonant forms). We can have in many of them keto-enol equilibria:
The position of the equilibria (that is, which form will predominate)
will depend on the pH of the solution (if in aqueous solution). In
phisyological conditions (than is, pH = 7), the ones drawn at the top will
predominate.
Heterocyclic Bases
Uracil
thymine cytosine
One particular group of hetero cyclic compounds are
the heterocyclic bases. These examples are extremely important compounds. Look
at the names of these compounds. If you have studied any biology, you will
probably recognize these names as being very important parts of DNA and RNA
molecules. The ones shown here are uracil, thymine, and cytosine.
In the biochemistry lesson on nucleic acids, you will learn about how
these heterocyclic bases bond to sugar molecules and phosphate groups to form
DNA and RNA. You will also learn about how they can bond to one another to pull
the two strands of the DNA together.
When the ring
system in an organic compounds contains at least one other element (e.g.
N, O, S, B, Si) other than carbon, it is classified as heterocyclic. At least one heterocyclic
ring component is found in about 50% of known organic compounds.
The most common
heterocyclic systems contain heteroatoms N, O or S and good examples of these
are six-membered heterocycle pyridine and five-membered heterocycles pyrrole,
furan and thiophene. Pyridine is one of the most common and best known
heterocycles. It is an excellent polar solvent and act as a donor ligand in
metal complexes. In a nicotinamide, pyridine is a structural part of an
important coenzyme, and the tobacco alkaloid nicotine is perhaps the best known
naturally occurring pyridine derivative. Pyrrole occurs widely in nature and is
a structural part of porphyrin haeme, chlorophyll and vitamin B12.
Furan is found in coal tar, and some terpenoids such as rose oil, contain the
furan ring in their chemical structure. The reduction of furan leads to the
heterocyclic ether tetrahydrofuran (THF), which is widely used as an organic
solvent. Thiophene, which is a sulfur containing heterocycle, occurs in nature
in some plant products but its greater importance is as an ingredient in
synthetic pharmaceuticals and dyestuffs.
N−Heterocycles
were involved at the very beginning of life in the genesis of DNA and play an essential
role in many living systems. The nucleic acid bases adenine (A), guanine (G),
cytosine (C) and thymine (T) are derivatives of the aromatic N−heterocycles
pyrimidine and purine. The base-pairing of DNA by H-bonding is illustrated in
Fig. Proteins, which are linear chains of α-amino acids are other
important biological macromolecules. One of the essential amino acids,
histidine, contains a heterocyclic imidazole ring in its chemical structure. Also histamine, which is a decarboxylation product of histidine
has an important role in living systems, e.g. as a contracting agent of
smooth muscles and as a substance involved in allergic reactions. The other
important amino acid tryptophan and many naturally occuring alkaloids are
indole derived structures. In tryptophane the heteroaromatic indole residue has
appeared preference for cation−π and π −π
interactions.
Most of the
important heterocycles mentioned here are aromatic. According to the
Hückel rule a monocyclic system containing 4n+2 π -electrons
(n=0,1,2,… ) is classified as aromatic. Figure
shows the orbital structure of the five-membered aromatic system
imidazole. Other criteria of aromaticity are bond lengths, ring current effects
and chemical shifts in 1H NMR spectra. All the heterocycles selected
for study in this work are aromatic 6π -electron systems.
The H-bonding systems of
DNA base-pairs between guanine (G) and cytosine (C), and adenine (A) and
thymine (T). In addition the chemical structures of histidine and tryptophan
proteins are shown. Histamine is a decarboxylation product of histidine.
An example of a
five-memberered N-heteroaromatic 6π -electron system. Protonation
of imidazole occurs on the lone pair of the nitrogen (in the plane of the ring)
and does not change the number of π -electrons.
Five-membered rings with one heteroatom
The parent aromatic
compounds of this family—pyrrole, furan, and thiophene—have the structures
shown.
The saturated derivatives are called pyrrolidine,
tetrahydrofuran, and thiophane, respectively. The bicyclic compounds made of a
pyrrole, furan, or thiophene ring fused to a benzene ring are called indole (or
isoindole), benzofuran, and benzothiophene, respectively.
As mentioned in the introductory section, the
nitrogen heterocycle pyrrole occurs in bone oil, in which it is formed by the
decomposition of proteins upon strong heating. Pyrrole rings are found in the
amino acids proline and hydroxyproline, which are components of many proteins
and which are present in particularly high concentrations in collagen, the
structural protein of bones, tendons, ligaments, and skin.
Pyrrole derivatives are widespread in the living
world. Pyrrole compounds are found among the alkaloids, a large class of
alkaline organic nitrogen compounds produced primarily by plants. Nicotine is
the best-known pyrrole-containing alkaloid. The heme group of the
oxygen-carrying protein hemoglobin and of related compounds such as myoglobin;
the chlorophylls, which are the light-gathering pigments of green plants and
other photosynthetic organisms; and vitamin B12 are all formed from four
pyrrole units joined in a larger ring system known as a porphyrin, such as that
of chlorophyll b, shown below.
The bile pigments are formed by decomposition of the porphyrin ring and
contain a chain of four pyrrole rings. Bilirubin, for example, the brownish
yellow pigment that gives feces its characteristic colour, is the end product
of the breakdown of heme from destroyed red blood cells.
The phthalocyanines are a group of synthetic pigments that contain four
isoindole units linked together in a large ring. A typical member of the family
is phthalocyanine blue (Monastral Fast Blue).
Numerous compounds produced in plants or animals contain one or more
indole units in their molecular structure. The important vat dye indigo, which
contains two indole units, has been used for thousands of years and was
formerly obtained from plants, but it is now synthesized on a large scale.
The closely related Tyrian purple, a dye obtained from species of snail
and used in classical times, is 6,6′-dibromoindigo
(with bromine atoms bonded to the numbered carbons in the structure above).
Tryptophan, an indole-containing essential amino acid found in most
proteins, is used by the body to make several important substances, including
the neurotransmitter serotonin and the B-complex vitamin niacin (see below
Six-membered rings with one heteroatom). Skatole, a degradation product of
tryptophan that retains the indole unit, contributes much of the strong odour
of mammalian feces. Indole-3-acetic acid (heteroauxin or β-indolylacetic
acid) is a plant-growth regulator and the most
important member of the auxin family of plant hormones (see hormone: The
hormones of plants). The structures of these compounds are:
Probably the best-known indole-containing compounds are the indole
alkaloids, which have been isolated from plants representing more than 30
families. The mushroom hallucinogens psilocin and psilocybin, the ergot fungus
alkaloids, the drugs reserpine and yohimbine, and the poison strychnine all
belong to this group.
The simplest member of the furan family of oxygen heterocycles, furan
itself, is converted industrially by hydrogenation to tetrahydrofuran.
Tetrahydrofuran is used as a solvent and for the production of adipic acid and
hexamethylenediamine, the raw materials for nylon-6,6,
the most common form of nylon. Other furan derivatives of industrial importance
are maleic anhydride and phthalic anhydride, which are constituents of resins
and plastics. These compounds are prepared in bulk by the oxidation of benzene
and naphthalene, respectively, as shown (V2O5 is a vanadium catalyst).
All carbohydrates, the biochemical family that includes the sugars and
starches, are composed of one or more simple sugar (monosaccharide) units.
These sugars are polyhydroxy aldehydes or polyhydroxy ketones that in aqueous
solution exist as equilibrium mixtures of their open-chain and cyclized forms.
Frequently the cyclized form of the sugar is a five-membered tetrahydrofuran
ring called a furanose, as shown below for fructose, or fruit sugar, as a
cyclized isomer (called a fructofuranose).
Other important examples of tetrahydrofuran ring systems are the sugars
ribose and deoxyribose, which are present in furanose form in, respectively,
RNA and DNA, the heredity-controlling components of all living organisms.
Dehydration of certain carbohydrates yields furan derivatives. Of great
commercial importance is the conversion of a carbohydrate in corncobs, oat
husks, and other agricultural waste into furan-2-aldehyde, or furfural, which
is used extensively as a solvent, in the manufacture of plastics, and in the
preparation of other furan derivatives. Many other furan derivatives occur
naturally, including vitamin C. The structures of furfural and vitamin C are:
The sulfur heterocycle thiophene and related compounds are found in coal
tar and crude petroleum. The most important biologically occurring thiophene
derivative is the B-complex vitamin biotin.
Six-membered
rings with one heteroatom
The nomenclature used for the various monocyclic
nitrogen-containing six-membered ring compounds is given below. Positions on
the ring are shown for pyridine, Arabic numerals being preferred to Greek
letters, although both systems are used. The pyridones are aromatic compounds
because of contributions to the resonance hybrid from charged resonance forms
such as that shown for 4-pyridone.
Mono-, di-, and trimethylpyridines—that is, pyridines with one, two, or
three attached methyl groups, respectively—are called picolines, lutidines, and
collidines, respectively, with the position of the methyl groups denoted by
numbers—e.g., 2,4,6-collidine. Pyridine-2-, -3-, and -4-carboxylic acids also
have widely used trivial names: picolinic, nicotinic (derived from nicotine, of
which it is an oxidation product), and isonicotinic acid, respectively.
Pyridine itself and the picolines, lutidines, and collidines occur in coal tar and
bone oil. Pyridine derivatives are also of great biological importance. For
example, nicotinic acid is more commonly known as the B-complex vitamin niacin;
a nutritionally equivalent form of niacin is nicotinamide, or niacinamide.
Pyridoxine is another member of the B complex, vitamin B6. The structures of
pyridoxine and nicotinamide are:
Two coenzymes involved in many important metabolic reactions in living
cells, nicotinamide adenine dinucleotide (NAD, also called coenzyme I) and
nicotine adenine dinucleotide phosphate (NADP, coenzyme II), are derived from
nicotinamide, and the coenzyme pyridoxal phosphate (codecarboxylase) is a
physiologically active form of pyridoxine. Many alkaloids contain a pyridine or
piperidine ring structure, among them nicotine (mentioned in the previous
section for its pyrrole ring) and piperine (one of the sharp-tasting
constituents of white and black pepper, from the plant species Piper nigrum),
with the structures shown.
Pyridine, which once was extracted commercially from coal tar but now is
prepared catalytically from tetrahydrofurfuryl alcohol and ammonia, is an
important solvent and intermediate used to make other compounds. Vinylpyridines
such as
are important
monomer building blocks for plastics, and fully saturated pyridine, piperidine,
is used in rubber processing and as a chemical raw material.
Pharmaceutically important pyridines include the tuberculostat isoniazid
(isonicotinic acid hydrazide), the anti-AIDS-virus drug nevirapine, the vasodilator nicorandil, used for treating angina, the
urinary-tract analgesic phenazopyridine, and the anti-inflammatory sulfa drug.
1-(1-phenylcyclohexyl) piperidine (PCP, phencyclidine) was originally used as
an anesthetic, but its powerful hallucinogenic properties have led to abuse.
Diquat, paraquat, clopyralid, and diflufenican are well-known pyridine
derivatives used as herbicides.
Shown in the structural formulas below are two isomeric benzopyridines
(upper pair) and two isomeric dibenzopyridines (lower pair), with their common
names and accepted numberings. All four compounds and some of their alkyl
derivatives have been obtained from coal tar. Each of them is also the parent
substance of a class of alkaloids. Of these, the quinolines (e.g., quinine and
other derivatives, still obtained from the Cinchona tree) and the isoquinoline
(e.g., morphine) groups are particularly well-known.
Quinoline itself can be used to manufacture nicotinic acid and other
compounds such as drugs and dyes. The production of synthetic quinoline far
exceeds that from coal tar. Morphine, codeine, and thebaine—all containing
partially reduced isoquinoline rings—are alkaloids of the opium poppy and have
been used for many centuries as hypnotics and analgesics. The semisynthetic
derivative of morphine, heroin, is an even more powerful hypnotic and a highly
addictive drug.
Important synthetic derivatives of the benzo- and dibenzopyridines
include cyanine dyes, used as sensitizers in silver halide photographic
emulsions, and quinophthalone dyes, applied in plastics, polymer textiles,
paper, cosmetics, transfer-printing processes, electronic photography, and
laser dyes. Other derivatives are useful bacteria-staining agents for
microscopy, antiseptics such as the coal-tar dye acriflavine, antimalarial agents
such as mepacrine (quinacrine) and chloroquine, antibacterial agents such as
ciprofloxacin, trypanocides (drugs that destroy trypanosomes, which are
parasitic protozoans responsible for Chagas disease, sleeping sickness, and
other serious infectious illnesses) such as ethidium bromide, and the reagent
oxine (8-hydroxyquinoline or 8-quinolinol), used in analytical chemistry.
Positively charged ions (cations) of pyrylium and thiopyrylium are the
parent six-membered, aromatic, monocyclic oxygen and sulfur compounds of their
respective groups.
An uncharged aromatic (completely conjugated) six-membered ring
containing an oxygen or sulfur atom is possible only if the ring contains a
carbonyl group (i.e., a ring carbon atom linked by a double bond to an oxygen
atom not in the ring), as in the pyrones.
The pyrans contain extra hydrogen atoms, the position of which is
indicated in structural diagrams by a number followed by an H. Certain sugars—a typical example is the monosaccharide
glucose—are called pyranoses because they contain six-membered tetrahydropyran
rings, with the structure:
Pyrone derivatives are present in natural products. Kojic acid, for
example, is an antibiotic derived by action of certain molds on starches or
sugars. The steroid bufotalin and its poisonous ester bufotoxin are obtained
from the skin glands of toads (genus Bufo; see steroid: Structural
relationships of the principal categories of steroids).
The benzopyrylium cation is the parent of a large number of natural
products. Chroman, or 3,4-dihydro-2H-1-benzopyran, is
itself not found in nature, but the chroman unit is present in many natural
products. Vitamin E (α-tocopherol), a substituted chroman, is found in
plant oils and the leaves of green vegetables, whereas coumarin, or 2H-1-benzopyran-2-one,
used in perfumes and flavourings, and its derivative dicoumarin (dicumarol, or
discoumarol), a blood anticoagulant, are products of living organisms.
The flavylium cation is the parent of the anthocyanidines, substances
that in chemical combination with sugars form the anthocyanin pigments, the
common red and blue colouring matters of flowers and fruits. The colour range
from yellow to reddish orange is provided by anthoxanthins, which constitute a
subgroup of flavonoids. The latter are derivatives of flavone
(2-phenyl-4-pyrone) in which one or more hydrogen atoms are replaced by hydroxy
or methoxy groups. The flavylium ion has the structure:
Five- and six-membered rings with two or
more heteroatoms
The names and numbering systems for the five-membered
heteroaromatic rings with two heteroatoms are:
Few pyrazoles occur naturally; the compounds of this class are usually
prepared by the reaction of hydrazines with 1,3-diketones.
Many synthetic pyrazole compounds are of importance as dyes and medicinals.
Among them are the fever-reducing analgesic aminopyrine, the anti-inflammatory
drug phenylbutazone, used in treating arthritis, the yellow food colour and
fibre dye tartrazine, and a series of dyes used as sensitizing agents in colour
photography.
Imidazoles are most important biologically; histidine, for example, is
an essential amino acid of particular importance in enzyme reactions. A
breakdown product of histidine, called histamine, has a variety of functions in
different organisms; in the human body it plays a crucial role in the immune
response, including allergic reactions—hence the importance of antihistamine
drugs. Histidine and histamine have the structures:
Among other naturally occurring compounds with an imidazole nucleus are
hydantoin, which is found in beet sap, and allantoin, which is related to the
metabolic product uric acid. Hydantoin derivatives, in particular phenytoin,
are important antiepileptic drugs. The imidazole ring is also present in the B
vitamin biotin (mentioned above for its thiophene unit; see above Five-membered
rings with one heteroatom).
The antibiotic cycloserine, produced by a bacterium, is one of the few
naturally occurring isoxazoles. A synthetic isoxazole, hymexazol, has found
practical use as soil and seed fungicide.
Thiazoles are of great biological importance. This ring system occurs in
thiamin (thiamine, vitamin B1), the bacitracin and penicillin antibiotics (from
a bacterium and a mold, respectively), and in numerous synthetic drugs, dyes,
and industrial chemicals. Synthetic drugs belonging to the thiazole family
include the antimicrobial agents sulfathiazole and
acinitrazole, the antidepressant pramipexole, and the antiasthmatic drug
cinalukast. Sulfathiazole has the structure:
Other thiazole compounds include rhodanine, the dye rhodanine red
derived from it, and the yellow dye primuline.
Most bicyclic systems derived from these five-membered rings are named
systematically—that is, by use of the prefix benz- or benzo- to indicate the
presence of the benzene ring. Benzimidazole, for example, is the name for the
compound:
A benzimidazole unit occurs in vitamin B12. Benzothiazole
derivatives are used for accelerating the vulcanization of rubber
(2-mercaptobenzothiazole), as herbicides (benazolin, mefenacet), and as
fungicides and antihelminthic drugs (thiabendazole).
The three monocyclic diazines—six-membered ring compounds with two
nitrogen heteroatoms—are named and numbered as shown.
The pyridazine derivative maleic hydrazide is a
herbicide, and some pyrazines occur naturally—the antibiotic aspergillic acid,
for example. The structures of the aforementioned compounds are:
The pyrazine ring is a component of many polycyclic compounds of
biological or industrial significance. Important members of the pyrazine family
include pteridines, alloxazines, and phenazines, which are discussed below in
this section.
Biologically and pharmacologically, however, the most important diazines
are the pyrimidines. Uracil, thymine, and cytosine, for example, with the
structures shown, are three of the five nucleotide bases that constitute the
genetic code in DNA and RNA.
The vitamin thiamin contains a pyrimidine ring (in addition to the
five-membered thiazole ring mentioned above), and synthetic barbiturates such
as amobarbital (amylobarbitone) are widely used drugs.
Various oxazine and thiazine derivatives are known, but monocyclic
thiazines are as yet of little importance. The parent tetrahydro-1,4-oxazine, commonly called morpholine, is produced on a
large scale for use as a solvent, corrosion inhibitor, and fungicide. The
morpholine ring is also present in the sedative-hypnotic drug trimetozine and
in some fungicides such as tridemorph and fenpropimorph. The structural formula
for morpholine is:
The benzodiazines are polycyclic compounds containing one or more
benzene rings fused to a diazine ring. Many have common names—e.g., cinnoline,
quinazoline, and phenazine.
Five other polycyclic systems in this general family are of
significance, their names, structures, and numbering systems being:
Quinoxaline alkaloids exist, and there are some phenazine natural
products. Phenazine dyes are used for fabrics (for example, indanthrones and
anthraquinone vat dyes; see anthraquinone dye) and for inks and printer toners
(nigrosines). The first synthetic phenazine dye, mauve (aniline purple), is
historically important; its structure is:
The phenoxazine system is a chromophoric (colour-imparting) part of the
molecular structures of the naturally occurring actinomycin antibiotics, which
are yellow-red in colour. Many polycyclic compounds containing a phenoxazine
ring are used as biological stains, fabric dyes, and light-emitting materials
in dye lasers (e.g., cresyl violet and nile blue).
Phenothiazine has been used as a worming agent for livestock and as an
insecticide. Drugs of the phenothiazine type include the antipsychotic agents chlorpromazine and thioridazine, the long-acting
antihistamine promethazine, and ethopropazine, used in treatment of
parkinsonism. A large group of dyes have the phenothiazine structure, including
methylene blue, a substance widely used as a biological stain and an
oxidation-reduction indicator. The structure of methylene blue is:
Biologically, the purines and pteridines are the most important polycyclic
diazines. Purine itself is not common, but the purine structure is present in
many natural substances. Two purine nucleotide bases, adenine and guanine,
occur together with the pyrimidine bases in DNA and RNA mentioned above.
Other natural purines include the alkaloids xanthine and caffeine (found
in tea, coffee, and cocoa), the alkaloid theobromine (found in cocoa), and uric
acid. The structures of caffeine, theobromine, and uric acid are:
Adenosine monophosphate, diphosphate, and triphosphate (AMP, ADP, and
ATP, respectively) are important participants in energy processes in the living
cell. Each of the compounds is composed of the nucleotide base adenine linked
to the sugar ribose, which in turn is linked to a linear “tail” of one, two, or
three phosphate groups, respectively, as shown.
Folic acid, also a pteridine, is a B-complex vitamin and an important
growth factor.
Rings with seven or more members
As the size of the ring increases, the range of compounds that can be
obtained by varying the number, type, and location of the heteroatoms increases
enormously. Nevertheless, the chemistry of heterocyclic compounds with rings
seven-membered or larger is much less developed than that of five- and
six-membered ring heterocycles, although these compounds are usually stable and
some of them have found practical application. Of the seven-membered ring
compounds, one-heteroatom heterocycles—azepines, oxepines, and thiepines—and
their derivatives are the most comprehensively studied.
The increase in ring size constrains these compounds to be nonplanar in
order to lessen the ring strain. Nonplanarity, however, affects aromaticity, so
these heterocycles react as cyclic polyenes (compounds with noninteracting,
alternating single and double bonds). Azepine and oxepine rings are important
constituents of numerous naturally occurring alkaloids and metabolic products
of marine organisms. The azepine derivative caprolactam is produced
commercially in bulk for use as an intermediate in the manufacture of nylon-6
and in production of films, coatings, and synthetic leather. Seven-membered
heterocycles with one or two nitrogen atoms in the ring are structural units of
widely used psychopharmaceuticals such as imipramine (trade name Prazepine)—the
first of the tricyclic antidepressants—and the tranquilizer diazepam (trade
name Valium).
Of the larger ring heterocycles, the most important are the crown
ethers, which contain one or more heterocyclic rings comprising 12 or more ring
atoms and involving a number of various heteroatoms, usually nitrogen, oxygen,
or sulfur. The heteroatoms are usually separated by two-carbon or three-carbon
units (ethylene or propylene units, respectively). The first crown ether,
dibenzo-18-crown-6, was synthesized in 1960.
The first number in a crown ether name indicates the total number of
atoms involved in the macrocycle (i.e., the large ring), while the second
indicates the number of heteroatoms in that ring. The remarkable feature of
crown ethers, which stimulated the explosive development of their chemistry, is
their ability to selectively bind the ions of metal elements (e.g., potassium
and sodium) and whole organic molecules inside their cavities, the selectivity
for a particular ion or molecule being directly related to the size of the
macrocycle. Because of this feature, crown ethers have found wide application
as ion transporters, as materials for ion-selective electrodes used in
environmental testing for various metal ions, as sensitizers in photography, in
medical diagnostics, and for the separation of radioactive isotopes.
Although crown ethers are not found in nature, some larger ring
heterocycles that possess similar pronounced binding abilities exist as natural
products. An example is the porphyrins, which are widely distributed as
biological pigments—e.g., the magnesium-binding chlorophylls and the
iron-binding heme groups of hemoglobin and myoglobin (see above Five-membered
rings with one heteroatom; see also chelate).
Structure and Properties of Nucleosides
and Nucleotides
Now we join one of the purines or pyrimidines to the
sugar (an N-glycosidic bond to the 1' carbon of the sugar). These structures
are called nucleosides:
Notice that the numbering convention for the sugar is now 1' through 5'.
When phosphates are now added to the 5' carbon, we have the final
structures to consider, the nucleotides:
We now add the final bit of nomenclature convention. The phosphates are
designated, moving out from the 5' carbon, as alpha, beta, and gamma. This is
very important to remember, since the position of radiolabeled phosphorous in
experimental protocols will determine the outcome.
The nomenclature of the nucleosides found in RNA and DNA are:
Base |
Nucleoside |
Deoxynucleoside |
adenine |
adenosine |
deoxyadenosine |
guanine |
guanosine |
deoxyguanosine |
cytosine |
cytidine |
deoxycytidine |
uracil |
uridine |
(not
found in DNA) |
thymidine |
(not
found in RNA) |
(deoxy)thymidine* |
For thymidine the deoxy is understood. In fact in the rare occurrence of
T in RNA (in some transfer RNAs) the nucleoside is called ribothymidine.
The nomenclature of the nucleotides use the
names of the nucleosides plus the number of phosphates.
A nucleotide is a substance that, on hydrolysis, yields per mole at
least 1 mole of a nitrogenous base, a sugar, and orthophosphate. A nucleoside
yields 1 mole each of a nitrogenous base and a sugar. The term nucleobase
refers to those nucleotides found in nucleic acids—adenine, guanine, cytosine,
and uracil in RNA, and adenine, guanine, cytosine, and thymine in DNA, plus the
quantitatively minor bases found in both nucleic acids. Other bases, such as
the nicotinamide found in NAD+ and NADP+, occur as parts of coenzymes or as
parts of metabolically activated biosynthetic intermediates, such as uridine
diphosphate glucose.
A mononucleotide is a nucleotide that, on hydrolysis, yields 1 mole each
of a base and a sugar plus at least 1 mole of orthophosphate. The term
nucleoside diphosphate usually refers to a mononucleotide which, on hydrolysis,
yields 1 mole each of a base and a sugar plus 2 moles of orthophosphate;
similarly, a nucleoside triphosphate yields 3 moles of orthophosphate per mole
of nucleotide. A dinucleotide yields, on complete hydrolysis, 2 moles each of
base and sugar, plus at least 1 mole of orthophosphate; a trinucleotide yields
3 moles each of base and sugar, plus 2 or more moles of orthophosphate.
Figure 1 shows the structures of the five common nucleobases (in their
most frequent tautomeric configuration) and several nucleosides,
mononucleotides, and oligonucleotides, as well as the numbering systems used.
Note that, in all nucleotides found in nucleic acids, a glycosidic bond links
N-9 of a purine base or N-1 of a pyrimidine base to C-1, the carbonyl carbon,
of either ribose or 2-deoxyribose. By convention, all positions in the sugar of
a nucleoside or nucleotide are given primed numbers. Thus, the adenine
nucleotide recovered from digestion of DNA with certain enzymes would be named
2′-deoxyadenosine 5′-monophosphate, identifying the position of the
phosphate esterified to the sugar, as well as the carbon of the sugar that is
in the reduced, or deoxy, configuration. Note that some modes of nucleic acid
digestion will yield 2′- or 3′-nucleotides, in which the phosphate
is esterified to positions 2′ or 3′ of the sugar, respectively.
Also, in the 3′,5′-cyclic nucleotides,
cyclic AMP and cyclic GMP, which play multiple roles in biological signal
transduction, the phosphate is esterified simultaneously to carbons 3′
and 5′. Because the nucleic acid biosynthetic intermediates are nucleoside
5′-phosphates, or 5′-nucleotides, these structures are shown
predominantly.
Structures of
the five common nucleobases and representative nucleosides and nucleotides.
Names and
Abbreviations of the Nucleotide Constituents of Nucleic Acids and of Cyclic
Nucleotides
Names |
Abbreviations |
Adenosine
5′-monophosphate, 5′-adenylic acid |
|
Cytidine
5′-monophosphate, 5′-cytidylic acid |
|
Guanosine
5′-monophosphate, 5′-guanylic acid |
|
Uridine
5′-monophosphate, 5′-uridylic acid |
|
One additional structural feature of nucleotides relates to the somewhat
hindered rotation about the glycosidic bond, which leads to two rather stable
orientations of bases with respect to the sugar, termed syn and anti. Because
it is more compact to draw, most of the structures shown here are represented
as syn, but the anti configuration predominates in nucleic acids (see Z-DNA).
dAMP in the syn
and anti configurations.
The important derivatives of pyrrole, furan and
thiophene.
The important derivatives of pyrrole, furan and
thiophene.
Five-membered
heterocyclec with two heteroatoms
Six-membered
heterocycles with two heteroatoms
Nucleic acids
A Nucleic acids are polymers of nucleotides joined by 3',5' -phosphodiester bonds; that is, a phosphate group links
the 3' carbon of a sugar to the 5' carbon of the next sugar in the chain. A
phosphate group is often found at the 5' end, and a hydroxyl group is often
found at the 3' end.
Types
of nucleic acids.
Two types of nucleic acids are found within cells
of higher organisms: deoxyribonucleic acid (DNA) and ribonucleic acid (RNA).
Nearly all the DNA is found in the cell nucleus. Its primary function is the
storage and transfer of genetic information. This information is used
(indirectly) to control many functions of a living cell. In addition, DNA is
passed from existing cell to new cells during cell division RNA occurs in all
parts of a cell. It functions primarily in synthesis of proteins, the molecules
that carry out essential cellular functions.
DNA has only one biological role, but it is the
more central one. The information to make all the functional macromolecules of
the cell (even DNA itself) is preserved in DNA and accessed through
transcription of the information into RNA copies. Coincident with its singular
purpose, there is only a single DNA molecule (or “chromosome”) in simple life
forms such as viruses or bacteria. Such DNA molecules must be quite large in
order to embrace enough information for making the macromolecules necessary to
maintain a living cell RNA has a number of important biological functions, and
on this basis, RNA molecules are categorized into several major types: messenger
RNA, ribosomal RNA, and transfer RNA. Eukaryotic cells contain an
additional type, small nuclear RNA (snRNA).
The DNA isolated from different cells and viruses
consists of two polynucleotide strands wound together to form a long, slender,
helical molecule, the DNA double helix. The strands run in opposite
directions; that is, they are antiparallel and are held together in the
double helical structure through interchain hydrogen bonds
n DNA
molecules are the carriers of the genetic information within а cell; that is,
they the molecules of heredity. Each time а cell divides, an exact copy of the
DNA of the present cell is needed for the new daughter cell. The process by
which new DNA molecule generated is DNA replication. DNA replication is the
process by which DNA molecules produce exact duplicates of themselves. The key
concept in understanding DNA replication is the base pairing associated with
the DNA double helix.
n We
can divide the overall process of protein synthesis into two steps. The first
step is called transcription and the second translation. Transcription
is the process by which DNA directs the synthesis of RNA molecules that carry
the coded information needed for protein synthesis. Translation is the
process by which the codes within RNA molecules are deciphered and а particular
protein molecule is formed.
Ribonucleic
acids (RNA).
Four major differences exist between RNA
molecules and DNA molecules.
1. The
sugar unit in the backbone of RNA is ribose; it is deoxyribose in DNA.
2. The
base thymine found in DNA is replaced by uracil in RNA. Uracil, instead of
thymine, pairs with (forms hydrogen bonds with) adenine in RNA.
3. RNA
is а single-stranded molecule; DNA is double-stranded (double helix). Thus RNA,
unlike DNA, does not contain equal amounts of specific bases.
RNA molecules are much smaller than DNA
molecules, ranging from as few as 75 nucleotides to а few thousand nucleotides.
The monomers for nucleic acid polymers,
nucleotides, have а more complex structure than polysaccharide monomers
(monosacharides) or protein monomers (amino acids). Within each nucleotide
monomer are three subunits. А nucleotide is, а molecule
composed of a pentose sugar bonded to both a group and a nitrogen-containing
hetero-cyclic base.
A nucleotide results when
phosphoric acid is esterified to a sugar OOH group of a nucleoside. The
nucleoside ribose ring has three OOH groups available for esterification, at C-2, C-3, and C-5 (although 2-deoxyribose has
only two).
The vast majority of monomeric nucleotides in the cell are ribonucleotides having
5-phosphate groups.
Nucleotide
formation.
The formation of а nucleotide from sugar, base,
and phosphate can be visualized as occurring in the following manner:
Heterocyclic compound, also called heterocycle, any of a major
class of
organic
chemical compounds characterized by the fact that some or all of the atoms in
their molecules are joined in rings containing at least one atom of an element
other than carbon (C). The cyclic part (from Greek kyklos, meaning “circle”) of
heterocyclic indicates that at least one ring structure is present in such a
compound, while the prefix hetero- (from Greek heteros, meaning “other” or
“different”) refers to the noncarbon atoms, or heteroatoms, in the ring. In
their general structure, heterocyclic compounds resemble cyclic organic compounds
that incorporate only carbon atoms in the rings—for example, cyclopropane (with
a three-carbon-atom ring) or benzene (with a six-carbon-atom ring)—but the
presence of the heteroatoms gives heterocyclic compounds physical and chemical
properties that are often quite distinct from those of their all-carbon-ring
analogs.
Heterocyclic compounds include many of the
biochemical material essential to life. For example, nucleic acids, the
chemical substances that carry the genetic information controlling inheritance,
consist of long chains of heterocyclic units held together by other types of
materials. Many naturally occurring pigments, vitamins, and antibiotics are
heterocyclic compounds, as are most hallucinogens. Modern society is dependent
on synthetic heterocycles for use as drugs, pesticides, dyes, and plastics
General aspects of heterocyclic
compounds
The most common heterocycles are those having
five- or six-membered rings and containing heteroatoms of nitrogen (N), oxygen
(O), or sulfur (S). The best known of the simple heterocyclic compounds are
pyridine, pyrrole, furan, and thiophene. A molecule of pyridine contains a ring
of six atoms—five carbon atoms and one nitrogen atom. Pyrrole, furan, and
thiophene molecules each contain five-membered rings, composed of four atoms of
carbon and one atom of nitrogen, oxygen, or sulfur, respectively.
Pyridine and pyrrole are both nitrogen
heterocycles—their molecules contain nitrogen atoms along with carbon atoms in
the rings. The molecules of many biological materials consist in part of
pyridine and pyrrole rings, and such materials yield small amounts of pyridine
and pyrrole upon strong heating. In fact, both of these substances were
discovered in the 1850s in an oily mixture formed by strong heating of bones. Today,
pyridine and pyrrole are prepared by synthetic reactions.Their chief commercial
interest lies in their conversion to other substances, chiefly dyestuffs and
drugs. Pyridine is used also as a solvent, a waterproofing agent, a rubber
additive, an alcohol denaturant, and a dyeing adjunct.
Furan is an oxygen-containing heterocycle
employed primarily for conversion to other substances (including pyrrole).
Furfural, a close chemical relative of furan, is obtained from oat hulls and
corncobs and is used in the production of intermediates for nylon. Thiophene, a
sulfur heterocycle, resembles benzene in its chemical and physical properties.
It is a frequent contaminant of the benzene obtained from natural sources and
was first discovered during the purification of benzene. Like the other
compounds, it is used primarily for conversion to other substances. Furan and
thiophene were both discovered in the latter part of the 19th century.
In general, the physical and chemical properties
of heterocyclic compounds are best understood by comparing them with ordinary
organic compounds that do not contain heteroatoms.
The nature of heteroaromaticity
Aromaticity denotes the significant stabilization
of a ring compound by a system of alternating single and double bonds—called a
cyclic conjugated system—in which six π electrons generally participate. A
nitrogen atom in a ring can carry a positive or a negative charge, or it can be
in the neutral form. An oxygen or sulfur atom in a ring can either be in the
neutral form or carry a positive charge. A fundamental distinction is usually
made between (1) those heteroatoms that participate in a cyclic conjugated
system by means of a lone, or unshared, pair of electrons that are in an
orbital perpendicular to the plane of the ring and (2) those heteroatoms that
do so because they are connected to another atom by means of a double bond.
An example of an atom of the first type is the
nitrogen atom in pyrrole, which is linked by single covalent bonds to two
carbon atoms and one hydrogen atom. Nitrogen has an outermost shell of five
electrons, three of which can enter into three covalent bonds with other atoms.
After the bonds are formed, as in the case of pyrrole, there remains an
unshared electron pair that can engage in cyclic conjugation. The aromatic
sextet in pyrrole is made up of two electrons from each of the two
carbon-carbon double bonds and the two electrons that compose the unshared
electron pair of the nitrogen atom. As a consequence, there tends to be a net
flow of electron density from the nitrogen atom to the carbon atoms as the
nitrogen’s electrons are drawn into the aromatic sextet. Alternatively, the
pyrrole molecule may be described as a resonance hybrid—that is, a molecule
whose true structure can only be approximated by two or more different forms,
called resonance forms.
An example of a heteroatom of the second type is
the nitrogen atom in pyridine, which is linked by covalent bonds to only two
carbon atoms. Pyridine also has a π-electron sextet, but the nitrogen atom
contributes only one electron to it, one additional electron being contributed
by each of the five carbon atoms in the ring. In particular, the unshared
electron pair of the nitrogen atom is not involved. Moreover, because
nitrogen’s attraction for electrons (its electronegativity) is greater than
that of carbon, electrons tend to move toward the nitrogen atom rather than
away from it, as in pyrrole.
Quite generally, heteroatoms may be referred to
as pyrrolelike or pyridine-like, depending on whether they fall into the first
or second class described above. The pyrrolelike heteroatoms −NR−
(R being hydrogen or a hydrocarbon group), −N−−,
−O−, and −S− tend to donate electrons into the
π-electron system, whereas the pyridine-like heteroatoms −N=,
−N+R=, −O+=, and −S+= tend to attract the π electrons of
a double bond.
In six-membered heteroaromatic rings, the
heteroatoms (usually nitrogen) are pyridine-like—for example, the compounds
pyrimidine, which contains two nitrogen atoms, and 1,2,4-triazine, which
contains three nitrogen atoms.
Six-membered heteroaromatic compounds cannot
normally contain pyrrolelike heteroatoms. Five-membered heteroaromatic rings,
however, always contain one pyrrolelike nitrogen, oxygen, or sulfur atom, and
they may also contain up to four pyridine-like heteroatoms, as in the compounds
thiophene (with one sulfur atom), 1,2,4-oxadiazole (with one oxygen atom and
two nitrogen atoms), and pentazole (with five nitrogen atoms).
The quantitative measurement of aromaticity—and
even its precise definition—has challenged chemists since German chemist August
Kekule formulated the ring structure for benzene in the mid-19th century.
Various methods based on energetic, structural, and magnetic criteria have been
widely used to measure the aromaticity of carbocyclic compounds. All of them,
however, are difficult to apply quantitatively to heteroaromatic systems
because of complications arising from the presence of heteroatoms.
Chemical reactivity can provide a certain
qualitative insight into aromaticity. The reactivity of an aromatic compound is
affected by the extra stability of the conjugated system that it contains; the
extra stability in turn determines the tendency of the compound to react by
substitution of hydrogen—i.e., replacement of a singly bonded hydrogen atom
with another singly bonded atom or group—rather than by addition of one or more
atoms to the molecule via the breaking of a double bond (see substitution
reaction; addition reaction). In terms of reactivity, therefore, the degree of
aromaticity is measured by the relative tendency toward substitution rather than
addition. By this criterion, pyridine is more aromatic than furan, but it is
difficult to say just how much more aromatic.
Ultraviolet,
infrared, nuclear magnetic resonance, and mass spectra
Spectroscopic studies of heterocyclic compounds,
like those of other organic compounds, have became of great importance as means
of identification of unknown materials, as criteria for purity, and as probes
for investigating the electronic structures of molecules, thereby explaining
and helping to predict their reactions. The ultraviolet spectrum of an organic
compound (the pattern of its light absorption in the ultraviolet region of the
spectrum) is characteristic of the π-electron system of the molecule—i.e.,
of the arrangement of double bonds within the structure. The ultraviolet
spectra of heteroaromatic compounds show general similarity to those of
benzenoid compounds (compounds with one or more benzene rings), and the effects
of substituents can usually be rationalized in a similar way.
The infrared spectrum of an organic compound,
with its complexity of bands, provides an excellent “fingerprint” of the
compound—far more characteristic than a melting point. It also can be used to
identify certain common groups, such as carbonyl (C=O) and imino, as well as
various heterocyclic ring systems.
Magnetic resonance spectra are indispensable
today for studies in heterocyclic chemistry. Proton resonance spectra, the most
common type, yield information regarding the number of hydrogen atoms in the
molecule, their chemical environment, and their relative orientation in space.
Mass spectra are used to determine not only the complete molecular formula of
the compound but also the molecular structure from the way the molecule
fragments.
Synthesis
and modification of heterocyclic rings
The important methods for synthesizing
heterocyclic compounds can be classified under five headings. Three are ways of
forming new heterocyclic rings from precursors containing either no rings
(acyclic precursors) or one fewer ring than the desired product; one is a way
of obtaining a heterocyclic ring from another heterocyclic ring or from a
carbocyclic ring; and one involves the modification of substituents on an
existing heterocyclic ring.
In the formation of rings from acyclic
precursors, the key step is frequently the formation of a carbon-heteroatom
linkage (C−Z, in which Z represents an atom of nitrogen, oxygen, sulfur,
or a more unusual element). The actual ring closure, or cyclization, however,
may involve the formation of a carbon-carbon bond. In any case, ring formation
reactions are divided into three general categories according to whether the
cyclization reaction occurs primarily as a result of nucleophilic or
electrophilic attack or by way of a cyclic transition state.
Nucleophilic
ring closure
To prepare compounds containing one heteroatom,
an open-chain hydrocarbon derivative containing two halogen element
atoms—specifically, chlorine, bromine (Br), or iodine (I)—either as halides (in
which the halogen atoms are attached directly to the hydrocarbon chain) or as
acyl halides (in which the halogen atoms belong to derivatives of carboxylic
acids) is reacted with the dihydro form of the heteroatom (ZH2, or an
equivalent reagent) to give nonaromatic heterocycles.
Diketones also can react with dihydro Z compounds
to give heterocycles. (A ketone is an organic compound that contains a carbonyl
group, the carbon atom of which is linked to two other carbon atoms belonging
to hydrocarbon groups. Diketones contain two such carbonyl groups.) Diketones
with the carbonyl groups separated by two carbon atoms, for example, can be
cyclized to form five-membered aromatic pyrroles, furans, and thiophenes. In
the case of diketones whose carbonyl groups are separated by three carbons,
six-membered rings may be formed.
In each of these reactions the heteroatom Z acts
as a nucleophile—an atom or a molecule that seeks a positively charged centre,
such as a partly unprotected atomic nucleus. The heteroatom attacks the
positively charged carbon atom produced by electron withdrawal because of the
presence of the halogen atom (in the first two reactions above) or of the
oxygen atom (in the last reaction).
Usually, such reactions proceed by means of
intermediates in which only one of the two C−Z bonds has formed. In
reactions involving halogens as halides, for instance, a compound such as
HZ−CH2−(CH2)n−CH2Br may form first.
This fact can be applied to heterocycle synthesis in that it is frequently
possible to make such intermediate compounds by other routes; these
intermediates then cyclize readily to form the desired ring. One procedure for
pyridine synthesis, for example, involves a condensation reaction employing an
intermediate with the carbon-nitrogen bond already formed.
Heterocycles containing two adjacent nitrogen
atoms, two oxygen atoms, or adjacent nitrogen and oxygen atoms also may be
prepared from precursors by the use of hydrazine (N2H4), hydroxylamine (NH2OH),
or hydrogen peroxide (H2O2) in place of the dihydro Z compound. Similarly, two
adjacent heteroatoms can be introduced by employing one of the reagents in the
reactions with diketones, discussed earlier in this section.
When a compound containing two nonadjacent
heteroatoms is desired, appropriate components can be put together, as in the
synthesis of a pyrimidine. Ring synthesis reactions in which the heteroatom acts
as a nucleophile can also employ precursors containing a ring, resulting in
two-ring compounds. These reactions involve the use of ortho-disubstituted
benzenes (ortho substituents being groups attached to adjacent carbon atoms in
the benzene ring). The formation of quinoline and quinazoline rings (see below
Major classes of heterocyclic compounds: Six-membered rings with one
heteroatom) is an example of this reaction type.
Electrophilic
ring closure
Heterocyclic ring-forming reactions in which the
heteroatom acts as an electrophile—an electron-seeking atom or molecule—are
rare, because nitrogen, oxygen, and sulfur atoms are themselves electron-rich
centres that act generally as nucleophiles. Nevertheless, electrophilic ring
closure reactions are known in which a heterocyclic ring is formed by a
reaction in which a carbon atom of the future ring acts as an electrophile.
Usually such reactions involve ring closure onto an existing benzene ring (or
other aromatic system), an electron-rich system that is generally subject to
attack by electrophilic reagents. An example of ring closures of this type is
the formation of quinoline from aniline and acrolein, a dehydration product of
glycerol. The initial heterocyclic product of the reaction is dihydroquinoline,
which must be dehydrogenated (must undergo removal of two hydrogen atoms) to
give the fully aromatic product, quinoline itself.
Ring closure by way of cyclic transition states
A most important method for the synthesis of
carbocyclic six-membered rings is the Diels-Alder diene reaction, named for its
Nobel Prize-winning discoverers, the German chemists Otto Diels and Kurt Alder.
In this reaction, illustrated below, a diene—a compound with two double
bonds—reacts with a dienophile (a diene-seeking reagent), which contains a pair
of carbon atoms linked by a double or triple bond. The product is a
cyclohexene, a compound with a six-membered ring containing a double bond.
Heterocycles likewise can be synthesized by the
Diels-Alder reaction, in which the dienophile contains a pair of heteroatoms
such as nitrogen linked by multiple bonds.
Of even greater use, however, is a related method
called the Huisgen dipolar cycloaddition reaction.
This reaction is an important means of preparing many types of five-membered rings,
especially those containing several heteroatoms. Pyrazoles, isoxazoles (see
below Major classes of heterocyclic compounds: Five- and six-membered rings
with two or more heteroatoms), and many less-common heterocycles can be
synthesized by this method.
Conversion
of one heterocyclic ring into another
Although there are many reactions of theoretical
importance in which one heterocyclic ring is converted into another, few are of
practical use. The preparation of pyridine from tetrahydrofurfuryl alcohol and
ammonia (see below Major classes of heterocyclic compounds: Six-membered rings
with one heteroatom) and the conversion of pyrylium salts into pyridinium salts
are good examples of such transformations. In addition, ring-atom
rearrangement, or “shuffling,” can be brought about with light (see
photochemical reaction) in five- and six-membered heteroaromatic compounds, and
ring contraction by extrusion of an atom or a group can occur under certain
conditions.
Modification
of an existing ring
Dehydrogenation of saturated or partially
saturated heterocyclic rings to thermodynamically more-stable heteroaromatic
compounds by heating with sulfur or by treatment with a palladium catalyst is
analogous to similar reactions involving carbocyclic compounds. The hydrogenation
of (addition of hydrogen to) heteroaromatic rings is, by contrast, usually more
difficult, for the heteroatoms tend to poison the catalyst. Finally, the
modification of substituents on heterocyclic rings is of highest importance in
synthesis, and reactions by which substituents may be altered are among the
most useful in heterocyclic chemistry.
Major
classes of heterocyclic compounds
The major classes of heterocycles containing the
common heteroatoms—nitrogen, oxygen, and sulfur—are reviewed in order of
increasing ring size, with compounds containing other heteroatoms left to a
final section. Classification by ring size is convenient because heterocyclic
rings of a given size have many common features. For heterocyclic (as for
carbocyclic) rings, certain broad generalizations can be made. Three- and
four-membered rings, because of their small size, are geometrically strained
and thus readily opened; they are also readily formed. Such heterocycles are
well-known reactive intermediates. Five- and six-membered rings are readily
formed and are very stable; their sizes also allow the development of aromatic
character. Seven-membered rings and larger are stable but less readily formed
and relatively less well investigated.
Three-membered
rings
The three-membered ring heterocycles containing
single atoms of nitrogen, oxygen, and sulfur—aziridine, oxirane (or ethylene
oxide), and thiirane, respectively—and their derivatives can all be prepared by
nucleophilic reactions, of the type shown. Thus, aziridine is formed by heating
β-aminoethyl hydrogen sulfate with a base (in this case Y is −OSO3H).
A reaction of this type is involved in the
pharmacological action of nitrogen mustards, which were among the first
anticancer drugs developed (see drug: Cancer chemotherapy). Intramolecular ring
closure, as in the case of the anticancer agent mechlorethamine, produces an
intermediate aziridinium ion, the biologically active agent, which attacks
rapidly proliferating cells such as cancer cells by inhibiting replication of
their DNA (deoxyribonucleic acid). Nitrogen mustards linked to steroids also
have been used as anticancer agents.
Commercially, oxirane and (to a lesser extent)
aziridine are important bulk industrial chemicals. Oxirane is prepared on a
large scale by the direct reaction of ethylene with oxygen.
The chemical reaction that is the most
characteristic of these three-membered rings is susceptibility to attack by
nucleophilic reagents to open the ring, as shown by:
The first step shown is the reverse of the
formation reaction shown at the top of this section. As indicated, a second
molecule of the three-membered ring may react with the first product. Further
reaction leads to long chainlike molecules (polymers) of the type C2H5O(CH2CH2Z)nCH2CH2ZH. Polymers and copolymers of oxirane
and aziridine are useful plastics.
The oxirane ring can also be opened by
hydrolysis—i.e., the breaking of a bond accompanied by the addition of the
elements of water (H and OH), which is similar to the first step of the ring-opening
reaction illustrated above. The result of this reaction is ethylene glycol
(HOCH2CH2OH), which serves as antifreeze in cooling and heating systems, in
brake fluid, and as a solvent in the paints and plastics industries.
In medicine, aziridine derivatives are used for
the treatment of cancer and in research as affinity probes (labeled chemicals
that react selectively with biological molecules of interest) for detection and
assay studies. The mitomycin family of antitumour antibiotics is the most well-known
class of natural products containing the aziridine ring.
Naturally occurring compounds containing one or
more oxirane rings are abundant. These molecules include insect juvenile
hormones, pheromones, and products of marine organisms. Often they are biologically
active and have promising therapeutic applications. For example, the fungal
product (−)-ovalicin, which contains two oxirane rings, has potential for
inhibiting development of solid tumours by cutting off their blood supply. An
important synthetic oxirane having one ring is fosfomycin, used as an
antibacterial drug, particularly in treating urinary tract infections.
Molecules containing thiirane rings are more
bactericidal than those containing oxirane rings, and some thiirane derivatives
have found application as tuberculostats (drugs that inhibit the growth of
tuberculosis-causing bacteria), whereas thiirane 1 oxides have been reported to
be insecticides, molluscicides, or herbicides.
Although aziridine, oxirane, and thiirane are
saturated heterocycles, they are much more reactive than the corresponding
open-chain amines, ethers, or sulfides because of the strain inherent in the
three-membered ring. This behaviour reflects the comparable enhanced reactivity
of the related three-membered carbocyclic compound cyclopropane.
Since 1950, five different classes of
three-membered ring compounds with two heteroatoms have been discovered. They are
derivatives of the parent ring systems diaziridine (containing N−N),
oxaziridine (O−N), thiaziridine (S−N), dioxirane (O−O), and
dithiirane (S−S). The oxathiirane system has no reported stable
representatives in its class.
Except for diaziridine systems, which are used in
the manufacture of plastic films and foamed plastics, as propellants and fuel
stabilizers, and in the synthesis of anticancer drugs and
psychopharmaceuticals, these compounds currently have limited practical
importance, but they offer interesting possibilities for future applications.
Four-membered
rings
Azetidine, oxetane, and thietane—four-membered
rings containing, respectively, one nitrogen, oxygen, or sulfur atom—are
prepared by nucleophilic displacement reactions similar to those used to
prepare the corresponding three-membered rings.
(In the reaction above, Y is usually Cl, Br, or
SO3H.) With four-membered rings, however, the reactions proceed less readily
than do the analogous reactions for three-membered rings. The ring-opening
reactions of four-membered heterocycles resemble qualitatively those of the
corresponding three-membered rings, but they occur rather less readily.
The most important heterocycles with
four-membered rings are two related series of antibiotics, the penicillins and
the cephalosporins. Both series contain the azetidinone ring (the suffix -one
indicating an oxygen atom linked with a double bond to a ring carbon atom).
Another common name for the azetidinone ring is the β-lactam ring, which
lends its name to the β-lactam antibiotics, the class to which the
penicillins and cephalosporins belong. The chemistry of azetidinones was
explored thoroughly during the intensive research into penicillin structure and
synthesis that took place during World War II. A practical synthesis of
penicillin was not achieved, however, until 1959.
Numerous oxetanes, the synthetic analogs of the
antiviral natural product oxetanocin, are under investigation as antifungal,
anti-inflammatory, anticancer, and antiviral agents. Oxetanones, whose ring
structure is analogous to that of the azetidinones except that the heteroatom
is oxygen, are widely applied in polymer manufacturing and in agriculture as
herbicides, fungicides, and bactericides. The parent thietane was found in
shale oil, whereas its odoriferous derivatives function as scent markers for
minks, ferrets, and European polecats. Thietanes are used in the production of
polymers, as bactericides and fungicides in paint, and as iron corrosion
inhibitors.
One of the important specialized pathways of a
number of amino acids is the synthesis of purine and pyrimidine nucleotides.
These nucleotides are important for a number of reasons. Most of them, not just
ATP, are the sources of energy that drive most of our reactions. ATP is the most
commonly used source but GTP is used in protein synthesis as well as a few
other reactions. UTP is the source of energy for activating glucose and
galactose. CTP is an energy source in lipid metabolism. AMP is part of the
structure of some of the coenzymes like NAD and Coenzyme A. And, of course, the
nucleotides are part of nucleic acids. Neither the bases nor the nucleotides
are required dietary components. We can both synthesize them de novo and
salvage and reuse those we already have.
Nitrogen
Bases
There are two kinds of nitrogen-containing bases
- purines and pyrimidines. Purines consist of a six-membered and a
five-membered nitrogen-containing ring, fused together. Pyridmidines
have only a six-membered nitrogen-containing ring. There are 4 purines and 4
pyrimidines that are of concern to us.
Purines
http://www.youtube.com/watch?v=uOAsqECXVco
Adenine and guanine are found in both DNA and RNA. Hypoxanthine and
xanthine are not incorporated into the nucleic acids as they are being
synthesized but are important intermediates in the synthesis and degradation of
the purine nucleotides.
http://www.youtube.com/watch?v=PHOjrY3zYdM
Pyrimidines
http://www.youtube.com/watch?v=KXr8bM69Nq4
Cytosine is found in both DNA and RNA. Uracil is found only in RNA.
Thymine is normally found in DNA. Sometimes tRNA will contain some thymine as
well as uracil.
Nucleosides
If a sugar, either ribose or 2-deoxyribose, is
added to a nitrogen base, the resulting compound is called a nucleoside.
Carbon 1 of the sugar is attached to nitrogen 9 of a purine base or to nitrogen
1 of a pyrimidine base. The names of purine nucleosides end in -osine
and the names of pyrimidine nucleosides end in -idine. The
convention is to number the ring atoms of the base normally and to use l', etc.
to distinguish the ring atoms of the sugar. Unless otherwise specificed, the
sugar is assumed to be ribose. To indicate that the sugar is 2'-deoxyribose, a d-
is placed before the name.
·
Adenosine
·
Guanosine
·
Inosine - the base in inosine is hypoxanthine
·
Uridine
·
Thymidine
·
Cytidine
Nucleotides
Adding one or more phosphates to the sugar
portion of a nucleoside results in a nucleotide.
Generally, the phosphate is in ester linkage to carbon 5' of the sugar. If more
than one phosphate is present, they are generally in acid anhydride linkages to
each other. If such is the case, no position designation in the name is
required. If the phosphate is in any other position, however, the position must
be designated. For example, 3'-5' cAMP indicates that a phosphate is in ester
linkage to both the 3' and 5' hydroxyl groups of an adenosine molecule and
forms a cyclic structure. 2'-GMP would indicate that a phosphate is in ester
linkage to the 2' hydroxyl group of a guanosine. Some representative names are:
·
AMP = adenosine monophosphate = adenylic acid
·
CDP = cytidine diphosphate
·
dGTP = deoxy guanosine triphosphate
·
dTTP = deoxy thymidine triphosphate
(more commonly designated TTP)
·
cAMP = 3'-5' cyclic adenosine
monophosphate
NOMENCLATURE
OF NUCLEIC BASES, NUCLEOSIDES, AND NUCLEOTIDES
Nucleobase |
Nucleoside |
Nucleotide 5’-monophosphate |
Adenine Guanine Thymine Cytosine Uracil Hypoxanthine Xanthine |
Adenosine Guanosine Thymidine Cytidine Uridine Inosine Xanthosine |
Adenosine 5’-monophosphate (adenylate, AMP) Guanosine 5’-monophosphate (guanylate, GMP) Thymidine 5’-monophosphate (thymidylate,
TMP) Cytidine 5’-monophosphate (cytidylate, CMP) Uridine 5’-monophosphate (uridylate, UMP) Inosine 5’-monophosphate (inosinate, IMP) Xanthosine 5’-monophosphate (xanthylate ,
XMP) |
Polynucleotides
Nucleotides are joined together by 3'-5'
phosphodiester bonds to form polynucleotides. Polymerization of ribonucleotides
will produce an RNA while polymerization of
deoxyribonucleotides leads to DNA.
Most, but not all, nucleic acids in the cell are associated with
protein. Dietary nucleoprotein is degraded by pancreatic enzymes and tissue
nucleoprotein by lysosomal enzymes. After dissociation of the protein and
nucleic acid, the protein is metabolized like any other protein.
The nucleic acids are hydrolyzed randomly by nucleases
to yield a mixture of polynucleotides. These are further cleaved by phosphodiesterases
(exonucleases) to a mixture of the mononucleotides. The specificity of the
pancreatic nucleotidases gives the 3'-nucleotides and that of the lysosomal
nucleotidases gives the biologically important 5'-nucleotides.
The nucleotides are hydrolyzed by nucleotidases
to give the nucleosides and Pi. This is probably the end product in
the intestine with the nucleosides being the primary form absorbed. In at least
some tissues, the nucleosides undergo phosphorolysis with nucleoside
phosphorylases to yield the base and ribose 1-P (or deoxyribose 1-P). Since
R 1-P and R 5-P are in equilibrium, the sugar phosphate can either be
reincorporated into nucleotides or metabolized via the Hexose Monophosphate
Pathway. The purine and pyrimidine bases released are either degraded or
salvaged for reincorporation into nucleotides.
There is significant turnover of all kinds of RNA as well as the
nucleotide pool. DNA doesn't turnover but portions of the molecule are excised
as part of a repair process.
Purine and pyrimidines from tissue turnover which are not salvaged are
catabolized and excreted. Little dietary purine is used and that which is
absorbed is largely catabolized as well. Catabolism of purines and pyrimidines
occurs in a less useful fashion than did the catabolism of amino acids in that
we do not derive any significant amount of energy from the catabolism of
purines and pyrimidines. Pyrimidine catabolism, however, does produce
beta-alanine, and the endproduct of purine catabolism, which is uric acid in
man, may serve as a scavenger of reactive oxygen species.
The metabolic requirements for the nucleotides and their cognate bases
can be met by both dietary intake or synthesis de
novo from low molecular weight precursors. Indeed, the ability to salvage
nucleotides from sources within the body alleviates any nutritional requirement
for nucleotides, thus the purine and pyrimidine bases are not required in the
diet. The salvage pathways are a major source of nucleotides for synthesis of
DNA, RNA and enzyme co-factors.
Extracellular hydrolysis of ingested nucleic acids occurs through the
concerted actions of endonucleases, phosphodiesterases and nucleoside
phosphorylases. Endonucleases degrade DNA and RNA at internal sites leading to
the production of oligonucleotides. Oligonucleotides are further digested by
phosphodiesterases that act from the ends inward yielding free nucleosides. The
bases are hydrolyzed from nucleosides by the action of phosphorylases that
yield ribose-1-phosphate and free bases. If the nucleosides and/or bases are
not re-utilized the purine bases are further degraded to uric acid and the
pyrimidines to β-aminoiosobutyrate,
NH3 and CO2.
Purine and pyrimidine bases which are not
degraded are recycled - i.e. reincorporated into nucleotides. This
recycling, however, is not sufficient to meet total body requirements and so
some de novo synthesis is essential. There are definite tissue
differences in the ability to carry out de novo synthesis. De novo
synthesis of purines is most active in liver. Non-hepatic tissues generally
have limited or even no de novo synthesis. Pyrimidine synthesis occurs
in a variety of tissues. For purines, especially, non-hepatic tissues rely
heavily on preformed bases - those salvaged from their own intracellular
turnover supplemented by bases synthesized in the liver and delivered to
tissues via the blood.
"Salvage" of purines is reasonable in
most cells because xanthine oxidase, the key enzyme in taking the purines all
of the way to uric acid, is significantly active only in liver and intestine.
The bases generated by turnover in non-hepatic tissues are not readily degraded
to uric acid in those tissues and, therefore, are available for salvage. The
liver probably does less salvage but is very active in de novo synthesis
- not so much for itself but to help supply the peripheral tissues.
De novo synthesis of
both purine and pyrimidine nucleotides occurs from readily available
components.
Phosphoribosyl
pyrophosphate (PRPP) is important in both, and in these pathways the structure
of ribose is retained in the product nucleotide, in contrast to its fate in the
tryptophan and histidine biosynthetic pathways discussed earlier. An amino acid
is an important precursor in each type of pathway: glycine for purines and
aspartate for pyrimidines. Glutamine again is the most important source of
amino groups — in five different steps in the de novo pathways. Aspartate is
also used as the source of an amino group in the purine pathways, in two steps.
Two other features deserve mention. First, there is evidence, especially in the
de novo purine pathway, that the enzymes are present as large, multienzyme
complexes in the cell, a recurring theme in our discussion of metabolism.
Second, the cellular pools of nucleotides (other than ATP) are quite small,
perhaps 1% or less of the amounts required to synthesize the cell’s DNA.
Therefore,
cells must continue to synthesize nucleotides during nucleic acid synthesis,
and in some cases nucleotide synthesis may limit the rates of DNA replication
and transcription. Because of the importance of these processes in dividing
cells, agents that inhibit nucleotide synthesis have become particularly
important to modern medicine. We examine here the biosynthetic pathways of
purine and pyrimidine nucleotides and their regulation, the formation of the
deoxynucleotides, and the degradation of purines and pyrimidines to uric acid
and urea. We end with a discussion of chemotherapeutic agentsthat affect
nucleotide synthesis.
In the first
committed step of the pathway, an amino group donated by glutamine is attached
at C-1 of PRPP.
The resulting
5-phosphoribosylamine is highly unstable, with a half-life of 30 seconds
at pH 7.5. The purine ring is subsequently built up on this structure. The
pathway described here is identical in all organisms, with the exception of one
step that differs in higher eukaryotes as noted below.