Page 185 - Academic Press Encyclopedia of Physical Science and Technology 3rd Organic Chemistry

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Encyclopedia of Physical Science and Technology EN007F-314 July 6, 2001 16:59

Heterocyclic Chemistry 341

Nucleic acids are polynucleotides. They are of two main H 2 N N N
types: deoxyribonucleic acid (DNA) and ribonucleic acid Me
N N
(RNA). Both are present in every living cell; they direct the N
synthesis of proteins and are responsible for the transfer NH 2 CONHCH(COOH)CH 2 CH 2 COOH
of genetic information. methotrexate
In 1953, Watson and Crick postulated that DNA was
formed by the twisting of two polynucleotide chains into S
a right-handed double helix. The chains are held together HN N
by the hydrogen bonding of two base pairs: thymine– or N 6-mercaptopurine
N H
uracil–adenine and cytosine–guanine. No other combina-
tion of those base pairs is possible.
E. Rings with Seven or More Members
H H
R O H N N N H O N 1. Synthesis
N H N N N H N N The famous rules of Woodward and Hofmann govern,
N N N N
among many other reactions, the contractions and expan-
O O H N
H sions of heterocyclic rings with seven or more members. A
thymine (R = H) adenine cytosine guanine
uracil (R = H) seven-membered heterocyclic ring can give a 4,5-system
strand A strand B strand A strand B on photolysis, as well as a benzene ring on thermolysis.
combination of base pairs in nucleic acids
hν
X ∆
X
A segment of a DNA phosphodiester chain with the
positions of attachment of the heterocyclic bases is shown. X = NR azepine
X = O oxzepine ∆
X = S thiepin
O XH
P ∆
HO X
O base
O
transformations of seven-membered heterocycles
O
O A nine-membered heterocyclic ring can give a 3,8-ring
P
HO O base system on photolysis, and also a 5,6-ring system on ther-
O
molysis. Some of these reactions are of considerable syn-
thetic importance.
O O
P H
HO
O hν ∆
X
segment of a DNA phosphodiester chain X X
H
transformations of nine-membered heterocycles, X = O, NR
5-Fluorouracil, used to treat breast and stomach can-
cers, resembles uracil, without which the cell cannot make
pyrimidine nucleotides. 5-Fluorouracil enters the biosyn- 2. Properties
thetic chain but forms an inactive complex which blocks
Azepine, oxepine, and thiepin have eight pielectrons (in-
the synthesis of pyrimidine nucleotides and hence inhibits
cluding the lone pair on the heteroatom). Thus, they have
DNAsynthesisincancercells.Methotrexateisaderivative
little aromatic character and are very reactive. The tran-
of folic acid and interferes with folic acid metabolism by
quilizing properties of certain diazepines, such as Librium
inhibiting the enzyme dihydrofolate reductase, essential
and Valium, have prompted much research in this area.
for the synthesis of purine and pyrimidine, and therefore
essential to the synthesis of DNA. Methotrexate finds use N NHMe Me O
N
HCl
in treating childhood leukemia and other cancers, particu-
+
larly in combination with other drugs. 6-Mercaptopurine Cl N _ Cl N
O
blocks purine nucleotide synthesis and is a purine an- Ph Ph
timetabolite in clinical use. librium valium (diazepam)