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Antimetabolite incorporation into DNA: Structural and thermodynamic basis for anticancer activity
Author(s) -
Gmeiner William H.
Publication year - 2002
Publication title -
biopolymers
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.10214
Subject(s) - chemistry , dna , nucleic acid , topoisomerase , cytidine , polymerase , biochemistry , dna replication , dna polymerase , computational biology , enzyme , biology
Antimetabolites are a class of effective anticancer drugs that structurally resemble naturally occurring biochemicals and interfere in essential biochemical processes. In this review, the recent literature describing investigations of the structural and thermodynamic basis for the anticancer activity of three antipyrimidines [1‐β‐ D ‐arabinofuranosyl cytidine (AraC). 2′,2′‐difluoro deoxycytidine (dFdC), and 5‐fluoro‐2′‐deoxyuridine (FdUrd)] is summarized. Our laboratory, and others, have shown that misincorporation of any of these three antipyrimidines into DNA perturbs the structure and decreases the stability of duplex DNA. These data are useful for rationalizing the effects of antipyrimidine misincorporation on the activities of proteins required for DNA replication and repair such as DNA topoisomerase 1 and DNA polymerases. The studies completed to date and summarized in this review demonstrate the utility of investigations into the structure–function relationships between antipyrimidine‐substituted DNA complexed with DNA‐modifying proteins for the purpose of understanding the basis for effective antipyrimidine cancer chemotherapy and the future design of novel anticancer drugs. © 2002 Wiley Periodicals, Inc. Biopolymers (Nucleic Acid Sci) 65: 180–189, 2002