Nonpolyglutamatable antifolates as inhibitors of thymidylate synthase (TS) and potential antitumour agents.
Thymidylate synthase (TS), an enzyme that catalyses the conversion of dUMP to dTMP, has been the focus of interest as a target in cancer chemotherapy for more than two decades. Over the last 10 years much research has been devoted to the design and development of nonpolyglutamatable inhibitors of TS as antitumour agents, mainly to over-come resistance due to unfavourable expression of folylpolyglutamate synthetase (FPGS). Lipophilic inhibitors of the enzyme were expected not to depend on the reduced folate carrier transporter (RFC) for cellular uptake, thus avoiding resistance due to an impaired RFC. Compounds of this type can be classified in three groups: A: nonclassical lipophilic inhibitors of TS, mainly folate-based analogues lacking the glutamate side chain; B: folate-based analogues in which the glutamate side chain has been modified in such a way that polyglutamation is precluded; and C: nonpolyglutamatable glutamate-containing inhibitors of TS. Compounds of group A included 5- or 6-substituted quinazolin-4-ones, benzo[flquinazolines, imidazotetrahydroquinoline- and benz[cd]indole-based inhibitors. The second group is mainly related to a series of g-linked dipeptide derivatives of ICIl98583, or analogues of this inhibitor where the glutamate residue was replaced with a range of a-amino acids. The third group is concerned with some 7-substituted derivatives of ICI198583 and the pyrrolo[3, 2-d]pyrimidine-based inhibitor 175. A large number of structurally diverse nonpolyglutamatable inhibitors of TS were synthesised some of which were potent inhibitors of the enzyme (human or E. coli) and in vitro cell growth. Three compounds, i.e. 49 (AG 337), 83 (AG 331), 123 (ZD9331) have reached the stage of clinical evaluation.
CRC Centre for Cancer Therapeutics at The Institute of Cancer Research, CRC Laboratory, 15 Cotswold Road, Sutton, Surrey, SM2 5NG, UK.
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D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000737:chemistry / Q000494:pharmacology*; D005493:Folic Acid Antagonists / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D010453:Peptide Synthases / Q000096:biosynthesis / Q000737:chemistry; D011799:Quinazolines / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*
D000964:Antimetabolites, Antineoplastic; D018691:Excitatory Amino Acid Antagonists; D005493:Folic Acid Antagonists; D007211:Indoles; D011799:Quinazolines; C094299:ZD 9331; C087748:AG 331; D013940:Thymidylate Synthase; D010453:Peptide Synthases; C023103:folylpolyglutamate synthetase; C099178:nolatrexed