NONPOLYGLUTAMATABLE ANTIFOLATES AS INHIBITOR OF THYMIDYLATE SYNTHASE (TS) AND POTENTIAL ANTITUMOR 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 che motherapy for more than two decades. Over the last 10 years much resea rch has been devoted to the design and development of nonpolyglutamata ble inhibitors of TS as antitumour agents, mainly to overcome resistan ce due to unfavourable expression of folylpolyglutamate synthetase (FP GS). Lipophilic inhibitors of the enzyme were expected not to depend o n the reduced folate carrier transporter (RFC) for cellular uptake, th us avoiding resistance due to an impaired RFC. Compounds of this type can be classified in three groups: A: nonclassical lipophilic inhibito rs of TS, mainly folate-based analogues lacking the glutamate side cha in; B: folate-based analogues in which the glutamate side chain has be en modified in such a way that polyglutamation is precluded; and C: no npolyglutamatable glutamate-containing inhibitors of TS. Compounds of group A included 5- or 6-substituted quinazolin-4-ones, benzo[f]quinaz olines, imidazotetrahydroquinoline- and benz[cd]indole-based inhibitor s. The second group is mainly related to a series of gamma-linked dipe ptide derivatives of ICI198583, or analogues of this inhibitor where t he glutamate residue was replaced with a range of alpha-amino acids. T he third group is concerned with some 7-substituted derivatives of ICI 198583 and the pyrrolo[3,2-d]pyrimidine-based inhibitor 175. A large n umber of structurally diverse nonpolyglutamatable inhibitors of TS wer e synthesised some of which were potent inhibitors of the enzyme (huma n or E. coil) and in vitro cell growth. Three compounds, i.e. 49 (AG 3 37), 83 (AG 331), 123 (ZD9331) have reached the stage of clinical eval uation.