Design and Synthesis of Cyclopenta[g]quinazoline-Based Antifolates as Inhibitors of Thymidylate Synthase and Potential Antitumor Agents^,

Abstract

Following the development of raltitrexed, the synthesis of nonpolyglutamatable inhibitors of TS that do not use the reduced folate carrier (RFC) for cellular entry should provide compounds which overcome mechanisms of resistance to folate-based inhibitors of TS that are associated with decreased/altered folylpolyglutamate synthetase (FPGS) expression and/or an impaired RFC. Examination of a computer graphics model of the humanized Escherichia coli TS enzyme with quinazoline inhibitors of TS, such as 1 bound in the active site of the enzyme, suggested that conformational restriction introduced by bridging the C9 with C7 to form a pentacycle may be beneficial for binding to TS. That led to the synthesis of a series of potent cyclopenta[g]quinazoline-based inhibitors of the enzyme in which the glutamyl residue associated with classical antifolates was replaced with a variety of glutamate-derived ligands; the most potent inhibitor being the L-Glu-gamma-D-GluT(alpha) derivative 7j. In the mouse L1210:1565 cell line (mutant RFC), the majority of these compounds had activity equal or only slightly greater compared with the parental L1210 cell line, indicating a reduced dependence on the RFC for cellular uptake in the L1210 cell line.

Hypoxic Regulation of Glucose Transport, Anaerobic Metabolism and Angiogenesis in Cancer: Novel Pathways and Targets for Anticancer Therapeutics

“…Although several studies have proposed inhibition of glucose transporters as a potential therapeutic angle [10,53,208,209] , clinicians should be aware of a potentially important caveat to this approach: high levels of GLUT1 are expressed in a number of tissues. In addition GLUT1 is abundantly expressed in endothelial cells in normal tissues ( fig.…”

Design, synthesis and biological evaluation of novel quinazoline derivatives as potential anti-cancer agents

“…Numerous quinazoline derivatives have been reported to have anti-cancer activity [4][5][6] . In that context, these agents have shown inhibitory activity against thymidylate synthase [5][6][7] , dihydrofolate reductase and various receptor tyrosine kinases [8][9][10] .…”

“…In that context, these agents have shown inhibitory activity against thymidylate synthase [5][6][7] , dihydrofolate reductase and various receptor tyrosine kinases [8][9][10] . Dasatinib, the standard used in this study, is a multi-targeted kinase inhibitor 11 .…”

BGC 945, a Novel Tumor-Selective Thymidylate Synthase Inhibitor Targeted to α-Folate Receptor–Overexpressing Tumors

“…1,15). These properties are due to the presence of modified glutamate ligands, which in the case of BGC 638 is an L-Glu-g-DGlu dipeptide (16,17). The addition of the second glutamate as the D-enantiomer rather than the L-enantiomer stabilizes antifolates with dipeptide ligands against enzymatic hydrolysis in vivo (18,19).…”