Tricyclic pyrone analogs: a new synthetic class of bifunctional anticancerdrugs that inhibit nucleoside transport, microtubule assembly, the viability of leukemic cells in vitro and the growth of solid tumors in vivo

Tricyclic pyrones (TPs) may represent a novel synthetic class of microtubul e (MT) de-stabilizing anticancer drugs previously shown by us to inhibit ma cromolecule synthesis, tubulin polymerization, and the proliferation of leu kemic and mammary tumor cells in vitro. A linear skeleton with a N-containi ng aromatic ring attached at C3 of the top A-ring, a central pyran a-ring a nd a six-membered bottom C-ring with no alkylation at C7 are required for t he antitumor activities of the lead compounds, a 3-pyridyl benzopyran (code name H10) and its somewhat weaker 2-pyridyl regioisomer (code name H19). I ncreasing concentrations of H10 do not alter the binding of [H-3]vinblastin e and [H-3]GTP td tubulin but mimic the ability of unlabeled colchicine (CL C) to reduce the amount of [H-3]CLC bound to tubulin, suggesting that Tps m ay interact with the CLC binding site to inhibit tubulin polymerization. Ex ogenous Mg2+ cations absolutely required for the binding of GTP to tubulin and Mi assembly cannot overcome the antitubulin action of H10. H10 reduces the viability of L1210 cells in vitro (IC50: 0.5 mu M) but its antitumor ac tivity may be related to its ability to inhibit tubulin polymerization and rapidly increase the mitotic index rather than to induce DNA cleavage and a poptosis. The anticancer potential of Tps in vivo is demonstrated by the fa ct that i.p. injections of the water-soluble H10-HCl decrease the growth of solid tumors in mice inoculated s.c. with Lewis lung carcinoma. A critical finding is that the antimitotic H10 is a bifunctional anticancer drug, whi ch also blocks the cellular transport of nucleosides (IC50: 6 mu M) to inhi bit DNA synthesis. Since few CLC site-binding antimitotic agents are active in solid tumor models in vivo, the ability of these new MT destabilizing T ps to totally block nucleoside transport might be valuable in polychemother apy to arrest tumor cells at several phases of their cycle, potentiate the action of antimetabolites and sensitize multidrug-resistant tumor cells. [( C) 1999 Lippincott Williams & Wilkins.].