Tricyclic pyrones (TPs) may represent a novel synthetic class of microtubule (MT) de-stabilizing anticancer drugs previously shown by us to inhibit macromolecule synthesis,
tubulin polymerization, and the proliferation of leukemic and mammary
tumor cells in vitro. A linear skeleton with a N-containing aromatic ring attached at C3 of the top A-ring, a central
pyran B-ring and a six-membered bottom C-ring with no alkylation at C7 are required for the antitumor activities of the lead compounds, a 3-pyridyl
benzopyran (code name H10) and its somewhat weaker 2-pyridyl regioisomer (code name H19). Increasing concentrations of H10 do not alter the binding of [3H]
vinblastine and [3H]
GTP to
tubulin but mimic the ability of unlabeled
colchicine (CLC) to reduce the amount of [3H]CLC bound to
tubulin, suggesting that TPs may interact with the CLC binding site to inhibit
tubulin polymerization. Exogenous Mg2+
cations absolutely required for the binding of
GTP to
tubulin and MT assembly cannot overcome the antitubulin action of H10. H10 reduces the viability of L1210 cells in vitro (IC50: 0.5 microM) but its antitumor activity may be related to its ability to inhibit
tubulin polymerization and rapidly increase the mitotic index rather than to induce DNA cleavage and apoptosis. The anticancer potential of TPs in vivo is demonstrated by the fact 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, which also blocks the cellular transport of
nucleosides (IC50: 6 microM) to inhibit
DNA synthesis. Since few CLC site-binding
antimitotic agents are active in solid
tumor models in vivo, the ability of these new MT destabilizing TPs to totally block
nucleoside transport might be valuable in
polychemotherapy to arrest
tumor cells at several phases of their cycle, potentiate the action of
antimetabolites and sensitize multidrug-resistant
tumor cells.