Antitumor activity of tricyclic pyrone analogs, a new synthetic class of microtubule de-stabilizing agents, in the murine EMT-6 mammary tumor cell line in vitro.

Novel tricyclic pyrone (TP) analogs synthesized in Hua's laboratory (code names H10, H14 and H16) were tested against a spectrum of known antimitotic drugs for their ability to disrupt microtubule (MT) dynamics, alter the mitotic index, and prevent murine EMT-6 mammary sarcoma cells from synthesizing DNA and proliferating in vitro. At 2-10 microM, H10 inhibits DNA synthesis, tubulin polymerization and tumor cell growth to a greater degree than H14, whereas H16 has no effect. A linear skeleton with a pyridyl ring at C-3 of the A-ring, a pyran B-ring and no alkylation at C-7 of the C-ring is required for the antitumor activity of these TPs. Since H10 mimics the effect of vincristine (VCR), but not that of paclitaxel, on tubulin polymerization, TPs may represent a novel synthetic class of MT de-stabilizing anticancer drugs. H10 is less potent than VCR against tubulin polymerization (IC50: 1.5 microM versus 0.15 microM) and tumor cell proliferation (IC50: 1.5 microM versus 5 nM) but inhibits DNA synthesis (IC50: 10 microM) more effectively than all other MT-disrupting agents tested, except tubulozole-C. Although TPs disrupt DNA synthesis and might affect several phases of the cell cycle, the ability of H10 to increase the percentage of mitotic cells indicates that these novel compounds may be cell cycle-specific anticancer drugs useful for arresting mammalian cells in M-phase.