ANTITUMOR-ACTIVITY OF TRICYCLIC PYRONE ANALOGS, A NEW SYNTHETIC CLASSOF 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 (c ode names H10, H14 and H16) were tested against a spectrum of known an timitotic drugs for their ability to disrupt microtubule (MT) dynamics , alter the mitotic index, and prevent murine EMT-6 mammary sarcoma ce lls from synthesizing DNA and proliferating in vitro. At 2-10 mu M, H1 0 inhibits DNA synthesis, tubulin polymerization and tumor cell growth to a greater degree than H14, whereas H16 has no effect. A linear ske leton with a pyridyl ring at C-3 of the A-ring, a pyran a-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 n ot that of paclitaxel, on tubulin polymerization, TPs may represent a novel synthetic class of MT de-stabilizing anticancer drugs. H10 is le ss potent than VCR against tubulin polymerization (IC50: 1.5 mu M vers us 0.15 mu M) and tumor cell proliferation (IC50: 1.5 mu M versus 5 nM ) but inhibits DNA synthesis (IC50: 10 mu M) more effectively than ail other MT-disrupting agents tested, except tubulozole-C. Although TPs disrupt DNA synthesis and might affect several phases of the cell cycl e, the ability of H10 to increase the percentage of mitotic cells indi cates that these novel compounds may be cell cycle-specific anticancer drugs useful for arresting mammalian cells in M-phase. [(C) 1998 Lipp incott-Raven Publishers.].