RESUMO
Octalactin A and B (code names K1 and K2) are eight-membered-ring lactones from a marine bacterium. K1 is reportedly cytotoxic. Since access to this natural product is severely limited, the entire synthesis of K1 has been achieved in K. Buszek's laboratory, and several of its structural and stereochemical analogs (code names K3-K9) have been tested for their ability to prevent murine L1210 leukemic cells from synthesizing macromolecules and growing in vitro. At 50 microM, K1 is inactive and the eight-membered lactone K4, an oxocene, is the only compound found to inhibit tumor cell growth by about 90% in the L1210 system. The long-term inhibition of L1210 cell growth by K4 is concentration dependent (IC50 around 10 microM) and not reversible following drug removal. The delayed and weaker cytotoxic effects of K4 suggest that the inhibition of tumor cell proliferation observed 1-4 days after K4 treatment is not solely caused by drug cytotoxicity. When compared to a spectrum of representative anticancer drugs, higher concentrations of K4 must be used to maximally inhibit tumor cell growth. In contrast to its antiproliferative activity, 50 microM K4 fails to alter the rates of DNA, RNA and protein synthesis in L1210 cells. This discrepancy between the ability of K4 to inhibit macromolecule synthesis and leukemic cell growth suggests that other molecular targets are involved in the antitumor action of this drug. At 50 microM, K4 inhibits the polymerization of purified tubulin by about 45%, and therefore may be a novel microtubule de-stabilizing drug weaker than vincristine. Even though other mechanisms may be involved in its antitumor action, the ability of K4 to partially disrupt microtubule dynamics indirectly suggests that this synthetic oxocene may be a cell cycle-specific anticancer drug that blocks mammalian cells in M-phase.
