[structure: see text] Chemical investigation of two field collections of marine cyanobacteria has led to the discovery of two new cytotoxic natural products, ankaraholides A (2) and B (3), along with the known compound swinholide A (1). Since swinholide-type compounds were previously localized to the heterotrophic bacteria of sponges, these findings raise intriguing questions about their true metabolic source.

Laulimalide is a potent, structurally unique microtubule-stabilizing agent originally isolated from the marine sponge Cacospongia mycofijiensis. Laulimalide exhibits an activity profile different from other microtubule-binding agents, notably including effectiveness against paclitaxel-resistant cells, but it is intrinsically unstable. Five analogues of laulimalide were designed to exhibit enhanced chemical stability yet retain its exceptional biological activities. Evaluations of these analogues showed that all are effective inhibitors of cancer-cell proliferation yet differ substantially in potency with an IC 50 range of 0.12-16.5 M. Although all of the analogues initiated cellular changes similar to laulimalide, including increased density of interphase microtubules, aberrant mitotic spindles, and ultimately apoptosis, differences among the analogues were apparent. The two most potent analogues, C 16-C17-des-epoxy laulimalide and C20-methoxy laulimalide, appear to have a mechanism of action identical to laulimalide. The C16-C17-des-epoxy, C20-methoxy laulimalide derivative, which incorporates both chemical changes of the most potent analogues, was significantly less potent and initiated the formation of unique interphase microtubules unlike the parent compound and other analogues. Two C2-C3-alkynoate derivatives had lower potency, and they initiated abnormal microtubule structures but did not cause micronucleation or extensive G2͞M accumulation. Significantly, paclitaxeland epothilone-resistant cell lines were less resistant to the laulimalide analogues. In summary, analogues of laulimalide designed to minimize or eliminate its intrinsic instability have been synthesized, and some have been found to retain the unique biological activities of laulimalide.antimitotics ͉ synthetic chemistry P aclitaxel (Taxol, Bristol-Myers Squibb), the first microtubule stabilizer identified, has proved to be of great value for the treatment of many types of cancer (1). The clinical successes of paclitaxel led to the development of a second-generation taxane, docetaxel (Taxotere, Aventis, Bridgewater, NJ), and initiated the intense search for other compounds with a similar mechanism of action. Several classes of structurally diverse microtubulestabilizing compounds have been identified. The first nontaxane stabilizers identified, the epothilones and discodermolide, had excellent preclinical activities and are being evaluated in clinical trials as anticancer agents.Laulimalide is a potent microtubule stabilizer that was originally isolated from the sponge Cacospongia mycofijiensis (2). Similar to the effects of other microtubule stabilizers, laulimalide increases the density of interphase microtubules and causes the formation of microtubule bundles and abnormal mitotic spindles, effects that culminate in mitotic arrest and initiation of apoptosis. Laulimalide stimulates the polymerization of bovine brain tubulin consistent with a direct interaction between the compound and tubulin (2, 3). Unlike the other stabilizers identified, ...

Symplostatin 1, an analog of dolastatin 10, was recently isolated from cyanobacteria of the genus Symploca. Symplostatin 1 is a potent inhibitor of cell proliferation with IC 50 values in the low nanomolar range and it exhibits efficacy against a variety of cancer cell types. Symplostatin 1 caused the formation of abnormal mitotic spindles and accumulation of cells in metaphase at concentrations that had only minor effects on interphase microtubules. At higher concentrations, symplostatin 1 caused the loss of interphase microtubules. Cell cycle analysis revealed that symplostatin 1 caused G 2 /M arrest, consistent with its effects on mitotic spindles. Symplostatin 1 initiated the phosphorylation of Bcl-2, formation of micronuclei and activation of caspase 3, indicating induction of apoptosis. The cellular effects of symplostatin 1 are consistent with other antimitotic tubulintargeting drugs. Tubulin polymerization experiments indicated that symplostatin 1 potently inhibits the assembly of purified tubulin, suggesting that tubulin may be its intracellular target. Some microtubule-targeting agents are reported to have antiangiogenic activity and therefore the effects of symplostatin 1 on endothelial cell proliferation and invasion were evaluated. Symplostatin 1 was found to be a potent inhibitor of both endothelial cell proliferation and invasion. Because of its potent and broad activity in vitro, symplostatin 1 was evaluated in vivo. Symplostatin 1 was active against murine colon 38 and murine mammary 16/C; however, it was poorly tolerated and the mice were slow to recover from the toxicity. The data indicate that symplostatin 1 has a mechanism of action similar to dolastatin 10.