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, ...
During the course of a mechanism-based screening program aimed at identifying new antimitotic agents, a novel microtubule depolymerizing piperazine derivative, 1-(5-chloro-2-methoxybenzoyl)-4-(3-chlorophenyl) piperazine, was identified. The compound, designated CB694, caused inhibition of proliferation of a wide range of cancer cell lines, with an average IC 50 of 85 nM. A multidrug-resistant cell line was sensitive to inhibition by CB694, suggesting that this compound is a poor substrate for transport by P-glycoprotein. CB694 caused formation of abnormal mitotic structures in HeLa cells. Specifically, CB694 caused a concentration-dependent increase in bipolar spindles with lagging chromosomes and, with slightly higher concentrations, formation of multipolar mitotic spindles. These mitotic abnormalities occurred at concentrations that did not cause significant changes in the appearance or quantity of interphase microtubules. Coincident with the formation of abnormal mitotic spindles, CB694 caused G 2 /M arrest. CB694 inhibited the assembly of purified tubulin with an IC 50 of 2.3 lM. Colchicine binding was strongly inhibited by CB694, suggesting that it binds to tubulin at the colchicine site. Bcl-2 phosphorylation and activation of ERK and JNK and caspase 3-dependent cleavage of PARP were observed in MDA-MB-435 cells treated with CB694. CB694 caused phosphorylation of Aurora A within 8 hr of treatment, and increases in Aurora A protein levels were coincident with mitotic accumulation. The efficacy of CB694 against a syngeneic murine transplantable solid tumor, Mammary 16/C, was also evaluated. CB694 was well tolerated and showed antitumor activity. ' 2005 Wiley-Liss, Inc.
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