Macrocyclization via Allyl Transfer:  Total Synthesis of Laulimalide

Enev, Valentin S.; Kaehlig, Hanspeter; Mulzer, Johann

doi:10.1021/ja016752q

Cited by 58 publications

(26 citation statements)

References 19 publications

(22 reference statements)

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“…Laulimalide was isolated from a variety of sponges in Pacific waters (Corley et al, 1988;Quiñ oà et al, 1988;Jefford et al, 1996;Mooberry et al, 1999), and it has been totally synthesized by many investigators (Enev et al, 2001;Ghosh et al, 2001;Mulzer and Ohler, 2001;Paterson et al, 2001;Crimmins et al, 2002;Nelson et al, 2002;Wender et al, 2002;Williams et al, 2002;Gallagher et al, 2004). Mooberry et al (1999) initially reported that laulimalide induced tubulin assembly, caused cells to accumulate at the G 2 /M phase of the cell cycle, and caused paclitaxel-like microtubule bundles to appear in cultured cells.…”

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confidence: 99%

Laulimalide and Paclitaxel: A Comparison of Their Effects on Tubulin Assembly and Their Synergistic Action When Present Simultaneously

Gapud¹,

Bai²,

Ghosh³

et al. 2004

Mol Pharmacol

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Previous work has shown that laulimalide, a sponge-derived natural product, resembles paclitaxel in enhancing tubulin assembly and in its effects on cellular microtubules. The two compounds, however, seem to have distinct binding sites on tubulin polymer. Nearly equimolar amounts of tubulin, laulimalide, and paclitaxel are recovered from microtubules formed with both drugs. In the present study, we searched for differences between laulimalide and paclitaxel in their interactions with tubulin polymer. Laulimalide was compared with paclitaxel and epothilone A, a natural product that competes with paclitaxel in binding to microtubules, for assembly properties at different temperatures and for effects of GTP and microtubule-associated proteins on assembly. Although minor differences were observed among the three drugs, their overall effects were highly similar, except that aberrant assembly products were observed more frequently with paclitaxel and that the polymers formed with laulimalide and epothilone A were more stable at 0°C. The most dramatic difference observed between laulimalide and epothilone A was that only laulimalide was able to enhance assembly synergistically with paclitaxel, as would be predicted if the two drugs bound at different sites in polymer. Because stoichiometric amounts of laulimalide and paclitaxel can cause extensive tubulin assembly, maximum synergy was observed at lower temperatures under reaction conditions in which each drug alone is relatively inactive. Laulimalide-induced assembly, like paclitaxel-induced assembly, was inhibited by drugs that inhibit tubulin assembly by binding at either the colchicine-or vinblastine-binding site. When radiolabeled GTP is present in a reaction mixture with either laulimalide or paclitaxel, nucleotide hydrolysis occurs with incorporation of radiolabeled GDP into polymer.

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confidence: 99%

Laulimalide and Paclitaxel: A Comparison of Their Effects on Tubulin Assembly and Their Synergistic Action When Present Simultaneously

Gapud¹,

Bai²,

Ghosh³

et al. 2004

Mol Pharmacol

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“…6; see also refs. [7][8][9][10][11][12][13][14][15]. However, laulimalide is intrinsically unstable and, under mildly acidic conditions, it is converted to isolaulimalide, a significantly less potent isomer, via ring opening of the sensitive C 16 -C 17 -epoxide by the C 20 -hydroxyl group.…”

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confidence: 99%

Microtubule-stabilizing agents based on designed laulimalide analogues

Mooberry

Randall-Hlubek

Leal

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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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, ...

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“…251−255 The latter problem is usually solved (Scheme 28) by performing the macrolactonization on the ynoic seco-acid and then reducing the triple bond, as illustrated in the synthesis of laulimalide. 255 Another alternative is to use softer coupling reagents that possess non-nucleophilic counterions 256 as shown in the synthesis of sorangicin A. 250 (Scheme 29)…”

Section: Macrolactonization Through the Formation Of A Mixed Anhydridmentioning

confidence: 99%