Synthesis and biological evaluation of (−)-laulimalide analogues

Gallagher, Brian M.; Fang, Francis G.; Johannes, Charles W.; Pesant, Marc; Tremblay, Martin; Zhao, Hongjuan; Akasaka, Kozo; Li, Xiangyi; Liu, Junke; Littlefield, Bruce A.

doi:10.1016/j.bmcl.2003.12.001

Cited by 53 publications

(32 citation statements)

References 33 publications

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“…In general, in analog studies published to date, introduction of a single modification into laulimalide has resulted in moderate to severe reduction in cytotoxic activity, whereas introduction of more than one modification generally has yielded almost inert compounds (Pryor et al, 2002;Ahmed et al, 2003;Wender et al, 2003Wender et al, , 2006Gallagher et al, 2004Gallagher et al, , 2005Mooberry et al, 2004;Paterson et al, 2005). Important findings thus far: 1) if the epoxide moiety of laulimalide is replaced with a trans-olefin bond, activity is reduced 23-to 51-fold against MCF-7 (Pryor et al, 2002;Ahmed et al, 2003; see above), 11-fold against MaTu (Ahmed et al, 2003), and 19-to 21-fold against MDA-MB-435 breast cancer cells (Wender et al, 2003;Mooberry et al, 2004) [a larger loss of activity against MDA-MB-435 cells was reported by Gallagher et al (2004)]; 2) if the C-2/C-3 olefin bond is changed from cis to trans, activity is reduced 10-to 14-fold against MaTu and MCF-7 cells, respectively (Ahmed et al, 2003) [again, a larger loss of activity against MDA-MB-435 cells was reported by Gallagher et al (2004)]; 3) if the C-30 methyl substituent at C-11 is removed, activity is reduced 9-fold against MDA-MB-435 cells (Wender et al, 2006) and 15-fold against A2780 ovarian cancer cells ; 4) if the hydroxyl at C-20 is methylated or acetylated, activity is reduced 40-to 42-fold against MDA-MB-435 cells (Wender et al, 2003;Gallagher et al, 2004;Mooberry et al, 2004); 5) if the hydroxyl at C-15 is acetylated, activity is reduced 10-fold against MDA-MB-435 cells, with larger reductions with other ester groups (Gallagher et al, 2004); 6) if the C-15 hydroxyl group is methylated, activity is reduced over 400-fold against MDA-MB-435 cells (Gallagher et al, 2004); 7) if an alkyne bond is introduced between C-2 and C-3, activity is reduced over 400-fold against MDA-MB-435 cells ; 8) possibly, if the side chain is eliminated or modified, activity is substantially reduced ; and 9) possibly, if configuration is reversed at C-15, activity is substantially reduced (Gallagher et al, 2004). Analogs that lack the C-30 methyl group and possess modified side chains have activities reduced by more than 2500-fold compared with laulimalide against A2780 cells .…”

Section: Discussionmentioning

confidence: 99%

“…Analogs that lack the C-30 methyl group and possess modified side chains have activities reduced by more than 2500-fold compared with laulimalide against A2780 cells . Likewise, analogs with reversal of configuration at C-15 and changes in the epoxide moiety have activities reduced over 75-fold compared with laulimalide against MDA-MB-435 cells (Gallagher et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…Laulimalide has been examined in multiple human cancer cell lines by many workers, and it has yielded IC 50 values in the 2 to 11 nM range (Mooberry et al, 1999;Pryor et al, 2002;Ahmed et al, 2003;Gallagher et al, 2004;Paterson et al, 2005;Wender et al, 2006). The IC 50 values of peloruside A in human cancer cell lines range from 6 to 66 nM (Hood et al, 2001(Hood et al, , 2002Gaitanos et al, 2004), and thus it may be less active than laulimalide.…”

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confidence: 99%

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Synergistic Effects of Peloruside A and Laulimalide with Taxoid Site Drugs, but Not with Each Other, on Tubulin Assembly

Hamel¹,

Day²,

Miller³

et al. 2006

Mol Pharmacol

124

114

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Previous studies on the drug content of pelleted tubulin polymers suggest that peloruside A binds in the laulimalide site, which is distinct from the taxoid site. In a tubulin assembly system containing microtubule-associated proteins and GTP, however, peloruside A was significantly less active than laulimalide, inducing assembly in a manner that was most similar to sarcodictyins A and B. Because peloruside A thus far seems to be the only compound that mimics the action of laulimalide, we examined combinations of microtubule-stabilizing agents for synergistic effects on tubulin assembly. We found that peloruside A and laulimalide showed no synergism but that both compounds could act synergistically with a number of taxoid site agents [paclitaxel, epothilones A/B, discodermolide, dictyostatin, eleutherobin, the steroid derivative 17␤-acetoxy-2-ethoxy-6-oxo-B-homo-estra-1,3,5(10)-trien-3-ol, and cyclostreptin]. None of the taxoid site compounds showed any synergism with each other. From an initial study with peloruside A and cyclostreptin, we conclude that the synergism phenomenon derives, at least in part, from an apparent lowering of the tubulin critical concentration with drug combinations compared with single drugs. The apparent binding of peloruside A in the laulimalide site led us to attempt construction of a pharmacophore model based on superposition of an energy-minimized structure of peloruside A on the crystal structure of laulimalide. Although the different sizes of the macrocycles limited our ability to superimpose the two molecules, atom correspondences that were observed were consistent with the difficulty so far experienced in creation of fully active analogs of laulimalide.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Synergistic Effects of Peloruside A and Laulimalide with Taxoid Site Drugs, but Not with Each Other, on Tubulin Assembly

Hamel¹,

Day²,

Miller³

et al. 2006

Mol Pharmacol

124

114

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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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“…For example, Smith and Malamas 7 subjected an ynolide intermediate to partial reduction as a way to stereoselectively form a cis -alkene in their synthesis of cis -normethyljatropholactone. Macrolactonization of alkynoates followed by partial reduction has also been used in the syntheses of phorboxazole B 8−10 and laulimalide 11−20 as a way to circumvent isomerization of the requisite cis -enoate during the macrolactonization step. In addition, Danishefsky and co-workers took advantage of ynolides as Diels–Alder dienophiles in their approach to resorcinylic fused macrolides.…”

Section: Introductionmentioning

confidence: 99%

Fragmentation of Bicyclic γ-Silyloxy-β-hydroxy-α-diazolactones as an Approach to Ynolides

Bayır

Brewer

2014

J. Org. Chem.

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Medium-sized ynolides were prepared by the Lewis acid-mediated fragmentation of bicyclic γ-silyloxy-β-hydroxy-α-diazolactones in which the Cβ–Cγ bond is the ring fusion bond. Although these lactone fragmentation substrates reacted somewhat less efficiently than their carbocyclic counterparts, the fragmentation provided 11-membered ynolides in up to 84% yield. Unlike prior fragmentations of similar substrates, elevated temperatures were required to obtain optimum yields of the ynolide products. The ynolides reported herein have ring sizes of 10 or 11, which are the smallest reported to date.

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Synthesis and biological evaluation of (−)-laulimalide analogues

Cited by 53 publications

References 33 publications

Synergistic Effects of Peloruside A and Laulimalide with Taxoid Site Drugs, but Not with Each Other, on Tubulin Assembly

Synergistic Effects of Peloruside A and Laulimalide with Taxoid Site Drugs, but Not with Each Other, on Tubulin Assembly

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

Fragmentation of Bicyclic γ-Silyloxy-β-hydroxy-α-diazolactones as an Approach to Ynolides

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