Microtubule‐Stabilizing Marine Metabolite Laulimalide and Its Derivatives: Synthetic Approaches and Antitumor Activity

Mulzer, Johann; Oehler, E.

doi:10.1002/chin.200348253

Cited by 6 publications

(8 citation statements)

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“…The process for determining the stereochemistry of these six new compounds was somewhat involved and only provisional assignments are proposed in the region from C-23 to C-27. First, 2 provided an important anchor point because its configuration of 5R, 9R, 11S, 15S, 16S, 17S, 19S, 20S, 23S has been previously determined by synthesis 18 and X-ray analysis. 38 Given that 2 rearranges to 1 means that the latter must have 5R, 9R, 11S, 15S, 16S, 17R, 19S, 20S, and 23S as well.…”

Section: Resultsmentioning

confidence: 99%

“…[14][15][16][17] These developments, plus the biological data summarized above, motivated 11 total syntheses for 2 from eight different research groups. 18 In addition, five different teams seeking to broaden the understanding of cytotoxicity structure-activity relationships (CSAR) have prepared 35 synthetic congeners of 2. 4,14,[19][20][21][22][23][24][25][26][27] None of the synthetic analogs obtained to date have exhibited greater in vitro cytotoxicty in comparison to that of 2.…”

Section: Introductionmentioning

confidence: 99%

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Sponge-Derived Fijianolide Polyketide Class: Further Evaluation of Their Structural and Cytotoxicity Properties

et al. 2007

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The sponge-derived polyketide macrolides fijianolides A (1) and B (2), isolaulimalide and laulimalide, have taxol-like microtubule-stabilizing activity, and the latter exhibits potent cytotoxicity. Insight on the biogeographical and phenotypic variations of Cacospongia mycofijiensis is presented that will enable a future study of the biosynthetic pathway that produces the fijianolides. In addition to fijianolides A and B, six new fijianolides, D-I (7-12), were isolated, each with modifications to the C-20 side chain of the macrolide ring. Compounds 7-12 exhibited a range of in vitro activities against HCT-116 and MDA-MB-435 cell lines. Fijianolides 8 and 10 were shown to disrupt interphase and mitotic division, but were less potent than 2. An in vivo evaluation of 2 using tumor-bearing severe combined immuno-deficiency mice demonstrated significant inhibition of growth in HCT-116 tumors over 28 days.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Sponge-Derived Fijianolide Polyketide Class: Further Evaluation of Their Structural and Cytotoxicity Properties

et al. 2007

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“…The first total synthesis of 36 was reported by Ghosh and co-workers . Several other synthetic approaches, reviewed by Mulzer and Ohler, have been developed. Notably, scientists at the Eisai Research Institute were able to synthesize sufficient quantities of laulimalide to enable in vivo efficacy studies .…”

Section: Mt-stabilizing Natural Products and Analogues Thereofmentioning

confidence: 99%

Microtubule Stabilizing Agents as Potential Treatment for Alzheimer’s Disease and Related Neurodegenerative Tauopathies

et al. 2012

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The microtubule (MT)-associated protein tau, which is highly expressed in the axons of neurons, is an endogenous MT-stabilizing agent that plays an important role in the axonal transport. Loss of MT-stabilizing tau function, caused by misfolding, hyperphosphorylation and sequestration of tau into insoluble aggregates, leads to axonal transport deficits with neuropathological consequences. Several in vitro and preclinical in vivo studies have shown that MT-stabilizing drugs can be utilized to compensate for the loss of tau function and to maintain/restore an effective axonal transport. These findings indicate that MT-stabilizing compounds hold considerable promise for the treatment of Alzheimer disease and related tauopathies. The present article provides a synopsis of the key findings demonstrating the therapeutic potential of MT-stabilizing drugs in the context of neurodegenerative tauopathies, as well as an overview of the different classes of MT-stabilizing compounds.

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“…Therefore, it became a priority to find laulimalide analogues with improved efficacy and stability, decreased toxicity, and that can be easily synthesized. This has proven challenging since, to the best of our knowledge, all studies published to date regarding the efficacy of laulimalide analogues show these novel compounds to be less potent than LA (Gallagher Jr et al, 2004;Gollner, Altmann, Gertsch, & Mulzer, 2009;Mooberry et al, 2004Mooberry et al, , 2008Mulzer &Öhler, 2003;Paterson et al, 2005;Wender, Hegde, Hubbard, Zhang, & Mooberry, 2003), and it is unknown how structural modifications alter the LA binding mode to tubulin, making the rational-design of laulimalide analogues challenging.…”

Section: Introductionmentioning

confidence: 97%

Analysis of the binding mode of laulimalide to microtubules: Establishing a laulimalide–tubulin pharmacophore

Churchill

Kłobukowski

Tuszyński³

2016

Journal of Biomolecular Structure and Dynamics

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Laulimalide (LA) is a microtubule-stabilizing agent, currently in preclinical studies. However, studying the binding of this species and successfully synthesizing potent analogues have been challenging. The LA binding site is located between tubulin protofilaments, and therefore LA is in contact with two adjacent [Formula: see text]-tubulin units. Here, an improved model of the binding mode of LA in microtubules is presented, using the newly available crystal structure pose and an extended tubulin heterodimer complex, as well as molecular dynamics simulations. With this model, a series of LA analogues developed by Mooberry and coworkers are also analyzed in order to establish important pharmacophores in LA binding and cytotoxicity. In the side chain, [Formula: see text]-[Formula: see text] interactions are important contributors to LA binding, as are water-mediated hydrogen bonds. An intramolecular hydrogen bond is correlated with high cytotoxicity, and is dependent on macrocycle conformation. Therefore, while the epoxide and olefin groups in the macrocycle do not engage in specific interactions with the protein, they are essential contributions to an active macrocycle conformation, and therefore potency. Calculations reveal that a balance in binding affinity is important for LA activity, where the more potent compounds have larger interactions with the adjacent tubulin unit than the less-active analogs. Several modifications are suggested for the rational design of LA analogues that should not disrupt the active macrocycle conformation.

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Microtubule‐Stabilizing Marine Metabolite Laulimalide and Its Derivatives: Synthetic Approaches and Antitumor Activity

Abstract: For Abstract see ChemInform Abstract in Full Text.

Cited by 6 publications

References 1 publication

Sponge-Derived Fijianolide Polyketide Class: Further Evaluation of Their Structural and Cytotoxicity Properties

Sponge-Derived Fijianolide Polyketide Class: Further Evaluation of Their Structural and Cytotoxicity Properties

Microtubule Stabilizing Agents as Potential Treatment for Alzheimer’s Disease and Related Neurodegenerative Tauopathies

Analysis of the binding mode of laulimalide to microtubules: Establishing a laulimalide–tubulin pharmacophore

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