Total synthesis of halichondrin B and norhalichondrin B

Aicher, Thomas D.; Buszek, Keith R.; Fang, Francis G.; Forsyth, Craig J.; Jung, Sun Ho; Kishi, Yoshito; Matelich, Michael C.; Scola, Paul M.; Spero, Denice M.; Yoon, Sunkyung

doi:10.1021/ja00034a086

Cited by 356 publications

(198 citation statements)

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“…Although HB's potent anticancer activity (2)(3)(4) led to interest by the U.S. National Cancer Institute in developing it as a novel chemotherapeutic, supply of HB from aquaculture prevented such efforts (5). Fortunately, HB's synthesis in 1992 by Kishi and colleagues (6)(7)(8), together with discovery that its activity resides in its macrocyclic C1-C38 moiety (Towle MJ, Kishi Y, Littlefield BA, original unpublished data, Eisai Research Institute, 1992; refs. 5, 7, 9, 10), provided both a renewable material source and allowed simplification and optimization.…”

Section: Introductionmentioning

confidence: 99%

Eribulin Induces Irreversible Mitotic Blockade: Implications of Cell-Based Pharmacodynamics for In vivo Efficacy under Intermittent Dosing Conditions

Towle

Salvato²,

Wels³

et al. 2011

Cancer Research

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107

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Eribulin (E7389), a mechanistically unique microtubule inhibitor in phase III clinical trials for cancer, exhibits superior efficacy in vivo relative to the more potent compound ER-076349, a fact not explained by different pharmacokinetic properties. A cell-based pharmacodynamic explanation was suggested by observations that mitotic blockade induced by eribulin, but not ER-076349, is irreversible as measured by a flow cytometric mitotic block reversibility assay employing full dose/response treatment. Cell viability 5 days after drug washout established relationships between mitotic block reversibility and long-term cell survival. Similar results occurred in U937, Jurkat, HL-60, and HeLa cells, ruling out cell type-specific effects. Studies with other tubulin agents suggest that mitotic block reversibility is a quantifiable, compound-specific characteristic of antimitotic agents in general. Bcl-2 phosphorylation patterns parallel eribulin and ER-076349 mitotic block reversibility patterns, suggesting persistent Bcl-2 phosphorylation contributes to long-term cell-viability loss after eribulin's irreversible blockade. Drug uptake and washout/retention studies show that [ Our results suggest that eribulin's in vivo superiority derives from its ability to induce irreversible mitotic blockade, which appears related to persistent drug retention and sustained Bcl-2 phosphorylation. More broadly, our results suggest that compound-specific reversibility characteristics of antimitotic agents contribute to interactions between cell-based pharmacodynamics and in vivo pharmacokinetics that define antitumor efficacy under intermittent dosing conditions. Cancer Res; 71(2); 496-505. Ó2011 AACR.

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Section: Introductionmentioning

confidence: 99%

Eribulin Induces Irreversible Mitotic Blockade: Implications of Cell-Based Pharmacodynamics for In vivo Efficacy under Intermittent Dosing Conditions

Towle

Salvato²,

Wels³

et al. 2011

Cancer Research

Self Cite

132

107

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“…Scarcity of the natural product once hampered efforts to develop halichondrin B as an anticancer drug, but a synthetic and structurally simplified derivative with retained high potency and the biologically active macrocyclic lactone C1 to C38 moiety of the parent compound was developed (3,4). Eribulin seems to exert its cytotoxic effects by interfering with microtubule dynamics (Fig.…”

Section: Pharmacodynamics and Mechanism Of Actionmentioning

confidence: 99%

Eribulin Mesylate

Jain

Vahdat

2011

Clinical Cancer Research

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Eribulin mesylate, a nontaxane, completely synthetic microtubule inhibitor, has recently been approved by the U.S. Food and Drug Administration as third-line treatment of metastatic breast cancer refractory to anthracyclines and taxanes. Eribulin is a synthetic analogue of halichondrin B, which inhibits microtubule polymerization by a mechanism distinct from other available antitubulin agents. Eribulin significantly increased overall survival (OS; median OS for the eribulin-treated group was 13.1 months versus 10.6 months for the group treated by investigator's choice) in a heavily pretreated metastatic breast cancer population. Eribulin has a manageable side-effect profile, notably neutropenia and fatigue, and a relatively low incidence of peripheral neuropathy. The mechanism of action, pharmacokinetics, preclinical antitumor activity, and clinical trials of eribulin in the metastatic breast cancer setting are reviewed here. Clin Cancer Res; 17(21); 6615-22. Ó2011 AACR.

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“…The occurrence in unrelated sponges of structurally similar compounds, particularly those which were otherwise known exclusively from microorganisms, led to speculation that such compounds were of microbial origin [2][3][4]. Since chemical synthesis of natural products can be problematic and expensive due to their structural complexity [5][6][7] the realization that at least some compounds may be produced by microbes raised hopes of obtaining a sustainable, essentially unlimited supply of compounds for testing and subsequent drug production (e.g., via cultivation of the relevant bacteria) [4,8]. The possibility of convergent evolution of biosynthetic pathways among different sponges has also been raised [9].…”

Section: Introduction Bioactive Compounds From Marine Resourcesmentioning

confidence: 99%