Abstract
BPR0L075 (2) is a potential anticancer drug candidate designed from Combretastatin A-4 (1) based on the bioisosterism principle. Metabolites of 2, proposed from in vitro human microsome studies, were synthesized, leading to the identification of metabolite-derived analogue 10 with 40-350 pM potency against various cancer cell lines. Insights gained from the major inactive metabolite of 2 led to the development of 29, with better pharmacokinetics and improved potency in the tumor xenograft model than 2.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology
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Cell Line, Tumor
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Colchicine / metabolism
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Drug Design
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Humans
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Indoles / chemical synthesis*
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Indoles / metabolism
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Indoles / pharmacokinetics
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Indoles / pharmacology
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Mice
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Rats
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Structure-Activity Relationship
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Tubulin Modulators / chemical synthesis
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Tubulin Modulators / pharmacology
Substances
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6-methoxy-3-(3',4',5'-trimethoxybenzoyl)-1H-indole
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Antineoplastic Agents
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Indoles
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Tubulin Modulators
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Colchicine