Abstract
We previously reported a potent tubulin inhibitor CH-2-77. In this study, we optimized the structure of CH-2-77 by blocking metabolically labile sites and synthesized a series of CH-2-77 analogues. Two compounds, 40a and 60c, preserved the potency while improving the metabolic stability over CH-2-77 by 3- to 4-fold (46.8 and 29.4 vs 10.8 min in human microsomes). We determined the high-resolution X-ray crystal structures of 40a (resolution 2.3 Å) and 60c (resolution 2.6 Å) in complex with tubulin and confirmed their direct binding at the colchicine-binding site. In vitro, 60c maintained its mode of action by inhibiting tubulin polymerization and was effective against P-glycoprotein-mediated multiple drug resistance and taxol resistance. In vivo, 60c exhibited a strong inhibitory effect on tumor growth and metastasis in a taxol-resistant A375/TxR xenograft model without obvious toxicity. Collectively, this work showed that 60c is a promising lead compound for further development as a potential anticancer agent.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / metabolism
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / therapeutic use*
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Binding Sites
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Drug Design
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Drug Screening Assays, Antitumor
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Drug Stability
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Female
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G2 Phase Cell Cycle Checkpoints / drug effects
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Humans
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Male
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Mice
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Mice, Inbred NOD
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Mice, SCID
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Microsomes, Liver / metabolism
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Molecular Structure
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Neoplasm Metastasis / prevention & control
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Neoplasms / drug therapy*
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Pyridines / chemical synthesis
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Pyridines / metabolism
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Pyridines / pharmacokinetics
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Pyridines / therapeutic use*
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Structure-Activity Relationship
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Tubulin / chemistry
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Tubulin / metabolism*
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Tubulin Modulators / chemical synthesis
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Tubulin Modulators / metabolism
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Tubulin Modulators / pharmacokinetics
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Tubulin Modulators / therapeutic use*
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Pyridines
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Tubulin
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Tubulin Modulators