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Pyrrole-Based Antitubulin Agents: Two Distinct Binding Modalities are Predicted for C-2 Analogs in the Colchicine Site.

ABSTRACT: 3,5-dibromo-4-(3,4-dimethoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester is a promising antitubulin lead agent that targets the colchicine site of tubulin. C-2 analogs were synthesized and tested for microtubule depolymerizing and antiproliferative activity. Molecular modeling studies using both GOLD docking and HINT (Hydropathic INTeraction) scoring revealed two distinct binding modes that explain the structural-activity relationships and are in accord with the structural basis of colchicine binding to tubulin. The binding mode of higher activity compounds is buried deeper in the site and overlaps well with rings A and C of colchicine, while the lower activity binding mode shows fewer critical contacts with tubulin. The model distinguishes highly active compounds from those with weaker activities and provides novel insights into the colchicine site and compound design.

SUBMITTER: Da C

PROVIDER: S-EPMC3352664 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Pyrrole-Based Antitubulin Agents: Two Distinct Binding Modalities are Predicted for C-2 Analogs in the Colchicine Site.

Da Chenxiao C Telang Nakul N Barelli Peter P Jia Xin X Gupton John T JT Mooberry Susan L SL Kellogg Glen E GE

ACS medicinal chemistry letters 20111101 1

3,5-dibromo-4-(3,4-dimethoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester is a promising antitubulin lead agent that targets the colchicine site of tubulin. C-2 analogs were synthesized and tested for microtubule depolymerizing and antiproliferative activity. Molecular modeling studies using both GOLD docking and HINT (Hydropathic INTeraction) scoring revealed two distinct binding modes that explain the structural-activity relationships and are in accord with the structural basis of colchicin ...[more]

PMID: 22611477

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Project description:IntroductionOne of the main reasons for disease recurrence in the curative breast cancer treatment setting is the development of drug resistance. Microtubule targeted agents (MTAs) are among the most commonly used drugs for the treatment of breaset cancer and therefore overcoming taxane resistance is of primary clinical importance. Our group has previously demonstrated that the microtubule dynamics of docetaxel-resistant MCF-7TXT cells are insensitivity to docetaxel due to the distinct expression profiles of β-tubulin isotypes in addition to the high expression of p-glycoprotein (ABCB1). In the present investigation we examined whether taxane-resistant breast cancer cells are more sensitive to microtubule destabilizing agents including vinca alkaloids and colchicine-site binding agents (CSBAs) than the non-resistant cells.MethodsTwo isogenic MCF-7 breast cancer cell lines were selected for resistance to docetaxel (MCF-7TXT) and the wild type parental cell line (MCF-7CC) to examine if taxane-resistant breast cancer cells are sensitive to microtubule-destabilizing agents including vinca alkaloids and CSBAs. Cytotoxicity assays, immunoblotting, indirect immunofluorescence and live imaging were used to study drug resistance, apoptosis, mitotic arrest, microtubule formation, and microtubule dynamics.ResultsMCF-7TXT cells were demonstrated to be cross resistant to vinca alkaloids, but were more sensitive to treatment with colchicine compared to parental non-resistant MCF-7CC cells. Cytotoxicity assays indicated that the IC50 of MCF-7TXT cell to vinorelbine and vinblastine was more than 6 and 3 times higher, respectively, than that of MCF-7CC cells. By contrast, the IC50 of MCF-7TXT cell for colchincine was 4 times lower than that of MCF-7CC cells. Indirect immunofluorescence showed that all MTAs induced the disorganization of microtubules and the chromatin morphology and interestingly each with a unique pattern. In terms of microtubule and chromain morphology, MCF-7TXT cells were more resistant to vinorelbine and vinblastine, but more sensitive to colchicine compared to MCF-7CC cells. PARP cleavage assay further demonstrated that all of the MTAs induced apoptosis of the MCF-7 cells. However, again, MCF-7TXT cells were more resistant to vinorelbine and vinblastine, and more sensitive to colchicine compared to MCF-7CC cells. Live imaging demonstrated that the microtubule dynamics of MCF-7TXT cells were less sensitive to vinca alkaloids, and more sensitive to colchicine. MCF-7TXT cells were also noted to be more sensitive to other CSBAs including 2MeOE2, ABT-751 and phosphorylated combretastatin A-4 (CA-4P).ConclusionDocetaxel-resistant MCF-7TXT cells have demonstrated cross-resistance to vinca alkaloids, but appear to be more sensitive to CSBAs (colchicine, 2MeOE2, ABT-751 and CA-4P) compared to non-resistant MCF-7CC cells. Taken together these results suggest that CSBAs should be evaluated further in the treatment of taxane resistant breast cancer.

Dataset Information

Pyrrole-Based Antitubulin Agents: Two Distinct Binding Modalities are Predicted for C-2 Analogs in the Colchicine Site.

Publications

Pyrrole-Based Antitubulin Agents: Two Distinct Binding Modalities are Predicted for C-2 Analogs in the Colchicine Site.

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