1. Identification and optimization of biphenyl derivatives as novel tubulin inhibitors targeting colchicine-binding site overcoming multidrug resistance.
- Author
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Cheng B, Zhu G, Meng L, Wu G, Chen Q, and Ma S
- Subjects
- Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Binding Sites drug effects, Biphenyl Compounds chemical synthesis, Biphenyl Compounds chemistry, Cell Proliferation drug effects, Colchicine chemistry, Dose-Response Relationship, Drug, Drug Resistance, Neoplasm drug effects, Drug Screening Assays, Antitumor, Female, Humans, Mammary Neoplasms, Experimental drug therapy, Mammary Neoplasms, Experimental metabolism, Mammary Neoplasms, Experimental pathology, Mice, Mice, Inbred BALB C, Microtubules drug effects, Microtubules metabolism, Molecular Structure, Polymerization drug effects, Structure-Activity Relationship, Tubulin Modulators chemical synthesis, Tubulin Modulators chemistry, Tumor Cells, Cultured, Antineoplastic Agents pharmacology, Biphenyl Compounds pharmacology, Colchicine pharmacology, Drug Resistance, Multiple drug effects, Tubulin metabolism, Tubulin Modulators pharmacology
- Abstract
Microtubule targeting agents (MTAs) are among the most successful chemotherapeutic drugs, but their efficacy is often limited by the development of multidrug resistance (MDR). Therefore, the development of novel MTAs with the ability to overcome MDR is urgently needed. In this contribution, through modification of the unsymmetric biaryl compounds, we discovered a novel compound dxy-1-175 with potent anti-proliferative activity against cancer cells. Mechanistic study revealed that dxy-1-175 inhibited tubulin polymerization by interacting with the colchicine-binding site of tubulin, which caused cell cycle arrest at G
2 /M phase. Based on the predicted binding model of dxy-1-175 with tubulin, a series of new 4-benzoylbiphenyl analogues were designed and synthesized. Among them, the hydrochloride compound 12e with improved solubility and good stability in human liver microsome, exhibited the most potent anti-proliferative activity with IC50 value in the low nanomolar range, and markedly inhibited the growth of breast cancer 4T1 xenograft in vivo. Notably, 12e effectively overcame P-gp-mediated MDR and our preliminary data suggested that 12e may not be a substrate of P-glycoprotein (P-gp). Taken together, our study reveals a novel MTA 12e targeting the colchicine-binding site with potent anticancer activity and the ability to circumvent MDR., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier Masson SAS.)- Published
- 2022
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