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Letters in Drug Design & Discovery

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ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

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Research Article

Design, Synthesis and Biological Evaluation of Dimethyl Cardamonin (DMC) Derivatives as P-glycoprotein-mediated Multidrug Resistance Reversal Agents

Author(s): Ximeng Shi, Yuyu Zhao, Licheng Zhou, Huanhuan Yin, Jianwen Liu* and Lei Ma*

Volume 17, Issue 10, 2020

Page: [1270 - 1282] Pages: 13

DOI: 10.2174/1570180817999200531162015

Price: $65

Abstract

Background: P-glycoprotein (P-gp) has been regarded as an important factor in the multidrug resistance (MDR) of tumor cells within the last decade, which can be solved by inhibiting Pgp to reverse MDR. Thus, it is an effective strategy to develop inhibitor of P-gp.

Objective: In this study, the synthesis of a series of derivatives had been carried out by bioisosterism design on the basis of Dimethyl Cardamonin (DMC). Subsequently, we evaluated their reversal activities as potential P-glycoprotein (P-gp)-mediated Multidrug Resistance (MDR) agents.

Methods: Dimethyl cardamonin derivatives were synthesized from acetophenones and the corresponding benzaldehydes in the presence of 40% KOH by Claisen-Schmidt reaction. Their cytotoxicity and reversal activities in vitro were assessed with MTT. Moreover, the compound B4 was evaluated by Doxorubicin (DOX) accumulation, Western blot and wound-healing assays deeply.

Results and Discussion: The results showed that compounds B2, B4 and B6 had the potency of MDR reversers with little intrinsic cytotoxicity. Meanwhile, these compounds also demonstrated the capability to inhibit MCF-7 and MCF-7/DOX cells migration. Besides, the most compound B4 was selected for further study, which promoted the accumulation of DOX in MCF-7/DOX cells and inhibited the expressionof P-gp at protein levels.

Conclusion: The above findings may provide new insights for the research and development of Pgp- mediated MDR reversal agents.

Keywords: MDR reversal agents, P-glycoprotein, DMC derivatives, bioisosterism, drug design, cell migration.

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