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

(E-pub Ahead of Print)

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

Journal Name: Letters in Drug Design & Discovery

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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. And their cytotoxicity and reversal activities in vitro were assessed with MTT. Moreover, the compound B4 were evaluated by doxorubicin (DOX) accumulation, Western blot and wound-healing assays deeply.

Results: The results showed that compounds B2, B4 and B6 had 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 expression of P-gp at protein levels.

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

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

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Article Details

(E-pub Ahead of Print)
DOI: 10.2174/1570180817999200531162015
Price: $95

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