2. Academic Validation
  3. Design, synthesis and biological evaluation of seco-DSP/DCK derivatives reversing P-glycoprotein-mediated paclitaxel resistance in A2780/T cells

Design, synthesis and biological evaluation of seco-DSP/DCK derivatives reversing P-glycoprotein-mediated paclitaxel resistance in A2780/T cells

  • Eur J Med Chem. 2023 Mar 15;250:115218. doi: 10.1016/j.ejmech.2023.115218.
Weijie Wang 1,  Qi Wan 1,  Mengru Li 2,  Feng Qu 1,  Hongrui Liu 3,  Ying Chen 4
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, 201203, China.
  • 2 Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, 201203, China.
  • 3 Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, 201203, China. Electronic address: [email protected].
  • 4 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, 201203, China. Electronic address: [email protected].
PMID: 36871374 DOI: 10.1016/j.ejmech.2023.115218
Abstract

P-glycoprotein transporter (P-gp, ABCB1) is a major contributor to multidrug resistance, making it a valuable target for the development of novel P-gp inhibitor to overcome multidrug resistance. In this study, forty-nine novel seco-DSPs and seco-DMDCK derivatives were synthesized and evaluated their chemo-sensitize abilities to paclitaxel in A2780/T cell lines. Most of them exhibited a comparable reversal multidrug-resistance activity than verapamil. Especially, compound 27f showed a remarkable chemo-sensitization with more than 425-fold reversal ratio in A2780/T cells. The study of preliminary pharmacological mechanism displayed that compound 27f was more effective to increase the accumulation of paclitaxel and Rhodamine 123 than verapamil via inhibiting P-gp for reversing multidrug-resistance. In addition, a higher than 40 μM IC50 values of hERG Potassium Channel inhibition concentration suggested that compound 27f hardly had relevant cardiac toxicity. These results indicated that compound 27f might be a potential candidate to further investigate for the development of chemosensitizer with MDR reversal activity.

Keywords

Chemosensitizer; Coumarin; MDR reversal activity; P-glycoprotein.

Figures
Products