Synthesis and evaluation of novel tetrahydroisoquinoline-benzo[h]chromen-4-one conjugates as dual ABCB1/CYP1B1 inhibitors for overcoming MDR in cancer.

Autor: Dong J; Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China. Electronic address: dongjinyun1989@163.com., Li Y; Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China., Jin Z; Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China., Wu Z; Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China., Cai M; Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China., Pan G; Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China., Ye W; Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 200241 Shanghai, China., Zhou W; Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 200241 Shanghai, China., Li Z; College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA., Tian S; Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China., Chen ZS; College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA., Qin JJ; Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China. Electronic address: jqin@ucas.ac.cn.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2024 Nov 15; Vol. 114, pp. 117944. Date of Electronic Publication: 2024 Oct 11.
DOI: 10.1016/j.bmc.2024.117944
Abstrakt: The emergence of multidrug resistance (MDR) in malignant tumors is one of the major threats encountered currently by many chemotherapeutic agents. Among the various mechanisms involved in drug resistance, P-glycoprotein (P-gp, ABCB1), a member of the ABC transporter family that significantly increases the efflux of various anticancer drugs from tumor cells, and the metabolic enzyme CYP1B1 are widely considered to be two critical targets for overcoming MDR. Unfortunately, no MDR modulator has been approved by the FDA to date. In this study, based on pharmacophore hybridization, bioisosteric and fragment-growing strategies, we designed and synthesized 11 novel tetrahydroisoquinoline-benzo[h]chromen-4-one conjugates as dual ABCB1/CYP1B1 inhibitors. Among them, the preferred compound A10 exhibited the best MDR reversal activity (IC 50  = 0.25 μM, RF = 44.4) in SW620/AD300 cells, being comparable to one of the most potent third-generation P-gp inhibitors WK-X-34. In parallel, this dual ABCB1/CYP1B1 inhibitory effect drives compound A10 exhibiting prominent drug resistance reversal activity to doxorubicin (IC 50  = 4.7 μM, RF = 13.7) in ABCB1/CYP1B1-overexpressing DOX-SW620/AD300-1B1 resistant cells, which is more potent than that of the CYP1B1 inhibitor ANF. Furthermore, although compound A2 possessed moderate ABCB1/CYP1B1 inhibitory activity, it showed considerable antiproliferative activity towards drug-resistant SW620/AD300 and MKN45-DDP-R cells, which may be partly related to the increase of PUMA expression to promote the apoptosis of the drug-resistant MKN45-DDP-R cells as confirmed by proteomics and western blot assay. These results indicated that the tetrahydroisoquinoline-benzo[h]chromen-4-one conjugates may provide a fundamental scaffold reference for further discovery of MDR reversal agents.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jinyun Dong reports financial support was provided by the National Natural Science Foundation of China. If there are other authors, they 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 © 2024 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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