1. α-naphthoflavone-derived cytochrome P450 (CYP)1B1 degraders specific for sensitizing CYP1B1-mediated drug resistance to prostate cancer DU145: Structure activity relationship.
- Author
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Chen P, Wang S, Cao C, Ye W, Wang M, Zhou C, Chen W, Zhang X, Zhang K, and Zhou W
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Benzoflavones chemical synthesis, Benzoflavones chemistry, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Cytochrome P-450 CYP1B1 metabolism, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Male, Molecular Structure, Prostatic Neoplasms metabolism, Prostatic Neoplasms pathology, Solubility, Structure-Activity Relationship, Antineoplastic Agents pharmacology, Benzoflavones pharmacology, Cytochrome P-450 CYP1B1 antagonists & inhibitors, Drug Resistance, Neoplasm drug effects, Prostatic Neoplasms drug therapy
- Abstract
We previously discovered extrahepatic cytochrome P450 1B1 (CYP1B1) degraders able to overcome drug resistance toward docetaxel using a PROTACs technology, however, the underexplored structure activity relationships and poor water solubility posed a major hurdle in the development of CYP1B1 degraders. Herein, continuous efforts are made to develop more promising α-naphthoflavone (ANF)-derived chimeras for degrading CYP1B1. Guided by the strongest ANF-derived CYP1B1 degrader 3a we ever reported, 17 ANF analogues are designed and synthesized to evaluate the CYP1B1 degradation and resultant resistance reversal. In degrading CYP1B1 and sensitizing drug resistance, 4d with a 1, 5-cis triazole coupling mode at (C3') of B ring of ANF exhibited the similar potency as 3a carrying a 1, 4-trans triazole fragment at (C4') of B ring, but more obvious selectivity of 4d toward CYP1B1 over CYP1A2 is observed. When an oxygen was inserted into the linker of 4d, 4f demonstrated better water solubility, a more potent ability in degrading CYP1B1 and reversing drug resistance, and a promising selectivity. Collectively, a substitution position, an alkyne-azide cyclization and a liker type significantly affect the ability of ANF-thalidomide conjugates in eliminating drug resistance of CYP1B1-expressing DU145 (DU145/CY) cells to docetaxel via targeted CYP1B1 degradation., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
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