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| Main Authors: | , , , , , , , , , , |
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| Format: | Artículo científico |
| Language: | en |
| Published: |
Journal of medicinal chemistry
2026
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| Subjects: | |
| Online Access: | https://pubmed.ncbi.nlm.nih.gov/41614618/ |
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Table of Contents:
- Marine-Derived Bromotyrosine Alkaloids as Potent hCYP1B1 Inhibitors to Overcome Paclitaxel Resistance. Xu, Quan Xiong, Yuan Fang, Yanfen Zhao, Bei Yang, Biyu Hao, Yu-Meng Dai, Hong-Xia Zhang, Xiangyang Chen, Yi Ge, Guang-Bo Li, Xu-Wen Humans Drug Resistance, Neoplasm Paclitaxel Animals Alkaloids Structure-Activity Relationship Cell Line, Tumor Cytochrome P-450 CYP1B1 Tyrosine Mice Antineoplastic Agents Human cytochrome P450 1B1 (hCYP1B1) overexpression is strongly associated with tumor drug resistance, making it an attractive target for overcoming chemotherapeutic resistance. Screening of a marine natural product library identified purpuramine D () as a potent hCYP1B1 inhibitor (IC = 11.89 nM). SAR-guided optimization led to a methylated oxime derivative , which exhibited a nearly 10-fold improvement in activity (IC = 1.32 nM). Mechanistic studies revealed that competitively binds to the hCYP1B1 catalytic pocket, supported by inhibition kinetics ( = 0.72 μM) and molecular dynamics simulations. In live cells, inhibited hCYP1B1-mediated 17β-estradiol hydroxylation (IC = 2.21 μM) and reversed paclitaxel (PTX) resistance in both A549/PTX and H460/PTX cells (22.9-26.5-fold sensitization). , synergized antitumor effects with PTX in an A549/PTX xenograft model (41.1% tumor growth inhibition) without evident toxicity. Collectively, represents a novel marine-derived, metabolically stable hCYP1B1 inhibitor with high potential to reverse chemoresistance.