Marine-Derived Bromotyrosine Alkaloids as Potent hCYP1B1 Inhibitors to Overcome Paclitaxel Resistance.
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| Autori principali: | , , , , , , , , , , |
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| Natura: | Artículo científico |
| Lingua: | en |
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Journal of medicinal chemistry
2026
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| _version_ | 1868266092663668738 |
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| author | 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 |
| author_facet | 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 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 |
| collection | PubMed - marine biology |
| 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. |
| format | Artículo científico |
| id | pubmed_41614618 |
| institution | PubMed |
| language | en |
| publishDate | 2026 |
| publisher | Journal of medicinal chemistry |
| record_format | pubmed |
| spellingShingle | 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 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. |
| title | Marine-Derived Bromotyrosine Alkaloids as Potent hCYP1B1 Inhibitors to Overcome Paclitaxel Resistance. |
| topic | Humans Drug Resistance, Neoplasm Paclitaxel Animals Alkaloids Structure-Activity Relationship Cell Line, Tumor Cytochrome P-450 CYP1B1 Tyrosine Mice Antineoplastic Agents |
| url | https://pubmed.ncbi.nlm.nih.gov/41614618/ |