Marine-Derived Bromotyrosine Alkaloids as Potent hCYP1B1 Inhibitors to Overcome Paclitaxel Resistance

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 (10) as a potent hCYP1B1 inhibitor (IC₅₀ = 11.89 nM). SAR-guided optimization led to a methylated oxime derivative 26a, which exhibited a nearly 10-fold improvement in activity (IC₅₀ = 1.32 nM). Mechanistic studies revealed that 26a competitively binds to the hCYP1B1 catalytic pocket, supported by inhibition kinetics (K_i = 0.72 μM) and molecular dynamics simulations. In live cells, 26a inhibited hCYP1B1-mediated 17β-estradiol hydroxylation (IC₅₀ = 2.21 μM) and reversed paclitaxel (PTX) resistance in both A549/PTX and H460/PTX cells (22.9-26.5-fold sensitization). In vivo, 26a synergized antitumor effects with PTX in an A549/PTX xenograft model (41.1% tumor growth inhibition) without evident toxicity. Collectively, 26a represents a novel marine-derived, metabolically stable hCYP1B1 inhibitor with high potential to reverse chemoresistance.