Inhibition of cytochrome P450 (CYP) 1B1 is a promising therapeutic strategy, as such an inhibitor could modulate the bioactivation of procarcinogens while reducing drug resistance. Based on docking studies, the synthesis of 12 estra-1,3,5(10)-triene derivatives containing a pyridin-3-/4-yl moiety at position C2, C3, or C4 was performed, and we measured their inhibitory activity on CYP1B1 using the ethoxyresorufin-O-deethylase (EROD) assay. The position of the nitrogen atom in the aromatic ring has little influence on their inhibition potency, but compounds with a pyridinyl at C2 of the steroid nucleus are more potent CYP1B1 inhibitors than those with a pyridinyl at C3 or C4. Estradiol derivatives (OH at C17β) are also 10-fold more potent inhibitors than estrone derivatives (carbonyl at C17). Thus, 2-(pyridin-3-yl)-estradiol (4a) is the best CYP1B1 inhibitor (IC₅₀ = 0.011 μM) from this series of compounds, and the best steroid inhibitor reported until now. It is also 7.5-fold more potent than the well-known nonsteroidal CYP1B1 inhibitor α-naphthoflavone (IC₅₀ = 0.083 μM).

中文翻译：

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基于结构的设计和合成新型Estrane-吡啶衍生物作为细胞色素P450（CYP）1B1抑制剂

抑制细胞色素P450（CYP）1B1是一种有前途的治疗策略，因为这种抑制剂可调节致癌物的生物激活，同时降低耐药性。根据对接研究，合成了12个在位置C2，C3或C4处含有吡啶-3- / 4-基部分的estra-1,3,5（10）-三烯衍生物，并测定了它们的抑制活性乙氧基间苯二酚-O对CYP1B1的作用-脱乙基酶（EROD）分析。芳香环中氮原子的位置对其抑制力影响不大，但在甾类原子核C2处具有吡啶基的化合物比在C3或C4处具有吡啶基的化合物更有效的CYP1B1抑制剂。雌二醇衍生物（C17β处的OH）也比雌酮衍生物（C17处的羰基）有效抑制剂高10倍。因此，2-（吡啶-3-基）-雌二醇（4a）是该系列化合物中最好的CYP1B1抑制剂（IC ₅₀ = 0.011μM），也是迄今为止报道的最好的类固醇抑制剂。它的效力也比著名的非甾体CYP1B1抑制剂α-萘黄酮（IC ₅₀ = 0.083μM）高7.5倍。