Targeting cytochrome P450 (CYP) 1B1 with steroid derivatives

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• 作者：Donald Poirier^a ; ^b ; ^{donald.poirier@crchul.ulaval.ca" class="auth_mail" title="E-mail the corresponding author} ; Jenny Roy^a ; ^b ; Francisco Corté ; s-Bení ; tez^a ; ^c ; Raphaë ; l Dutour^a ; ^b
• 关键词：CYP1B1 ; Enzyme ; Inhibitor ; Screening ; Steroid
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 November 2016
• 年：2016
• 卷：26
• 期：21
• 页码：5272-5276
• 全文大小：1057 K

文摘

Inhibition of cytochrome P450 1B1 (CYP1B1) represents a promising therapeutic strategy, because it would enable action at three different levels: (1) by inhibiting the formation of mutagenic 4-hydroxy-estradiol, (2) by inhibiting the bioactivation of procarcinogens, and (3) by reducing drug-resistance. Surprisingly, few steroids were reported as inhibitors of CYP1B1. From a screening performed with 90 steroid derivatives, we identified thioestrone (class="boldFont">B19) as an inhibitor (IC₅₀ = 3.4 μM) of CYP1B1. Molecular modeling studies showed that the 3-SH group of class="boldFont">B19 is closer (3.36 Å) to the iron atom of the heme system than the 3-OH group of enzyme substrates estrone and estradiol (4.26 Å and 3.58 Å, respectively). class="boldFont">B19 also produced a better docking GOLD score that correlated with the inhibitory results obtained. The estrane derivative class="boldFont">B19 represents an interesting lead compound that can be easily modified to extend the structure–activity relationship study and to provide a next generation of more powerful CYP1B1 inhibitors.