Design, synthesis, biological activity evaluation and structure-activity relationships of new steroidal aromatase inhibitors. The case of C-ring and 7β substituted steroids

化学 芳香化酶 戒指(化学) 立体化学 依西美坦 甲基 类固醇 区域选择性 结构-活动关系 体外 有机化学 生物化学 群(周期表) 催化作用 医学 癌症 乳腺癌 激素 内科学
作者
Fernanda M.F. Roleira,Saúl C. Costa,Ana R. Gomes,Carla Varela,Cristina Amaral,Tiago V. Augusto,Georgina Correia‐da‐Silva,Isabella Romeo,Giosuè Costa,Stefano Alcaro,Natércia Teixeira,E. J. Tavares da Silva
出处
期刊:Bioorganic Chemistry [Elsevier]
卷期号:131: 106286-106286 被引量:6
标识
DOI:10.1016/j.bioorg.2022.106286
摘要

In this work, new steroidal aromatase inhibitors (AIs) were designed, synthesized, and tested. In one approach, C-ring substituted steroids namely those functionalized at C-11 position with an α or β hydroxyl group or with a carbonyl group as well as C-9/C-11 steroidal olefins and epoxides were studied. It was found that the carbonyl group at C-11 is more beneficial for aromatase inhibition than the hydroxyl group, and that the C-ring epoxides were more potent than the C-ring olefins, leading to the discovery of a very strong AI, compound 7, with an IC50 of 0.011 μM, better than Exemestane, the steroidal AI in clinical use, which presents an IC50 of 0.050 μM. In another approach, we explored the biological activity of A-ring C-1/C-2 steroidal olefins and epoxides in relation to aromatase inhibition and compared it with the biological activity of C-ring C-9/C-11 steroidal olefins and epoxides. On the contrary to what was observed for the C-ring olefins and epoxides, the A-ring epoxides were less potent than A-ring olefins. Finally, the effect of 7β-methyl substitution on aromatase inhibition was compared with 7α-methyl substitution, showing that 7β-methyl is better than 7α-methyl substitution. Molecular modelling studies showed that the 7β-methyl on C-7 seems to protrude into the opening to the access channel of aromatase in comparison to the 7α-methyl. This comparison led to find the best steroidal AI (12a) of this work with IC50 of 0.0058 μM. Compound 12a showed higher aromatase inhibition capacity than two of the three AIs currently in clinical use.
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