In this work, new potent steroidal aromatase inhibitors both in microsomes and in breast cancer cells have been found. The synthesis of the 3,4-(ethylenedioxy)androsta-3,5-dien-17-one (12), a new steroid containing a heterocycle dioxene fused in the A-ring, led to the discovery of a new reaction for which a mechanism is proposed. New structure-activity relationships were established. Some 5 beta-steroids, such as compound 4 beta,5 beta-epoxyandrostan-17-one (9), showed aromatase inhibitory activity, because they adopt a similar A-ring conformation as those of androstenedione, the natural substrate of aromatase. Moreover, new chemical features to increase planarity were disclosed, specifically the 3 alpha,4 alpha-cyclopropane ring, as in 3 alpha,4 alpha-methylen-5 alpha-androstan-17-one (5) (IC50 = 0.11 mu M), and the Delta(9-11) double bond in the C-ring, as in androsta-4,9(11)-diene-3,17-dione (13) (IC50 = 0.25 mu M). In addition, induced-fit docking (IFD) simulations and site of metabolism (SoM) predictions helped to explain the recognition of new potent steroidal aromatase inhibitors within the enzyme. These insights can be valuable tools for the understanding of the molecular recognition process by the aromatase and for the future design of new steroidal inhibitors. (C) 2016 Elsevier Ltd. All rights reserved.
Exploring new chemical functionalities to improve aromatase inhibition of steroids
Costa G;Alcaro S;
2016-01-01
Abstract
In this work, new potent steroidal aromatase inhibitors both in microsomes and in breast cancer cells have been found. The synthesis of the 3,4-(ethylenedioxy)androsta-3,5-dien-17-one (12), a new steroid containing a heterocycle dioxene fused in the A-ring, led to the discovery of a new reaction for which a mechanism is proposed. New structure-activity relationships were established. Some 5 beta-steroids, such as compound 4 beta,5 beta-epoxyandrostan-17-one (9), showed aromatase inhibitory activity, because they adopt a similar A-ring conformation as those of androstenedione, the natural substrate of aromatase. Moreover, new chemical features to increase planarity were disclosed, specifically the 3 alpha,4 alpha-cyclopropane ring, as in 3 alpha,4 alpha-methylen-5 alpha-androstan-17-one (5) (IC50 = 0.11 mu M), and the Delta(9-11) double bond in the C-ring, as in androsta-4,9(11)-diene-3,17-dione (13) (IC50 = 0.25 mu M). In addition, induced-fit docking (IFD) simulations and site of metabolism (SoM) predictions helped to explain the recognition of new potent steroidal aromatase inhibitors within the enzyme. These insights can be valuable tools for the understanding of the molecular recognition process by the aromatase and for the future design of new steroidal inhibitors. (C) 2016 Elsevier Ltd. All rights reserved.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
