A small library of both [2,3-h] and [3,2-f] novel pyrroloquinolines equipped with an azolylmethyl group was designed and synthesized as non steroidal CYP19 aromatase inhibitors. The results showed that azolylmethyl derivatives 11, 13, 14, 21 and 22 exhibited an inhibitory potency on aromatase comparable to Letrozole chosen as a reference compound. When assayed on CYP11B1 (steroid-11β-hydroxylase) and CYP17 (17α-hydroxy/17,20-lyase), compound 22 was found to be the best and most selective CYP19 inhibitor of them all. In a panel of nine human cancer cell lines, all compounds were either slightly cytotoxic or not at all. Docking simulations were carried out to inspect crucial enzyme/inhibitor interactions such as hydrophobic interactions, hydrogen bonding and heme iron coordination. This study, along with the prediction of the pharmacokinetics of compounds 11, 13, 14, 21 and 22, demonstrates that the pyrroloquinoline scaffold represents a starting point for the development of new pyrroloquinoline-based aromatase inhibitors.

Design, Synthesis, and Structure–Activity Relationships of Azolylmethylpyrroloquinolines as Nonsteroidal Aromatase Inhibitors

FERLIN, MARIA GRAZIA;CARTA, DAVIDE;BORTOLOZZI, ROBERTA;MORO, STEFANO;BASSO, GIUSEPPE;VIOLA, GIAMPIETRO
2013

Abstract

A small library of both [2,3-h] and [3,2-f] novel pyrroloquinolines equipped with an azolylmethyl group was designed and synthesized as non steroidal CYP19 aromatase inhibitors. The results showed that azolylmethyl derivatives 11, 13, 14, 21 and 22 exhibited an inhibitory potency on aromatase comparable to Letrozole chosen as a reference compound. When assayed on CYP11B1 (steroid-11β-hydroxylase) and CYP17 (17α-hydroxy/17,20-lyase), compound 22 was found to be the best and most selective CYP19 inhibitor of them all. In a panel of nine human cancer cell lines, all compounds were either slightly cytotoxic or not at all. Docking simulations were carried out to inspect crucial enzyme/inhibitor interactions such as hydrophobic interactions, hydrogen bonding and heme iron coordination. This study, along with the prediction of the pharmacokinetics of compounds 11, 13, 14, 21 and 22, demonstrates that the pyrroloquinoline scaffold represents a starting point for the development of new pyrroloquinoline-based aromatase inhibitors.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11577/2684131
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