Expansion of the 4-(Diethylamino)benzaldehyde Scaffold to Explore the Impact on Aldehyde Dehydrogenase Activity and Antiproliferative Activity in Prostate Cancer

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2022 Feb 25

PMID 35212533

Authors

Ali I M Ibrahim

Elisabet Batlle

Smarakan Sneha

Rafael Jimenez

Raquel Pequerul

Xavier Pares

Till Rungeler

Vibhu Jha

Tiziano Tuccinardi

Maria Sadiq

Fiona Frame

Norman J Maitland

Jaume Farres

Klaus Pors

Affiliations

Soon will be listed here.

Abstract

Aldehyde dehydrogenases (ALDHs) are overexpressed in various tumor types including prostate cancer and considered a potential target for therapeutic intervention. 4-(Diethylamino)benzaldehyde (DEAB) has been extensively reported as a pan-inhibitor of ALDH isoforms, and here, we report on the synthesis, ALDH isoform selectivity, and cellular potencies in prostate cancer cells of 40 DEAB analogues; three analogues (, , and ) showed potent inhibitory activity against ALDH1A3, and two analogues ( and ) showed potent inhibitory activity against ALDH3A1. Significantly, 16 analogues displayed increased cytotoxicity (IC = 10-200 μM) compared with DEAB (>200 μM) against three different prostate cancer cell lines. Analogues and were more potent than DEAB against patient-derived primary prostate tumor epithelial cells, as single agents or in combination treatment with docetaxel. In conclusion, our study supports the use of DEAB as an ALDH inhibitor but also reveals closely related analogues with increased selectivity and potency.

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