Expansion of the 4-(Diethylamino)benzaldehyde Scaffold to Explore the Impact on Aldehyde Dehydrogenase Activity and Antiproliferative Activity in Prostate Cancer
Ibrahim, Ali I. M. (Al-Zaytoonah University of Jordan)
Batlle, Elisabet (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Sneha, Smarakan (University of Bradford)
Jiménez, Rafael (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Pequerul, Raquel (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Parés i Casasampera, Xavier (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Rüngeler, Till (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Jha, Vibhu (University of Pisa. Department of Pharmacy)
Tuccinardi, Tiziano (University of Pisa. Department of Pharmacy)
Sadiq, Maria (University of York. Department of Biology)
Frame, Fiona (University of York. Department of Biology)
Maitland, Norman J. (University of York. Department of Biology)
Farrés, Jaume (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Pors, Klaus (University of Bradford)

Date:	2022
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 (14, 15, and 16) showed potent inhibitory activity against ALDH1A3, and two analogues (18 and 19) 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 14 and 18 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.
Grants:	Agencia Estatal de Investigación PID-2020-119424-RB-I00
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Published in:	Journal of Medicinal Chemistry, Vol. 65, Issue 5 (February 2022) , p. 3833-3848, ISSN 1520-4804

DOI: 10.1021/acs.jmedchem.1c01367
PMID: 35212533

16 p, 4.0 MB

The record appears in these collections:
Articles > Research articles
Articles > Published articles