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

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

  • J Med Chem. 2022 Mar 10;65(5):3833-3848. doi: 10.1021/acs.jmedchem.1c01367.
Ali I M Ibrahim 1 2,  Elisabet Batlle 1 3,  Smarakan Sneha 1,  Rafael Jiménez 3,  Raquel Pequerul 3,  Xavier Parés 3,  Till Rüngeler 3,  Vibhu Jha 4,  Tiziano Tuccinardi 4,  Maria Sadiq 1 5,  Fiona Frame 5,  Norman J Maitland 5,  Jaume Farrés 3,  Klaus Pors 1
Affiliations

Affiliations

  • 1 Institute of Cancer Therapeutics, School of Pharmacy and Medical Sciences, Faculty of Life Sciences, University of Bradford, Yorkshire BD7 1DP, U.K.
  • 2 Faculty of Pharmacy, Al-Zaytoonah University of Jordan, Amman 11733, Jordan.
  • 3 Department of Biochemistry and Molecular Biology, Faculty of Biosciences, Universitat Autònoma de Barcelona, Bellaterra, Barcelona E-08193, Spain.
  • 4 Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy.
  • 5 Cancer Research Unit, Department of Biology, University of York, Heslington, Yorkshire YO10 5DD, U.K.
PMID: 35212533 DOI: 10.1021/acs.jmedchem.1c01367
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 (IC50 = 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.

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