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

Research output: Contribution to journalArticlepeer-review

Author(s)

  • Ali I M Ibrahim
  • Elisabet Batlle
  • Smarakan Sneha
  • Rafael Jiménez
  • Raquel Pequerul
  • Xavier Parés
  • Till Rüngeler
  • Vibhu Jha
  • Tiziano Tuccinardi
  • Maria Sadiq
  • Fiona Frame
  • Norman J Maitland
  • Jaume Farrés
  • Klaus Pors

Department/unit(s)

Publication details

JournalJOURNAL OF MEDICINAL CHEMISTRY
DateE-pub ahead of print - 25 Feb 2022
DatePublished (current) - 10 Mar 2022
Issue number5
Volume65
Number of pages16
Pages (from-to)3833-3848
Early online date25/02/22
Original languageEnglish

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.

Bibliographical note

© 2022 American Chemical Society

    Research areas

  • Aldehyde Dehydrogenase, Benzaldehydes, Humans, Male, Prostatic Neoplasms/drug therapy

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