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

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.