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

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 50 = 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.

In Vitro Evaluation of ALDH1A3-Affinic Compounds on Breast and Prostate Cancer Cell Lines as Single Treatments and in Combination with Doxorubicin

“…As shown in Figure 2 , these cell lines were confirmed to express the ALDH1A3 enzyme and were, therefore, considered suitable for use in the cell viability experiments. As the figure shows, there might be a variation in the expression of ALDH1A3 enzyme in these cell lines, in line with previous work reported in the literature [ 12 , 22 , 29 ].…”

“…Recently, our group has discovered a number of compounds with ALDH-affinic properties ( Figure 1 ), compounds 1 – 6 , 15 – 19 , 23 – 28 , and 32 – 34 , which have been investigated on several ALDH-expressing cancer cell lines and have shown promising cytotoxic results [ 21 , 22 ]. These compounds have been found to work via a variety of mechanisms, ranging from inhibiting to activating particular ALDH isoforms [ 21 , 22 ].…”

“…Recently, our group has discovered a number of compounds with ALDH-affinic properties ( Figure 1 ), compounds 1 – 6 , 15 – 19 , 23 – 28 , and 32 – 34 , which have been investigated on several ALDH-expressing cancer cell lines and have shown promising cytotoxic results [ 21 , 22 ]. These compounds have been found to work via a variety of mechanisms, ranging from inhibiting to activating particular ALDH isoforms [ 21 , 22 ]. In particular, compound 15 was the most potent ALDH1A3 inhibitor, followed by compounds 16 , 18 , and 1, with remaining enzyme activities of 0.14%, 4.27%, 16.01%, and 21.07%, respectively, compared to the control enzyme activity [ 21 ].…”

“…In particular, compound 15 was the most potent ALDH1A3 inhibitor, followed by compounds 16 , 18 , and 1, with remaining enzyme activities of 0.14%, 4.27%, 16.01%, and 21.07%, respectively, compared to the control enzyme activity [ 21 ]. In these studies, non-small cell lung cancer cell lines (NSCLC) (A549 and H1299) [ 21 ] and prostate cancer cell lines (PC-3, LNCaP, and DU145) [ 22 ] have been used. A549 has been shown to express ALDH1A1, ALDH1A3, and ALDH3A1 isoforms [ 23 , 24 ], which were found to be absent in H1299 [ 24 ].…”

“…A549 has been shown to express ALDH1A1, ALDH1A3, and ALDH3A1 isoforms [ 23 , 24 ], which were found to be absent in H1299 [ 24 ]. PC-3 has been shown to express ALDH1A1, ALDH1A3 [ 25 ], and ALDH3A1 [ 22 ]; LNCaP has been shown to express the ALDH1A3 isoform [ 22 , 25 ], and DU145 has been shown to express ALDH1A1 and ALDH1A3 isoforms [ 22 ].…”