Design, Synthesis, Biological Evaluation and In Silico Study of Benzyloxybenzaldehyde Derivatives as Selective ALDH1A3 Inhibitors

Abstract

Aldehyde dehydrogenase 1A3 (ALDH1A3) has recently gained attention from researchers in the cancer field. Several studies have reported ALDH1A3 overexpression in different cancer types, which has been found to correlate with poor treatment recovery. Therefore, finding selective inhibitors against ALDH1A3 could result in new treatment options for cancer treatment. In this study, ALDH1A3-selective candidates were designed based on the physiological substrate resemblance, synthesized and investigated for ALDH1A1, ALDH1A3 and ALDH3A1 selectivity and cytotoxicity using ALDH-positive A549 and ALDH-negative H1299 cells. Two compounds (ABMM-15 and ABMM-16), with a benzyloxybenzaldehyde scaffold, were found to be the most potent and selective inhibitors for ALDH1A3, with IC50 values of 0.23 and 1.29 µM, respectively. The results also show no significant cytotoxicity for ABMM-15 and ABMM-16 on either cell line. However, a few other candidates (ABMM-6, ABMM-24, ABMM-32) showed considerable cytotoxicity on H1299 cells, when compared to A549 cells, with IC50 values of 14.0, 13.7 and 13.0µM, respectively. The computational study supported the experimental results and suggested a good binding for ABMM-15 and ABMM-16 to the ALDH1A3 isoform. From the obtained results, it can be concluded that benzyloxybenzaldehyde might be considered a promising scaffold for further drug discovery aimed at exploiting ALDH1A3 for therapeutic intervention.

Identification of a novel ALDH1A3‐selective inhibitor by a chemical probe with unrelated bioactivity: An approach to affinity‐based drug target discovery

“…The similarity in the values for IC 50 and K D furthermore suggested that this inhibitory activity was caused by the binding affinity we had observed. Given that selective inhibitors of ALDH1A3 have been successively reported (Gelardi et al, 2021;Ibrahim et al, 2021;Jiménez et al, 2019), the potency and selectivity of the compound we have discovered will have some significance, and the precise SAR analyses will be reported elsewhere.…”

Aldehyde Dehydrogenase Enzyme Functions in Acute Leukemia Stem Cells

“…ALDH1A1, ALDH1A3, ALDH2 and ALDH3A1 have structural and functional differences in substrate binding site, cofactor dissociation, enzyme kinetics, and ratelimiting steps, which facilitates the design of selective inhibitors and enzymatic activity tracers; in particular, ALDH1A1 substrate binding pocket has a wider access tunnel than ALDH2 or ALDH3A1, allowing ALDH1A1 to accommodate larger and more rigid ligands than other ALDH isoforms [138,139].…”

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

“…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 ].…”

“…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 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.…”