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

Ibrahim, A.I.M.
; 
Ikhmais, B.
; 
Batlle, Elisabet
; 
AbuHarb, W.K.
; ; 
Jaradat, K.T.
; 
Jiménez, R.
; 
Pequerul, R.
; 
Parés, X.
; 
Farrés, J.
... show 1 more
Publication Date
2021-09-23
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Keywords
Aldehyde dehydrogenase, ALDH1A1, ALDH1A3, ALDH3A1, A549 cells, H1299 cells, Non-small cell lung cancer, Cytotoxicity, In silico, ALDH1A3 inhibitors
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© 2021 the Authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
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Peer-Reviewed
Yes
Open Access status
openAccess
Accepted for publication
2021-09-13
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Life Sciences Publications
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Ibrahim_et_al_2021
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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 13.0 µM, 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.
URI
https://bradscholars.brad.ac.uk/handle/10454/20481
Version
Published version
Citation
Ibrahim AIM, Ikhmais B, Batlle E, et al (2021) Design, Synthesis, Biological Evaluation and In Silico Study of Benzyloxybenzaldehyde Derivatives as Selective ALDH1A3 Inhibitors. Molecules. 26(19): 5770.
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https://doi.org/10.3390/molecules26195770
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Article
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