Design, synthesis, biological evaluation and in silico study of benzyloxybenzaldehyde derivatives as selective aldh1a3 inhibitors
Ibrahim, Ali I. M. (Al-Zaytoonah University of Jordan. Faculty of Pharmacy)
Ikhmais, Balqis (Al-Zaytoonah University of Jordan. Faculty of Pharmacy)
Batlle, Elisabet (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Abuharb, Waed K. (Al-Zaytoonah University of Jordan. Faculty of Pharmacy)
Jha, Vibhu (University of Pisa. Department of Pharmacy)
Jaradat, Khaled T. (American University of the Middle East. College of Engineering and Technology)
Jiménez, Rafael (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Pequerul, Raquel (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Parés i Casasampera, Xavier (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Farrés, Jaume (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Pors, Klaus (University of Bradford. Faculty of Life Sciences)

Data:	2021
Resum:	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.
Ajuts:	Agencia Estatal de Investigación PID2020-119424RB-I00
Nota:	Altres ajuts: This research was funded by Al-Zaytoonah University of Jordan, grant number 2019- 2018/18/03 and by UoB International Development Fund Scheme PhD, grant code studentship to E.B. R.J. is a recipient of a PIF predoctoral fellowship from Universitat Autònoma de Barcelona.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Aldehyde dehydrogenase ; ALDH1A1 ; ALDH1A3 ; ALDH3A1 ; A549 cells ; H1299 cells ; Non-small cell lung cancer ; Cytotoxicity ; In silico
Publicat a:	Molecules, Vol. 26 Núm. 19 (september 2021) , p. 5770, ISSN 1420-3049

DOI: 10.3390/molecules26195770
PMID: 34641313

23 p, 5.4 MB

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