Scaffold hopping based designing of selective ALDH1A1 inhibitors to overcome cyclophosphamide resistance: synthesis and biological evaluation.
| Autor: | Narendra G; Department of Pharmaceutical Sciences and Drug Research, Punjabi University Patiala Punjab 147002 India mmlpup73@gmail.com +91 17522 83075 +91 95015 42696., Raju B; Department of Pharmaceutical Sciences and Drug Research, Punjabi University Patiala Punjab 147002 India mmlpup73@gmail.com +91 17522 83075 +91 95015 42696., Verma H; Department of Pharmaceutical Sciences and Drug Research, Punjabi University Patiala Punjab 147002 India mmlpup73@gmail.com +91 17522 83075 +91 95015 42696., Kumar M; Department of Pharmaceutical Sciences and Drug Research, Punjabi University Patiala Punjab 147002 India mmlpup73@gmail.com +91 17522 83075 +91 95015 42696., Jain SK; Department of Pharmaceutical Sciences, Guru Nanak Dev University Amritsar India., Tung GK; Centre for Basic and Translational Research in Health Sciences, Guru Nanak Dev University Amritsar India., Thakur S; Department of Pharmaceutical Sciences, Guru Nanak Dev University Amritsar India., Kaur R; Department of Botany and Environmental Sciences, Guru Nanak Dev University Amritsar India., Kaur S; Department of Botany and Environmental Sciences, Guru Nanak Dev University Amritsar India., Sapra B; Department of Pharmaceutical Sciences and Drug Research, Punjabi University Patiala Punjab 147002 India mmlpup73@gmail.com +91 17522 83075 +91 95015 42696., Silakari O; Department of Pharmaceutical Sciences and Drug Research, Punjabi University Patiala Punjab 147002 India mmlpup73@gmail.com +91 17522 83075 +91 95015 42696. |
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| Jazyk: | angličtina |
| Zdroj: | RSC medicinal chemistry [RSC Med Chem] 2023 Nov 30; Vol. 15 (1), pp. 309-321. Date of Electronic Publication: 2023 Nov 30 (Print Publication: 2024). |
| DOI: | 10.1039/d3md00543g |
| Abstrakt: | Aldehyde dehydrogenase 1A1 (ALDH1A1) is an isoenzyme that catalyzes the conversion of aldehydes to acids. However, the overexpression of ALDH1A1 in a variety of malignancies is the major cause of resistance to an anti-cancer drug, cyclophosphamide (CP). CP is a prodrug that is initially converted into 4-hydroxycyclophosphamide and its tautomer aldophosphamide, in the liver. These compounds permeate into the cell and are converted as active metabolites, i.e. , phosphoramide mustard (PM), through spontaneous beta-elimination. On the other hand, the conversion of CP to PM is diverted at the level of aldophosphamide by converting it into inactive carboxyphosphamide using ALDH1A1, which ultimately leads to high drug inactivation and CP resistance. Hence, in combination with our earlier work on the target of resistance, i.e. , ALDH1A1, we hereby report selective ALDH1A1 inhibitors. Herein, we selected a lead molecule from our previous virtual screening and implemented scaffold hopping analysis to identify a novel scaffold that can act as an ALDH1A1 inhibitor. This results in the identification of various novel scaffolds. Among these, on the basis of synthetic feasibility, the benzimidazole scaffold was selected for the design of novel ALDH1A1 inhibitors, followed by machine learning-assisted structure-based virtual screening. Finally, the five best compounds were selected and synthesized. All synthesized compounds were evaluated using in vitro enzymatic assay against ALDH1A1, ALDH2, and ALDH3A1. The results disclosed that three molecules A1, A2, and A3 showed significant selective ALDH1A1 inhibitory potential with an IC Competing Interests: There is no conflict of interest to declare. (This journal is © The Royal Society of Chemistry.) |
| Databáze: | MEDLINE |
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