New 2-oxoindole derivatives as multiple PDGFRα/ß and VEGFR-2 tyrosine kinase inhibitors.

Autor: Ezelarab HAA; Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519 Minia, Egypt., Abd El-Hafeez AA; Pharmacology and Experimental Oncology Unit, Department of Cancer Biology, National Cancer Institute, Cairo University, Cairo, Egypt. Electronic address: amer.ali@nci.cu.edu.eg., Ali TFS; Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519 Minia, Egypt., Sayed AM; Department of Pharmacognosy, Faculty of Pharmacy, Nahda University, 62513 Beni-Suef, Egypt; Department of Pharmacognosy, Collage of Pharmacy, Almaaqal University, 61014 Basrah, Iraq., Hassan HA; Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519 Minia, Egypt. Electronic address: heba.hasan@mu.edu.eg., Beshr EAM; Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519 Minia, Egypt., Abbas SH; Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519 Minia, Egypt. Electronic address: samar_hafez@mu.edu.eg.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2024 Apr; Vol. 145, pp. 107234. Date of Electronic Publication: 2024 Feb 22.
DOI: 10.1016/j.bioorg.2024.107234
Abstrakt: Two new series of N-aryl acetamides 6a-o and benzyloxy benzylidenes 9a-p based 2-oxoindole derivatives were designed as potent antiproliferative multiple kinase inhibitors. The results of one-dose NCI antiproliferative screening for compounds 6a-o and 9a-p elucidated that the most promising antiproliferative scaffolds were 6f and 9f, which underwent five-dose testing. Notably, the amido congener 6f was the most potent derivative towards pancreatic ductal adenocarcinoma MDA-PATC53 and PL45 cell lines (IC 50  = 1.73 µM and 2.40 µM, respectively), and the benzyloxy derivative 9f was the next potent one with IC 50 values of 2.85 µM and 2.96 µM, respectively. Both compounds 6f and 9f demonstrated a favorable safety profile when tested against normal prostate epithelial cells (RWPE-1). Additionally, compound 6f displayed exceptional selectivity as a multiple kinase inhibitor, particularly targeting PDGFRα, PDGFRβ, and VEGFR-2 kinases, with IC 50 values of 7.41 nM, 6.18 nM, and 7.49 nM, respectively. In contrast, the reference compound Sunitinib exhibited IC 50 values of 43.88 nM, 2.13 nM, and 78.46 nM against the same kinases. The derivative 9f followed closely, with IC 50 values of 9.9 nM, 6.62 nM, and 22.21 nM for the respective kinases. Both 6f and 9f disrupt the G2/M cell cycle transition by upregulating p21 and reducing CDK1 and cyclin B1 mRNA levels. The interplay between targeted kinases and these cell cycle regulators underpins the G2/M cell cycle arrest induced by our compounds. Also, compounds 6f and 9f fundamentally resulted in entering MDA-PATC53 cells into the early stage of apoptosis with good percentages compared to the positive control Sunitinib. The in silico molecular-docking outcomes of scaffolds 6a-o and 9a-p in VEGFR-2, PDGFRα, and PDGFRβ active sites depicted their ability to adopt essential binding interactions like the reference Sunitinib. Our designed analogs, specifically 6f and 9f, possess promising antiproliferative and kinase inhibitory properties, making them potential candidates for further therapeutic development.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: