Compound 6b is identified as a promising lead candidate for further development as a VEGFR-2-targeted anticancer agent and stable backbone behavior, regulated ligand fluctuations, preserved structural compactness, and sustained hydrogen bonding within the 6b-VEGFR-2 complex are identified.
Abstract
A novel series of N-butyl isatin (indolin-2-one) derivatives was designed and synthesized as potential VEGFR-2-targeted anticancer agents, drawing inspiration from the oxindole-based inhibitor sunitinib. The synthesized compounds were assessed for antiproliferative activity against colorectal cancer cell lines (HT29 and HCT116) and for their inhibitory potential on VEGFR-2. Compound 6b exhibited the highest potency, demonstrating strong VEGFR-2 inhibition comparable to that of sunitinib. Mechanistic investigations in HCT116 cells demonstrated that 6b induced G0/G1 cell cycle arrest and promoted apoptosis, which was associated with the upregulation of p53 and Bax, downregulation of Bcl-2, and suppression of Cyclin D1 and Cyclin E expression. Furthermore, 6b markedly decreased VEGF-A expression, supporting modulation of VEGF/VEGFR-2-associated signaling. Molecular docking studies involving VEGFR-2 (PDB ID: 4AGD) demonstrated favorable binding of compound 6b in the ATP-binding pocket, establishing essential interactions with essential residues. Docking validation was established through the successful redocking of sunitinib, yielding an RMSD of 0.44 Å. Additionally, 500 ns molecular dynamics simulations indicated stable backbone behavior, regulated ligand fluctuations, preserved structural compactness, and sustained hydrogen bonding within the 6b-VEGFR-2 complex. The findings collectively identify compound 6b as a promising lead candidate for further development as a VEGFR-2-targeted anticancer agent.
A novel series of benzofuran-based aryl urea derivatives incorporating a 1,3,4-thiadiazole linker were designed as dual VEGFR-2/BRAFWT inhibitors using sorafenib as a pharmacophoric template, with compound 7j emerging as the most active analogue.
Marwa I Serag, Mohamed R. Elnagar, Wafaa A. Ewes et al.· Bioorganic & Medicinal Chemi...· 0 citations
A series of benzo[d]imidazole-isatin hybrids (4a-d, 6a-d, and 8a-d) was developed and synthesized as prospective dual inhibitors of VEGFR-2 and c-MET to address tumor growth and resistance-related signaling pathways. The biological assessment demonstrated encouraging dual kinase inhibitory action, with compound 8b identified as the most balanced inhibitor, displaying IC50 values of 92 nM and 63 nM against VEGFR-2 and c-MET, respectively. In-vitro antiproliferative evaluation against MDA-MB-231 and A549 cancer cell lines revealed notable cytotoxicity for compound 8b, yielding IC50 values of 2.37 μM and 1.79 μM, respectively, exceeding the efficacy of the reference medication sunitinib. Additionally, 8b exhibited a favorable selectivity profile for normal MCF-10A cells. Mechanistic studies demonstrated that 8b caused substantial G2/M cell cycle arrest and facilitated apoptosis in MDA-MB-231 cells. Biomarker studies revealed a reduction in VEGF-A, MMP-9, and Bcl-2 levels, alongside an increase in Bax and Caspase-3, suggesting potential anti-angiogenic and pro-apoptotic characteristics in-vitro. Molecular docking analyses provided supporting models for the identified biological activities and exhibited advantageous binding interactions within both kinase active sites. These data collectively suggest that chemical 8b may serve as a promising candidate for further anticancer research.
Mohamed El-Naggar, Rofaida Salem, Mona M. Kabeel et al.· Bioorganic & Medicinal Chemi...· 0 citations
Two novel classes of hybrid quinazolin-2,4-diones 2–17, privileged with urea and/or carbamate moieties, as EGFR-TK inhibitors represent promising lead candidates for developing novel EGFR inhibitors for cancer treatment.
Mohamed El-Naggar, Fawzy Abdelshafy, A. Mosallam et al.· Journal of Computer-Aided Mo...· 0 citations
(R)-A17, a novel, highly selective PARP1 inhibitor featuring a unique tricyclic scaffold, is developed and established as a promising candidate and the design strategy for the next-generation PARP1-targeted therapy is validated.
Zhongning Guo, Rongrong Sun, Lin-Yu Yang et al.· Journal of Medicinal Chemist...· 0 citations
Discovering novel anticancer drugs with high efficacy and minimal toxicity is of great importance in anticancer drug research and development. Apoptosis is a critical regulatory mechanism in cancer progression mediated by BCL2 family proteins and BAX, which together play a key role in the regulation of programmed cell death. In this study, a series of some novel methyl 2-(substitutedphenyl)-1H-benzimidazole-5(6)-carboxylate (2a-2p) and methyl 2-(substitutedphenyl)-benzoxazole-5-carboxylate (3a-3p) derivatives were designed, synthesized, and evaluated for anticancer activity against LNCaP, HepG2, and A549 cell lines, together with their effects on BCL2 and BAX mRNA expression. Although the benzoxazole derivatives did not exhibit the desired activity against the tested cell lines, several benzimidazole derivatives showed notable anticancer effects. Notably, methyl 2-(4-tert-butylphenyl)-1H-benzimidazole-5(6)-carboxylate (2l) was found to be more potent than the reference drug across all tested cell lines. Moreover, methyl 2-(4-isopropylphenyl)-1H-benzimidazole-5(6)-carboxylate (2h) exhibited activity comparable to the reference drug against the LNCaP cell line, while demonstrating superior potency against the other two cell lines. The effects of these two compounds on the expression levels of BCL2 and BAX were found to be consistent with the in vitro cytotoxicity results. Furthermore, molecular docking studies revealed that their interactions with both proteins were consistent with the experimental findings. In addition, in silico ADMET predictions indicated favorable oral bioavailability and low toxicity risks. These findings underscore the critical role of the benzimidazole scaffold and the effects of para substituents, identifying compounds 2h and 2l as promising lead candidates for the development of selective anticancer agents.
Gözde Çakmak, Y. Erzurumlu, S. Ozguven et al.· European journal of medicina...· 0 citations
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