Overall, 2-oxoindoline-based hydroxamic acids, particularly those bearing extended alkyl linkers, represent promising scaffolds for further development of HDAC-targeted anticancer agents.
Abstract
Histone deacetylase (HDAC) inhibitors are important epigenetic anticancer agents that regulate gene expression, induce cell cycle arrest, and promote apoptosis. In this study, a novel series of 2-oxoindoline-capped hydroxamic acids was designed, synthesized and evaluated for their capacity to inhibit histone deacetylases and suppress cancer cell proliferation. The screening panel incorporated multiple cancer models spanning different organ systems, including colorectal adenocarcinoma (SW620, HCT116), triple-negative breast cancer (MDA-MB-231), non-small cell lung carcinoma (A549), and prostate cancer (PC-3). Comparative assessment against non-transformed fibroblasts (MRC-5) enabled evaluation of selectivity and tolerability profiles. Several derivatives exhibited potent HDAC inhibition at submicromolar concentrations, with compounds 7c, 10b, and 10c showing stronger activity than the reference inhibitor SAHA. Among them, compound 10c demonstrated broad antiproliferative effects while maintaining relatively low toxicity toward normal cells. Mechanistic investigations revealed that 10c induced S-phase cell cycle arrest and promoted apoptosis in SW620 colorectal cancer cells. Molecular docking studies against multiple HDAC isoforms supported the experimental findings by revealing favorable zinc coordination and key interactions within the catalytic pocket. To further elucidate the binding behavior and dynamic features of the most active derivatives, molecular dynamics simulations were performed for HDAC complexes with 7c, 10b, and 10c. The simulations revealed stable protein–ligand interactions without perturbation of the overall protein structure, while highlighting distinct binding dynamics among the compounds, with 10c exhibiting the highest binding persistence, followed by 7c and 10b. In addition, in silico ADME and toxicity predictions were carried out for compound 10c as a representative highly active derivative, indicating acceptable drug-like properties and a favorable safety profile. Overall, 2-oxoindoline-based hydroxamic acids, particularly those bearing extended alkyl linkers, represent promising scaffolds for further development of HDAC-targeted anticancer agents.
Histone deacetylase 8 (HDAC8) has emerged as a promising therapeutic target due to its role in epigenetic regulation. In this study, novel non-hydroxamate-based quinoline analogues were designed and explored as HDAC8-selective inhibitors that exhibit nanomolar HDAC8 enzymatic inhibition. Notably, compounds BHC-10 and BHC-13 showed 30 and 42 nM activity, respectively. Compounds exhibiting below 500 nM activity were evaluated for their in vitro cellular activity, and two compounds, BHC-2 and BHC-10, showed promising activity in neuroblastoma cell lines (IMR-32 and SH-SY5Y). Based on both enzymatic and cellular assays, compounds BHC-2, BHC-10, and BHC-13 were selected for further evaluation using clonogenic growth assays, apoptosis assays, and cell cycle analysis. Clonogenic assays revealed a significant, dose-dependent reduction in colony formation. Flow cytometry analysis indicated a dose-dependent increase in apoptotic cell populations and induction of cell cycle arrest at the S phase. Mechanistic studies confirmed target engagement through enhanced acetylation of SMC3, as demonstrated by western blot analysis. Additionally, molecular docking analysis provided insights into the binding interactions of these compounds with the HDAC8 protein. Two compounds from the current work, BHC-10 and BHC-13, emerged as more potent and selective than the reference compound B. Together, the current findings establish these compounds as promising HDAC8 modulators with potential for therapeutic development in neuroblastoma.
N. V. M. Rao Bandaru, Vandana Joshi, M. Schweipert et al.· RSC Advances· 0 citations
Compound 4v emerged as a leading candidate, showing EGFR kinase inhibitory activity comparable to Erlotinib, and computational analysis of 4v and EGFR molecular binding suggests that it serves as a superior binder to the inactive EGFR conformation.
Amr Elagamy, Mohamed S. Nafie, Ahmed Elnahrawy et al.· European journal of medicina...· 0 citations
Abstract Two novel series of hydroxamic acid hybrids were designed and synthesised as anticancer agents via histone deacetylase isozymes (HDACs) inhibitors. Antiproliferative effects of novel compounds were evaluated against DU-145 and PC-3 (prostate cancer) and MG-63 (osteosarcoma) cell lines. Compound 5d emerged as the most potent against DU-145 and PC-3 (prostate cancer) with IC50 values of 0.93 and 1.05 µM, exhibiting inhibiting HDAC 2, 4, 6, and 8 with IC50 values of 0.86, 0.17, 1.17, and 0.15 µM respectively. As a result, it was selected for mechanistic investigations. Apoptotic cell death modality was predominantly detected in the three cell lines, accompanied by cell cycle arrest in the S phase in prostate cancer cell lines, whereas it caused cell cycle arrest in MG-63 osteosarcoma cells in the G0/G1 phase. Docking studies confirmed its high affinity for HDACs, and an atomistic standard 100 ns dynamic simulation supported the stability of these interactions. In conclusion, all these findings suggested the potential use of this compound for treating prostate cancer with bone metastasis.
Aya I. Abd El-hameed, Ibrahim M. Salem, Rasha M. Allam et al.· Journal of Enzyme Inhibition...· 0 citations
In vivo validation in PC-3 xenograft mice confirmed that 11 M exerted robust tumor growth suppression with low systemic toxicity, accompanied by DNMT3A downregulation and MAPK pathway activation, substantiating its multi-target therapeutic mechanism.
Mechanistic studies revealed that compound 7e induced significant apoptosis, promoted S-phase cell cycle arrest, and effectively inhibited cell migration in HCT-116 cells, identifying him as a promising dual VEGFR-2/CDK6 inhibitor with potent and selective anticancer activity.
Hazem Elkady, Walid E. Elgammal, I. Eissa et al.· RSC Advances· 0 citations
AIMS
To design, synthesize, and biologically evaluate novel bis-thiazole derivatives as potential PIM-1 kinase inhibitors for breast cancer therapy.
MATERIALS AND METHODS
A series of new bis-thiazole derivatives were synthesized and evaluated for their antiproliferative activity against MDA-MB-231 and MCF-7 breast cancer cell lines. The most active compound 15c was further investigated for PIM-1 kinase inhibition, selectivity toward normal WI38 cells, apoptosis induction, and molecular interactions with the PIM-1 active site.
RESULTS AND CONCLUSION
Among the synthesized compounds, derivative 15c exhibited the highest antiproliferative activity against MDA-MB-231 and MCF-7 cells, with IC50 values of 2.17 and 1.46 μM, respectively. It demonstrated potent PIM-1 inhibitory activity (IC50 = 0.74 μM), a favorable selectivity index, and low toxicity toward WI38 cells. Furthermore, 15c significantly increased p53 and Bax levels by 6.8- and 6.2-folds, respectively, while reducing Bcl-2 levels to 0.34-fold relative to the control, indicating apoptosis induction. Molecular docking studies revealed strong binding interactions with key amino acid residues within the PIM-1 active site. Hence, compound 15c represents a promising PIM-1 kinase inhibitor with potent antiproliferative and pro-apoptotic activities, supporting its potential as a candidate for breast cancer treatment.
Alaa M. Abu Alnjaa, Jihan Qurban, E. Abbas et al.· Future Medicinal Chemistry· 0 citations
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