Dhawan Bharti, Alam Mohammad Sarwar, Hamid Hinna, Yadav Anubha, Akhter Gowsia, Dar Mohd Jamal, Alam Ozair, S Yogisha
Department of Chemistry, School of Chemical and Life Sciences, Jamia Hamdard, Hamdard Nagar, 110062, New Delhi, India.
Amity Institute of Molecular Medicine and Stem Cell Research, Amity University, Uttar Pradesh, Sector-125, Noida, India.
Naunyn Schmiedebergs Arch Pharmacol. 2025 Mar 3. doi: 10.1007/s00210-025-03853-1.
Owing to anti-cancer potency of the benzodiazepinone derivatives, the study aims to synthesize a library of thiourea-tethered benzodiazepinone derivatives targeting JAK-3 kinase for anti-breast cancer potency. Test compounds showed favourable in silico interactions with the active site of JAK-3 kinase. Compound 5i demonstrated a significant JAK-3 kinase inhibitory potential of 68.28% and appreciable growth inhibition (72.9%) of MDA-MB-468 (breast cancer cells) as per the anti-proliferative screening done by NCI-USA. In addition, 5i was also found to induce apoptosis moderately by 12.4% in the late apoptosis quadrant and arrested cell cycle at the G2/M phase. The wound healing assay demonstrated the anti-metastatic impact of drug 5i by reducing the migratory potential of MDA-MB-468 cells and was found to be stable within the target protein in the molecular dynamic simulation. All the synthesized compounds exhibited drug-appropriate pharmacokinetic profiles as corroborated by computational ADMET analysis. The study indicates that the synthesized library of benzodiazepinone derivatives is efficacious and compound 5i has emerged as a promising hit candidate, and can be explored further for development of potent JAK-3 kinase inhibitors targeting breast cancer.
由于苯并二氮杂䓬酮衍生物具有抗癌效力，本研究旨在合成一系列与硫脲相连的苯并二氮杂䓬酮衍生物库，以靶向JAK-3激酶发挥抗乳腺癌效力。测试化合物在计算机模拟中显示出与JAK-3激酶活性位点的良好相互作用。根据美国国立癌症研究所（NCI）进行的抗增殖筛选，化合物5i表现出68.28%的显著JAK-3激酶抑制潜力以及对MDA-MB-468（乳腺癌细胞）可观的生长抑制率（72.9%）。此外，发现5i还能在晚期凋亡象限中适度诱导12.4%的细胞凋亡，并使细胞周期停滞在G2/M期。伤口愈合试验通过降低MDA-MB-468细胞的迁移潜力证明了药物5i的抗转移作用，并且在分子动力学模拟中发现其在靶蛋白内是稳定的。计算ADMET分析证实，所有合成化合物均表现出适合药物的药代动力学特征。该研究表明，合成的苯并二氮杂䓬酮衍生物库是有效的，化合物5i已成为一个有前景的候选药物，可进一步探索用于开发针对乳腺癌的强效JAK-3激酶抑制剂。
