Centre of Excellence in Natural Products and Therapeutics, Department of Biotechnology and Bioinformatics, Sambalpur University, Jyoti Vihar, Burla, Sambalpur, 768019, Odisha, India.
Fluoro-Agrochemicals Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 007, India.
Chem Biol Interact. 2023 Sep 1;382:110606. doi: 10.1016/j.cbi.2023.110606. Epub 2023 Jun 15.
We present N-imidazopyridine-noscapinoids, a new class of noscapine derivatives that bind to tubulin and exhibit antiproliferative activity against triple positive (MCF-7) and triple negative (MDA-MB-231) breast cancer cells. The N-atom of the isoquinoline ring of noscapine scaffold was altered in silico by coupling the imidazo [(Ye et al., 1998; Ke et al., 2000) 1,21,2-a] pyridine pharmacophore to rationally develop a series of N-imidazopyridine-noscapinoids (7-11) with high tubulin binding affinity. The predicted ΔG of the N-imidazopyridine-noscapinoids 7-11 varied from -27.45 to -36.15 kcal/mol, a much lower value than noscapine with ΔG -22.49 kcal/mol. The cytotoxicity of N-imidazopyridine-noscapinoids was evaluated using hormone dependent MCF-7, triple negative MDA-MB-231 breast cancer cell lines and primary breast cancer cells. The cytotoxicity of these compounds (represented as IC concentration) ranges between 4.04 and 33.93 μM against breast cancer cells without affecting normal cells (IC value > 952 μM). All the compounds (7-11) perturbed the cell cycle progression at G2/M phase and triggered apoptosis. Among all the N-imidazopyridine-noscapinoids, N-5-Bromoimidazopyridine-noscapine (9) showed promising antiproliferative activity and was selected for detailed investigation. The onset of apoptosis treated with 9 using MDA-MB-231 revealed morphological changes like cellular shrinkage, chromatin condensation, membrane blebbing, and apoptotic bodies formation. Along with elevated reactive oxygen species (ROS), there was a loss of mitochondrial membrane potential, suggesting induction of apoptosis to cancer cells. Compound 9 was also found to significantly regress the implanted tumour in nude mice as xenografts of MCF-7 cells without any apparent side effects after drug administration. We conclude that N-imidazopyridine-noscapinoids possess excellent potential as a promising drug for treating breast cancers.
我们提出了 N-咪唑并吡啶类北美黄连碱衍生物，这是一类新的北美黄连碱衍生物，能够与微管蛋白结合，并对三阳性（MCF-7）和三阴性（MDA-MB-231）乳腺癌细胞表现出抗增殖活性。通过将咪唑并[（叶等人，1998 年；柯等人，2000 年）1,21,2-a]吡啶药效团偶联到异喹啉环的 N 原子上，对北美黄连碱骨架进行了计算机模拟修饰，从而合理地开发了一系列具有高微管蛋白结合亲和力的 N-咪唑并吡啶类北美黄连碱衍生物（7-11）。N-咪唑并吡啶类北美黄连碱衍生物 7-11 的预测 ΔG 值范围为-27.45 至-36.15 kcal/mol，远低于北美黄连碱的-22.49 kcal/mol。使用依赖激素的 MCF-7、三阴性 MDA-MB-231 乳腺癌细胞系和原代乳腺癌细胞评估了 N-咪唑并吡啶类北美黄连碱衍生物的细胞毒性。这些化合物的细胞毒性（表示为 IC浓度）范围为 4.04 至 33.93 μM，对乳腺癌细胞有活性，而对正常细胞没有影响（IC 值>952 μM）。所有化合物（7-11）均干扰细胞周期在 G2/M 期的进展，并触发细胞凋亡。在所有 N-咪唑并吡啶类北美黄连碱衍生物中，N-5-溴代咪唑并吡啶类北美黄连碱（9）表现出有希望的抗增殖活性，因此被选为进一步研究。用 9 处理 MDA-MB-231 后，细胞凋亡的起始会导致细胞收缩、染色质浓缩、膜起泡和凋亡小体形成等形态变化。同时，活性氧（ROS）水平升高，线粒体膜电位丧失，提示诱导癌细胞凋亡。在裸鼠中，9 也被发现能够显著抑制 MCF-7 细胞异种移植的植入肿瘤，且在药物给药后没有明显的副作用。我们得出结论，N-咪唑并吡啶类北美黄连碱衍生物具有作为治疗乳腺癌的潜在药物的优异潜力。
