Dash Pooja, Pragyandipta Pratyush, Kantevari Srinivas, Naik Pradeep Kumar
Research Centre of Excellence in Natural Products and Therapeutics, Department of Biotechnology and Bioinformatics, Sambalpur University, Jyoti Vihar, Burla, Sambalpur, Odisha, 768019, India.
Fluoro-Agrochemicals Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 007, India.
J Comput Aided Mol Des. 2025 Jun 25;39(1):36. doi: 10.1007/s10822-025-00617-0.
In this study we present a novel class of N-imidazopyridine (impy) derivatives (12-15) of noscapine by tethering the imidazo[1,2-a]pyridine core to the N-atom of the isoquinoline ring of the lead molecule noscapine. These derivatives were found to have better docking scores (- 6.213 to - 7.897 kcal/mol) than noscapine (- 4.960 kcal/mol). Further, the calculated binding energy ranged between - 25.85 to - 35.57 kcal/mol, as determined by MD simulations and MM-PBSA calculations. Tubulin binding assay also revealed higher binding affinity for compounds 12, 13, 14, and 15 with the equilibrium dissociation constant (K) value of 78 ± 3.8 µM, 66 ± 1.7 µM, 56 ± 1.8 µM, and 35 ± 2.4 µM, respectively. These derivatives also exhibited potent cytotoxicity against breast cancer cell lines (MCF-7 & MDA-MB-231), with IC values ranging from 3.7 to 32.4 µM, without any toxicity to normal human embryonic kidney (HEK) cells (IC value > 1500 µM). FACS analysis revealed early apoptotic (45%) and late apoptotic cells (35%) when treated with the N-imidazopyridine derivatives (15) and arrested the cell cycle at the G2/M phase. Moreover, the impy derivative 15 was found to reduce the volume of implanted tumor in nude mice using xenografts of MCF-7 cells without any severe toxicity. Thus, we can infer that N-imidazopyridine-noscapinoids have increased potential as anticancer agents.
在本研究中，我们通过将咪唑并[1,2-a]吡啶核心连接到先导分子那可丁异喹啉环的N原子上，展示了一类新型的那可丁N-咪唑并吡啶（impy）衍生物（12 - 15）。发现这些衍生物比那可丁（-4.960 kcal/mol）具有更好的对接分数（-6.213至-7.897 kcal/mol）。此外，通过分子动力学模拟和MM-PBSA计算确定，计算出的结合能在-25.85至-35.57 kcal/mol之间。微管蛋白结合试验还显示化合物12、13、14和15具有更高的结合亲和力，其平衡解离常数（K）值分别为78±3.8 μM、66±1.7 μM、56±1.8 μM和35±2.4 μM。这些衍生物对乳腺癌细胞系（MCF-7和MDA-MB-231）也表现出强大的细胞毒性，IC值范围为3.7至32.4 μM，而对正常人胚肾（HEK）细胞无任何毒性（IC值>1500 μM）。流式细胞术分析显示，用N-咪唑并吡啶衍生物（15）处理时，早期凋亡细胞（45%）和晚期凋亡细胞（35%）出现，并使细胞周期停滞在G2/M期。此外，发现impy衍生物15使用MCF-7细胞异种移植可减少裸鼠体内植入肿瘤的体积，且无任何严重毒性。因此，我们可以推断N-咪唑并吡啶-那可丁类化合物作为抗癌剂具有更大的潜力。
