Nagireddy Praveen Kumar Reddy, Kommalapati Vamsi Krishna, Siva Krishna Vagolu, Sriram Dharmarajan, Tangutur Anjana Devi, Kantevari Srinivas
Fluoro and Agrochemicals Division and Applied Biology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, Telangana, India.
Medicinal Chemistry and Antimycobacterial Research Laboratory, Pharmacy Group, Birla Institute of Technology & Science Pilani, Hyderabad Campus, Hyderabad 500078, Telangana, India.
ACS Omega. 2019 Nov 5;4(21):19382-19398. doi: 10.1021/acsomega.9b02789. eCollection 2019 Nov 19.
Noscapine, a phthalide isoquinoline alkaloid isolated from the opium poppy is traditionally being used as an anticough drug. With a safe in vitro toxicological profile, noscapine and its analogues have been explored to show microtubule-regulating properties and anticancer activity against various mammalian cancer cell lines. Since then, our group and other research groups worldwide are working on developing new noscapinoids to tap its potential as the leading drug molecule. With our continuing efforts, we herein present synthesis and anticancer evaluation of a series of imidazothiazole-coupled noscapinoids and . Natural α-noscapine was -demethylated to nornoscapine and then reacted with 4-(chloromethyl) thiazole-2-amine. The resultant noscapinoid was coupled with various bromomethyl ketones to give -imidazothiazolyl noscapinoids in very good yields. Similarly, natural α-noscapine was -demethylated using sodium azide/sodium iodide, reacted with 4-(chloromethyl)thiazole-2-amine, and coupled with bromomethyl ketones to result in -imidazothiazolyl noscapinoids . All the new analogues and were fully characterized by their NMR and mass spectral analysis. In vitro cytotoxicity assay was performed for compounds , , and against four different cancer cell lines: HeLa (cervical), MIA PaCa-2 (pancreatic), SK-N-SH (neuroblastoma), and DU145 (prostate cancer). Among these conjugates, , , , , , , and showed potent cytotoxicity with low IC values. Further, flow cytometry analysis revealed that MIA PaCa-2 cells treated with these compounds induced . In addition, Western blot analysis revealed that the cells treated with these conjugates accumulate tubulin in the soluble fraction and also elevate cyclin-B1 protein expression levels. Moreover, the conjugates also increased the expression of caspase-3 and PARP levels which is indicative of apoptotic cell death. In silico molecular docking studies showed several noncovalent interactions like van der Waals and hydrogen-bonding with tubulin protein and with good binding energy. The results indicated that these noscapine analogues may serve as novel compounds that can possibly inhibit tubulin protein and can be considered for further optimization as a clinical candidate for treating pancreatic cancer.
那可丁是从罂粟中分离出的一种苯酞异喹啉生物碱，传统上用作镇咳药。鉴于其在体外毒理学方面的安全性，人们对那可丁及其类似物进行了研究，发现它们具有微管调节特性以及对多种哺乳动物癌细胞系的抗癌活性。从那时起，我们团队以及全球其他研究团队一直致力于开发新的那可丁类化合物，以挖掘其作为领先药物分子的潜力。经过持续努力，我们在此展示了一系列咪唑并噻唑偶联的那可丁类化合物的合成及抗癌评估。天然α - 那可丁经去甲基化生成去甲那可丁，然后与4 - （氯甲基）噻唑 - 2 - 胺反应。所得的那可丁类化合物与各种溴甲基酮反应，以非常高的产率得到 - 咪唑并噻唑基那可丁类化合物。同样，天然α - 那可丁使用叠氮化钠/碘化钠进行去甲基化，与4 - （氯甲基）噻唑 - 2 - 胺反应，并与溴甲基酮偶联，得到 - 咪唑并噻唑基那可丁类化合物。所有新的类似物 和 均通过核磁共振和质谱分析进行了全面表征。对化合物 、 和 针对四种不同癌细胞系进行了体外细胞毒性测定：HeLa（宫颈癌）、MIA PaCa - 2（胰腺癌）、SK - N - SH（神经母细胞瘤）和DU145（前列腺癌）。在这些缀合物中， 、 、 、 、 、 和 表现出强效细胞毒性，IC值较低。此外，流式细胞术分析表明，用这些化合物处理的MIA PaCa - 2细胞诱导了 。另外，蛋白质印迹分析显示，用这些缀合物处理的细胞使微管蛋白在可溶部分积累，并且还提高了细胞周期蛋白B1的蛋白表达水平。此外，这些缀合物还增加了半胱天冬酶 - 3和PARP的水平，这表明细胞发生凋亡性死亡。计算机辅助分子对接研究显示，这些化合物与微管蛋白之间存在范德华力和氢键等多种非共价相互作用，并具有良好的结合能。结果表明，这些那可丁类似物可能作为新型化合物，能够抑制微管蛋白，可考虑进一步优化作为治疗胰腺癌的临床候选药物。
