Khan Irfan, Ganapathi Thipparapu, Rehman Md Muzaffar-Ur-, Shareef Mohd Adil, Kumar C Ganesh, Kamal Ahmed
Organic Synthesis and Process Chemistry Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India; Academy of Scientific and Innovative Research, Ghaziabad 201002, India.
Stem Cell Research Division, National Institute of Nutrition (NIN), Indian Council of Medical Research (ICMR), Hyderabad 500007, Telangana, India.
Bioorg Med Chem Lett. 2021 Jul 15;44:128094. doi: 10.1016/j.bmcl.2021.128094. Epub 2021 May 6.
To continue the quest of newer anticancer agents, herein a novel class of 1,4-Dihydroindenopyrazole linked oxadiazole conjugates 9(a-r) was designed, synthesized and experimented for their anti-proliferative activities against four different cancer cell lines (human) such as MDA MB-231 (breast), PANC-1 (pancreatic), MCF-7 (breast), and Caco-2 (Colorectal) by using MTT assay. Among the series compound 9h and 9 m demonstrated significant potency against the PANC-1 (human pancreatic cancer cells) with IC value 7.4 μM and 4.3 μM respectively. While compound 9 m was found to be equipotent to standard Gomitabine (IC = 4.2 μM). The detailed biological assays revealed S phase cell cycle arrest and their ability to propagate apoptosis by activating caspase 3 and 9 enzymes which was confirmed by Annexin-FITC assay and caspase assay. Moreover, docking study suggested their binding modes and interactions with caspase-3. In addition, in silico studies revealed that they exhibit good pharmacokinetics and drug likeliness properties. Furthermore, 3D-QSAR was carried out to achieve a pharmacophoric model with CoMFA (q = 0.631, r = 0.977) and CoMSIA (q = 0.686, r = 0.954) on PANC-1 cancer cells which were established, generated and validated to be reliable models for further design and optimization of newer molecules with enhanced anticancer activity.
为了继续探索新型抗癌药物，本文设计、合成并实验了一类新型的1,4-二氢茚并吡唑连接的恶二唑共轭物9(a - r)，通过MTT法检测其对四种不同人类癌细胞系（MDA MB - 231（乳腺癌）、PANC - 1（胰腺癌）、MCF - 7（乳腺癌）和Caco - 2（结直肠癌））的抗增殖活性。在该系列化合物中，化合物9h和9m对PANC - 1（人胰腺癌细胞）显示出显著的活性，IC值分别为7.4 μM和4.3 μM。同时发现化合物9m与标准药物吉西他滨等效（IC = 4.2 μM）。详细的生物学检测显示S期细胞周期阻滞，并且它们能够通过激活半胱天冬酶3和9来诱导凋亡，这通过膜联蛋白 - FITC检测和半胱天冬酶检测得到证实。此外，对接研究表明了它们与半胱天冬酶 - 3的结合模式和相互作用。另外，计算机模拟研究表明它们具有良好的药代动力学和类药性质。此外，在PANC - 1癌细胞上进行了3D - QSAR以建立CoMFA（q = 0.631，r = 0.977）和CoMSIA（q = 0.686，r = 0.954）的药效团模型，这些模型已建立、生成并验证为可靠模型，用于进一步设计和优化具有增强抗癌活性的新分子。
