Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow 226025, India.
Department of Pharmacy, Birla Institute of Technology & Science - Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad- 500078, Telangana State, India.
Anticancer Agents Med Chem. 2018;18(5):719-738. doi: 10.2174/1871520617666170419122916.
Colon cancer is one of the most widespread disease, the mortality rate is high due to cancer metastasis and the development of drug resistance. In this regards, new chemotherapeutic agents with specific mechanisms of action and significant effect on patient's survival are the new era for the colon cancer drug development.
The main objective of present study was to design, synthesize of a novel series of 1,3,4-thiadiazole derivatives (VR1 to VR35) and screen them against HT-29 human colon cancer cell line.
Newly 1,3,4-thiadiazole scaffold were designed, synthesized and further, characterized by FTIR, NMR (1H and 13C), MS and elemental analyses. Before the synthesis, molecular dynamic simulation and ADME studies were performed to find out the most potent lead compounds. Later, SRB assay using HT-29 cells and ELISA assays were performed to explore activity and molecular targets of VR24 and VR27 and find out whether in silico data had a similar pattern in the molecular level.
The results of docking study revealed that both VR24 and VR27 had interaction energy >-5 kcal/mol with various assigned molecular targets and the ligand-protein complexes were found to be stable with IL-6. The computational analysis of molecules showed good ADMET profiling. Later, the in vitro anticancer study was conducted where VR24 and VR27 were found to be active against HT-29 cells (GI50<10 µM). Finally, ELISA assays revealed that both the compounds had higher inhibition properties to various biomarker of colon cancer like IL-6 and COX-2.
Collectively, these result suggested that VR24 and VR27 inhibited the assigned molecular targets, imparting their ameliorative effects against colon cancer. Due to these encouraging results, we concluded that both VR24 and VR27 may be effective against colon cancer therapy in future.
结肠癌是最广泛传播的疾病之一，由于癌症转移和耐药性的发展，其死亡率很高。在这方面，具有特定作用机制和对患者生存有显著影响的新型化疗药物是结肠癌药物开发的新时代。
本研究的主要目的是设计、合成一系列新型 1,3,4-噻二唑衍生物（VR1 至 VR35），并对其进行筛选，以评估其对 HT-29 人结肠癌细胞系的抑制作用。
设计、合成了新型 1,3,4-噻二唑骨架，并通过 FTIR、NMR（1H 和 13C）、MS 和元素分析进行了进一步的表征。在合成之前，进行了分子动力学模拟和 ADME 研究，以找出最有效的先导化合物。随后，通过 HT-29 细胞的 SRB 测定和 ELISA 测定，研究了 VR24 和 VR27 的活性和分子靶点，并探讨了计算机模拟数据在分子水平上是否具有相似的模式。
docking 研究结果表明，VR24 和 VR27 与各种指定的分子靶点均具有相互作用能>-5 kcal/mol，配体-蛋白复合物与 IL-6 结合稳定。分子的计算分析表明具有良好的 ADMET 特性。随后进行了体外抗癌研究，结果发现 VR24 和 VR27 对 HT-29 细胞具有活性（GI50<10 µM）。最后，ELISA 测定结果表明，两种化合物对各种结肠癌生物标志物（如 IL-6 和 COX-2）均具有更高的抑制作用。
综上所述，这些结果表明 VR24 和 VR27 抑制了指定的分子靶点，从而发挥了对结肠癌的改善作用。由于这些令人鼓舞的结果，我们得出结论，VR24 和 VR27 可能在未来对结肠癌的治疗有效。
