Department of Chemistry, Dnyanprassarak Mandal's College & Research Centre, Assagao, Bardez, 403507, India.
Department of Chemistry, Dnyanprassarak Mandal's College & Research Centre, Assagao, Bardez, 403507, India.
Bioorg Chem. 2021 Dec;117:105331. doi: 10.1016/j.bioorg.2021.105331. Epub 2021 Sep 4.
Herein, we designed and synthesized 1,5-benzodiazepines as a lead molecule for anticancer activity and as potent synergistic activity with drug Methotrexate. Working under the framework of green chemistry principles, series of 1,5-benzodiazepine derivatives (3a-3a) were synthesized using biocatalyst i.e. thiamine hydrochloride under solvent free neat heat conditions. These compounds were screened for in vitro anti cancer activity against couple of cancer cell lines (HeLa and HEPG2) and normal human cell line HEK-293 via MTT assay. The IC values for the compounds were in the range 0.067 to 0.35 µM, better than Paclitaxel and compatible with the drug Methotrexate. Compound 3x was found to be influential against both the cell lines with IC values of 0.067 ± 0.002 µM against HeLa and 0.087 ± 0.003 µM against HEPG2 cell line, having activity as compatible to the standard drug Methotrexate. Bioinformatic analysis showed that these compounds are good tyrosine kinase inhibitors which was then proved using enzyme inhibition assay. The studies of apoptosis revealed late apoptotic mode of cell death for the compounds against HEPG2 cancer cell line using flow cytometry method. Synergistic studies of compound 3x and drug Methotrexate showed that the combination was highly active against cancer HeLa and HEPG2 cell line with IC50 value 0.046 ± 0.002 µM and 0.057 ± 0.002 µM respectively, which was well supported by apoptosis pathway. Further the compounds proved its scope as DNA intercalating agents, as its molecular docking and DNA binding studies revealed that the compounds would fit well into the DNA strands.
在此，我们设计并合成了 1,5-苯并二氮杂卓作为抗癌活性的先导分子，并与药物甲氨蝶呤具有很强的协同活性。在绿色化学原则的框架下，使用生物催化剂即盐酸硫胺素，在无溶剂的条件下进行热反应，合成了一系列 1,5-苯并二氮杂卓衍生物（3a-3a）。通过 MTT 法，对这些化合物进行了体外抗几种癌细胞系（HeLa 和 HEPG2）和正常人类细胞系 HEK-293 的抗癌活性筛选。化合物的 IC 值范围为 0.067 至 0.35 μM，优于紫杉醇，与药物甲氨蝶呤相兼容。化合物 3x 被发现对两种细胞系都有影响，对 HeLa 的 IC 值为 0.067 ± 0.002 μM，对 HEPG2 细胞系的 IC 值为 0.087 ± 0.003 μM，与标准药物甲氨蝶呤的活性相当。生物信息学分析表明，这些化合物是良好的酪氨酸激酶抑制剂，随后通过酶抑制试验得到证实。细胞凋亡研究表明，这些化合物对 HEPG2 癌细胞系的细胞凋亡模式为晚期凋亡。用流式细胞术对化合物 3x 与药物甲氨蝶呤的协同作用进行研究，结果表明，该组合对癌症 HeLa 和 HEPG2 细胞系的活性很高，IC50 值分别为 0.046 ± 0.002 μM 和 0.057 ± 0.002 μM，这得到了凋亡途径的很好支持。此外，这些化合物还证明了它们作为 DNA 嵌入剂的应用范围，因为其分子对接和 DNA 结合研究表明，这些化合物将很好地适合 DNA 链。
