Parupalli Ramulu, Akunuri Ravikumar, Spandana Akella, Phanindranath Regur, Pyreddy Suneela, Bazaz Mohd Rabi, Vadakattu Manasa, Joshi Swanand Vinayak, Bujji Sushmitha, Gorre Balakishan, Yaddanapudi Venkata Madhavi, Dandekar Manoj P, Reddy Velma Ganga, Nagesh Narayana, Nanduri Srinivas
Department of Chemical Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, Telangana State, India.
CSIR-Centre for Cellular and Molecular Biology, Medical Biotechnology Complex, ANNEXE II, Uppal Road, Hyderabad 500007, India.
Bioorg Chem. 2023 Jun;135:106478. doi: 10.1016/j.bioorg.2023.106478. Epub 2023 Mar 17.
Cancer is associated with uncontrolled cell proliferation invading adjoining tissues and organs. Despite the availability of several chemotherapeutic agents, the constant search for newer approaches and drugs is necessitated owing to the ever-growing challenge of resistance. Over the years, DNA has emerged as an important druggable therapeutic drug due to its role in critical cellular processes such as cell division and maintenance. Further, evading apoptosis stands out as a hallmark of cancer. Hence, designing new compounds that would target DNA and induce apoptosis plays an important role in cancer therapy. In the current work, we carried out the synthesis and anticancer evaluation of 1-aryl-4,6-dihydrobenzo[b]pyrazolo[3,4-d]azepin-5(1H)-ones/thiones (26 compounds) against selected human cancer cell lines. Among these, compounds 8ae, 8ad, 8cf, 10ad and Kenpaullone have shown good inhibitory properties against HeLa cells (IC < 2 µM) with good selectivity over the non-cancerous human embryonic kidney (Hek293T) cells. In cell cycle analysis, the compounds 8ad and 8cf have exhibited G/M cell cycle arrest in HeLa cells. In addition, the compounds 8ad and 8cf induced apoptosis in a dose-dependent manner in the Annexin-V FITC staining assay. The DAPI staining clearly demonstrated the condensed and fragmented nuclei in 8ad, 8cf, 8ae and Kenpaullone-treated HeLa cells. In addition, these compounds strongly suppressed the healing after 48 h in in vitro cell migration assay. The DNA binding experiments indicated that compounds 8ae, 8cf, and 8ad as well as Kenpaullone interact with double-stranded DNA by binding in grooves which may interrupt the DNA replication and kill fast-growing cells. Molecular docking studies revealed the binding pose of 8ad and Kenpaullone at HT1 binding pocket of double-stranded DNA. Compounds 8ad and 8cf demonstrated moderate topo II inhibition which could be a possible reason for their anticancer properties. Compounds 8ad and 8cf may cause the topo II and DNA covalent complex, which leads to the inhibition of DNA replication and transcription. This eventually increases the DNA damage in cells and promotes cell apoptosis. With the above interesting biological profile, the new 1-aryl-2,6-dihydrobenzo[b]pyrazolo[3,4-d]azepin-5(4H)-one/thione derivatives have emerged as promising leads for the discovery of new anticancer agents.
癌症与不受控制的细胞增殖有关，会侵袭相邻的组织和器官。尽管有多种化疗药物可供使用，但由于耐药性这一日益严峻的挑战，仍有必要不断寻找更新的方法和药物。多年来，DNA因其在细胞分裂和维持等关键细胞过程中的作用，已成为一种重要的可成药治疗药物。此外，逃避细胞凋亡是癌症的一个标志。因此，设计能够靶向DNA并诱导细胞凋亡的新化合物在癌症治疗中起着重要作用。在当前的工作中，我们对1-芳基-4,6-二氢苯并[b]吡唑并[3,4-d]氮杂卓-5(1H)-酮/硫酮（26种化合物）针对选定的人类癌细胞系进行了合成和抗癌评估。其中，化合物8ae、8ad、8cf、10ad和肯帕罗利对HeLa细胞显示出良好的抑制特性（IC<2μM），对非癌性人胚胎肾（Hek293T）细胞具有良好的选择性。在细胞周期分析中，化合物8ad和8cf在HeLa细胞中表现出G/M期细胞周期阻滞。此外，在膜联蛋白-V FITC染色试验中，化合物8ad和8cf以剂量依赖性方式诱导细胞凋亡。DAPI染色清楚地显示了用8ad、8cf、8ae和肯帕罗利处理的HeLa细胞中浓缩和碎片化的细胞核。此外，在体外细胞迁移试验中，这些化合物在48小时后强烈抑制愈合。DNA结合实验表明，化合物8ae、8cf、8ad以及肯帕罗利通过在沟槽中结合与双链DNA相互作用，这可能会中断DNA复制并杀死快速生长的细胞。分子对接研究揭示了8ad和肯帕罗利在双链DNA的HT1结合口袋处的结合姿势。化合物8ad和8cf表现出中等程度的拓扑异构酶II抑制作用，这可能是它们具有抗癌特性的一个可能原因。化合物8ad和8cf可能会导致拓扑异构酶II与DNA形成共价复合物，从而抑制DNA复制和转录。这最终会增加细胞中的DNA损伤并促进细胞凋亡。凭借上述有趣的生物学特性，新型1-芳基-2,6-二氢苯并[b]吡唑并[3,4-d]氮杂卓-5(4H)-酮/硫酮衍生物已成为发现新型抗癌药物的有前景的先导化合物。
