Chemistry Department, Faculty of Science, Minia University, El-Minia 61519, Egypt.
Chemistry Department, Faculty of Science, Minia University, El-Minia 61519, Egypt.
Bioorg Chem. 2019 Apr;85:585-599. doi: 10.1016/j.bioorg.2019.02.027. Epub 2019 Feb 13.
A large number of natural products containing the propellane scaffold have been reported to exhibit cytotoxicity against several cancers; however, their mechanism of action is still unknown. Anticancer drugs targeting DNA are mainly composed of small planar molecule/s that can interact with the DNA helix, causing DNA malfunction and cell death. The aim of this study was to design and synthesize propellane derivatives that can act as DNA intercalators and/or groove binders. The unique structure of the propellane derivatives and their ability to display planar ligands with numerous possible geometries, renders them potential starting points to design new drugs targeting DNA in cancer cells. New substituted furo-imidazo[3.3.3]propellanes were synthesized via the reaction of substituted alkenylidene-hydrazinecarbothioamides with 2-(1,3-dioxo-2,3-dihydro-1H-2-ylidene)propanedinitrile in tetrahydrofuran at room temperature. The structures of the products were confirmed by a combination of elemental analysis, NMR, ESI-MS, IR and single crystal X-ray analysis. Interestingly, 5c, 5d and 5f showed an ability to interact with Calf Thymus DNA (CT-DNA). Their DNA-binding mode was investigated using a combination of absorption spectroscopy, DNA melting, viscosity, CD spectroscopy measurements, as well as competitive binding studies with several dyes. Their cytotoxicity was evaluated against the NCI-60 panel of cancer cell lines. 5c, 5d and 5f exhibited similar anti-proliferative activity against the A549 non-small cell lung cancer (NSCLC) cell line. Further mechanistic studies revealed their ability to induce DNA damage in the A549 cell line, as well as apoptosis, evidenced by elevated Annexin V expression, enhanced caspase 3/7 activation and PARP cleavage. In this study, we present the potential for designing novel propellanes to provoke cytotoxic activity, likely through DNA binding-induced DNA damage and apoptosis.
大量含有推进烷骨架的天然产物已被报道具有细胞毒性，可抑制多种癌症；然而，其作用机制尚不清楚。作用于 DNA 的抗癌药物主要由可与 DNA 螺旋相互作用的小型平面分子组成，导致 DNA 功能失常和细胞死亡。本研究旨在设计和合成可作为 DNA 嵌入剂和/或沟结合剂的推进烷衍生物。推进烷衍生物的独特结构及其能够展示具有多种可能构象的平面配体的能力，使其成为设计针对癌细胞中 DNA 的新型药物的潜在起点。新取代的呋喃-咪唑并[3.3.3]推进烷衍生物通过取代的烯基腙硫代甲酰胺与 2-(1,3-二氧代-2,3-二氢-1H-2-亚基)丙二腈在四氢呋喃中于室温下反应合成。通过元素分析、NMR、ESI-MS、IR 和单晶 X 射线分析相结合，确认了产物的结构。有趣的是，5c、5d 和 5f 显示出与小牛胸腺 DNA（CT-DNA）相互作用的能力。使用吸收光谱、DNA 熔解、粘度、CD 光谱测量以及与几种染料的竞争性结合研究相结合，研究了它们的 DNA 结合模式。它们的细胞毒性针对 NCI-60 癌症细胞系面板进行了评估。5c、5d 和 5f 对非小细胞肺癌（NSCLC）A549 细胞系表现出相似的抗增殖活性。进一步的机制研究表明，它们能够在 A549 细胞系中诱导 DNA 损伤，并通过升高的 Annexin V 表达、增强的 caspase 3/7 激活和 PARP 切割诱导细胞凋亡。在本研究中，我们提出了设计新型推进烷以引发细胞毒性的潜力，可能通过 DNA 结合诱导的 DNA 损伤和细胞凋亡。
