Design,synthesis, and DNA interaction studies of furo-imidazo[3.3.3]propellane derivatives: Potential anticancer agents |
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| Affiliation: | 1. Chemistry Department, Faculty of Science, Minia University, El-Minia 61519, Egypt;2. Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, El-Minia 61519, Egypt;3. Institute of Organic Chemistry, Karlsruhe Institute of Technology, Fritz-Haber-Weg 6, Karlsruhe 76131, Germany;4. Institute of Toxicology and Genetics, Hermann-von-Helmholtz-Platz 1, D-76344 Eggenstein-Leopoldshafen, Germany;5. Department of Chemistry, University of Helsinki, P.O. Box 55, A.I. Virtasen aukio I, Helsinki 00014, Finland;6. Division of Chemical Biology and Medicinal Chemistry, The University of Texas at Austin, Austin, TX 78712, USA;1. State Key Laboratory for Mechanical Behavior of Materials, Xi’an Jiaotong University, 710049 Xi’an, PR China;2. Suzhou Institute of Nano-tech and Nano-bionics, Chinese Academy of Sciences, 215123 Suzhou, PR China;1. Department of Chemistry, Faculty of Science, University of Sistan and Baluchestan, P.O. Box 98135-674, Zahedan, Iran;2. Biomaterials Group, Nanotechnology and Advanced Materials, Materials and Energy Research Center, Karaj, Iran;1. Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India;2. Medicinal Chemistry and Biotechnology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India;3. Centre for Advanced Materials & Industrial Chemistry (CAMIC), School of Science, RMIT-University, GPO BOX 2476, Melbourne 3001, Australia;4. CSIR-CCMB, Medical Biotechnology Division, Annexure-II, Hyderabad 500007, India;5. School of Pharmaceutical Education and Research (SPER), Jamia Hamdard, New Delhi 110 062, India;1. School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, Zhejiang 310035, China;2. Yueqing Hospital of TCM, Yueqing, Zhejiang 325600, China;3. Bureau of Jiulongshan, Nature Reserve, Suichang, Zhejiang 323300, China |
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| Abstract: | 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. |
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| Keywords: | Furo-imidazo[3.3.3]-propellanes Alkenylidene-hydrazinecarbothioamides Dicyanomethylene-1,3-indanedione DNA non-intercalative interaction DNA damage induction Non-small cell lung cancer |
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