Alaa A Hassan1, Ashraf A Aly2, Nasr K Mohamed2, Kamal M El Shaieb2, Maysa M Makhlouf2, El-Shimaa M N Abdelhafez3, Stefan Bräse4, Martin Nieger5, Kevin N Dalby6, Tamer S Kaoud7. 1. Chemistry Department, Faculty of Science, Minia University, El-Minia 61519, Egypt. Electronic address: alaahassan2001@mu.edu.eg. 2. Chemistry Department, Faculty of Science, Minia University, El-Minia 61519, Egypt. 3. Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, El-Minia 61519, Egypt. 4. Institute of Organic Chemistry, Karlsruhe Institute of Technology, Fritz-Haber-Weg 6, Karlsruhe 76131, Germany; 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. 7. Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, El-Minia 61519, Egypt; Division of Chemical Biology and Medicinal Chemistry, The University of Texas at Austin, Austin, TX 78712, USA. Electronic address: tkaood1@utexas.edu.
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.
A large number of natural products containing the n class="Chemical">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 A549non-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 propellanesto provoke cytotoxic activity, likely through DNA binding-induced DNA damage and apoptosis.
Keywords:
Alkenylidene-hydrazinecarbothioamides; DNA damage induction; DNA non-intercalative interaction; Dicyanomethylene-1,3-indanedione; Furo-imidazo[3.3.3]-propellanes; Non-small cell lung cancer
Authors: Ashraf A Aly; Essmat M El-Sheref; Momtaz E M Bakheet; Mai A E Mourad; Stefan Bräse; Mahmoud A A Ibrahim; Martin Nieger; Boyan K Garvalov; Kevin N Dalby; Tamer S Kaoud Journal: Bioorg Chem Date: 2018-10-23 Impact factor: 5.275
Authors: Ayon Chakraborty; Subhashree P Dash; Alok K Panda; Rama Acharyya; Ashis Biswas; Subhadip Mukhopadhyay; Sujit K Bhutia; Aurélien Crochet; Yogesh P Patil; M Nethaji; Rupam Dinda Journal: Dalton Trans Date: 2015-04-07 Impact factor: 4.390
Authors: Brian C Bales; Tetsuya Kodama; Yvonne N Weledji; Marguerite Pitié; Bernard Meunier; Marc M Greenberg Journal: Nucleic Acids Res Date: 2005-09-26 Impact factor: 16.971