Design, synthesis, and DNA interaction studies of furo-imidazo[3.3.3]propellane derivatives: Potential anticancer agents

Alaa A. Hassan, Ashraf A. Aly, Nasr K. Mohamed, Kamal M. El Shaieb, Maysa M. Makhlouf, El Shimaa M.N. Abdelhafez, Stefan Bräse, Martin Nieger, Kevin N. Dalby, Tamer S. Kaoud

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)585-599
Number of pages15
JournalBioorganic Chemistry
Volume85
DOIs
StatePublished - Apr 2019

Fingerprint

Antineoplastic Agents
Derivatives
DNA
Cells
Drug Delivery Systems
DNA Damage
Spectrum Analysis
Cytotoxicity
Intercalating Agents
Apoptosis
Nucleic Acid Denaturation
Caspase 7
Cell Line
Neoplasms
Competitive Binding
Annexin A5
Biological Products
Viscosity
Non-Small Cell Lung Carcinoma
Caspase 3

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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Drug Discovery
  • Organic Chemistry

Cite this

Hassan, A. A., Aly, A. A., Mohamed, N. K., El Shaieb, K. M., Makhlouf, M. M., Abdelhafez, E. S. M. N., ... Kaoud, T. S. (2019). Design, synthesis, and DNA interaction studies of furo-imidazo[3.3.3]propellane derivatives: Potential anticancer agents. Bioorganic Chemistry, 85, 585-599. https://doi.org/10.1016/j.bioorg.2019.02.027

Design, synthesis, and DNA interaction studies of furo-imidazo[3.3.3]propellane derivatives : Potential anticancer agents. / Hassan, Alaa A.; Aly, Ashraf A.; Mohamed, Nasr K.; El Shaieb, Kamal M.; Makhlouf, Maysa M.; Abdelhafez, El Shimaa M.N.; Bräse, Stefan; Nieger, Martin; Dalby, Kevin N.; Kaoud, Tamer S.

In: Bioorganic Chemistry, Vol. 85, 04.2019, p. 585-599.

Research output: Contribution to journalArticle

Hassan, AA, Aly, AA, Mohamed, NK, El Shaieb, KM, Makhlouf, MM, Abdelhafez, ESMN, Bräse, S, Nieger, M, Dalby, KN & Kaoud, TS 2019, 'Design, synthesis, and DNA interaction studies of furo-imidazo[3.3.3]propellane derivatives: Potential anticancer agents', Bioorganic Chemistry, vol. 85, pp. 585-599. https://doi.org/10.1016/j.bioorg.2019.02.027
Hassan, Alaa A. ; Aly, Ashraf A. ; Mohamed, Nasr K. ; El Shaieb, Kamal M. ; Makhlouf, Maysa M. ; Abdelhafez, El Shimaa M.N. ; Bräse, Stefan ; Nieger, Martin ; Dalby, Kevin N. ; Kaoud, Tamer S. / Design, synthesis, and DNA interaction studies of furo-imidazo[3.3.3]propellane derivatives : Potential anticancer agents. In: Bioorganic Chemistry. 2019 ; Vol. 85. pp. 585-599.
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