2. Academic Validation
  3. New benzenesulfonamide scaffold-based cytotoxic agents: Design, synthesis, cell viability, apoptotic activity and radioactive tracing studies

New benzenesulfonamide scaffold-based cytotoxic agents: Design, synthesis, cell viability, apoptotic activity and radioactive tracing studies

  • Bioorg Chem. 2020 Mar:96:103577. doi: 10.1016/j.bioorg.2020.103577.
Yassin M Nissan 1,  Khaled O Mohamed 2,  Wafaa A Ahmed 3,  Dina M Ibrahim 4,  Marwa M Sharaky 3,  Tamer M Sakr 5,  Mohamed A Motaleb 6,  Ahmed Maher 7,  Reem K Arafa 8
Affiliations

Affiliations

  • 1 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr Elini St., Cairo 11562, Egypt; Pharmaceutical Chemistry Department, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), Giza, Egypt.
  • 2 Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Egypt.
  • 3 National Cancer Institute, Cancer Biology Department, Cairo University, Egypt.
  • 4 Faculty of Science, Cairo University, Cairo, Egypt.
  • 5 Pharmaceutical Chemistry Department, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), Giza, Egypt; Radioactive Isotopes and Generator Department, Hot Labs Center, Atomic Energy Authority, P.O. Box 13759, Cairo, Egypt. Electronic address: tamer_sakr78@yahoo.com.
  • 6 Labeled Compounds Department, Hot Labs Center, Atomic Energy Authority, P.O. Box 13759, Cairo, Egypt.
  • 7 Biochemistry Department, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), Giza, Egypt.
  • 8 Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, 12578 Cairo, Egypt. Electronic address: rkhidr@zewailcity.edu.eg.
PMID: 31978683 DOI: 10.1016/j.bioorg.2020.103577
Abstract

A new series of thiazolidinone (5a-g), thiazinone (9a-g) and dithiazepinone (9a-g) heterocycles bearing a benzenesulfonamide scaffold was synthesized. Cytotoxicity of these derivatives was assessed against MCF-7, HepG2, HCT-116 and A549 Cancer cell lines and activity was compared to the known cytotoxic agents doxorubicin and 5-FU where the most active compounds displayed better to nearly similar IC50 values to the reference compounds. For assessing selectivity, the most active derivatives against MCF-7, 5b, 5c and 5e, were also assessed against the normal breast cell line MCF-10 A where they demonstrated high selective cytotoxicity to cancerous cells over that to normal cells. Further, the effect of the most active compounds 5b-e on MCF-7 and HepG2 cell cycle phase distribution was assessed and the tested sulfonamide derivatives were found to induce accumulation of cells in the <2n phase. To further confirm Apoptosis induction, Caspase 8 and 9 levels in MCF-7 and HepG2 were evaluated before and after treatment with compounds 5b-e and were found to be significantly higher after exposure to the test agents. Since 5c was the most active, its effect on the cell cycle regulation was confirmed where it showed inhibition of the CDK2/cyclin E1. Finally, in vivo biodistribution study using radioiodinated-5c revealed a significant uptake and targeting ability into solid tumor in a xenograft mouse model.

Keywords

Benzenesulfonamide scaffold-based derivatives; Caspase 8 and 9 levels; Cell cycle phase distribution analysis; Cytotoxicity.

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