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  3. New benzothienopyran and benzothienopyranopyrimidine derivatives as topoisomerase I inhibitors: Design, synthesis, anticancer screening, apoptosis induction and molecular modeling studies

New benzothienopyran and benzothienopyranopyrimidine derivatives as topoisomerase I inhibitors: Design, synthesis, anticancer screening, apoptosis induction and molecular modeling studies

  • Bioorg Chem. 2023 Aug:137:106638. doi: 10.1016/j.bioorg.2023.106638.
Nadia A Khalil 1,  Eman M Ahmed 2,  Ashraf F Zaher 2,  Shimaa M Alhamaky 3,  Nada Osama 4,  Mona S El-Zoghbi 5
Affiliations

Affiliations

  • 1 Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo 11562, Egypt. Electronic address: nadia.khalil@phrma.cu.edu.eg.
  • 2 Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo 11562, Egypt.
  • 3 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Menoufia University, Shibin El kom, Gamal Abd El-Nasir Street, Shibin Elkom, 32511 Menoufia, Egypt.
  • 4 Biochemistry Department, Faculty of Pharmacy, Menoufia University, Gamal Abd El Nasr st., Shibin Elkom, 32511 Menoufia, Egypt.
  • 5 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Menoufia University, Shibin El kom, Gamal Abd El-Nasir Street, Shibin Elkom, 32511 Menoufia, Egypt. Electronic address: mona.said@phrm.menofia.edu.eg.
PMID: 37257374 DOI: 10.1016/j.bioorg.2023.106638
Abstract

New benzothienopyran and benzothienopyranopyrimidine derivatives were synthesized based on the structural requirements of Topoisomerase I inhibitors. All target compounds exhibited strong cytotoxic activity with GI50 range of 70.62 %-87.29 % in one dose NCI (USA) screening against 60 human tumor cell lines. Among the tested derivatives, eight compounds namely 4d, 4e, 4f, 5b, 5e, 6b, 6d, and 6f demonstrated broad spectrum and potent Anticancer efficacy in five dose screening against all tested panels. DNA relaxation assay for the latter compounds showed that 4d, 5b, and 6f exhibited excellent inhibitory activity with IC50 range of 2.553-4.495 µM as compared to indenoisoquinoline reference drug (IC50 = 3.911 ± 0.21 µM). Moreover, the most active compounds were investigated for being Topoisomerase poisons or catalytic inhibitors using DNA nicking assay. Compounds 4d and 6f were found to be potential Topo I poisons, whereas compound 5b has acted as Topo I suppressor. Analyzing cell cycle and induction of Apoptosis for the most active compound 4d, revealed growth arrest at the S phase in MDA-MB-435 cells similarly to indenoisoquinoline reference drug. Additionally, in silico molecular modeling study for eight most active cytotoxic compounds in five dose screening demonstrated interaction with DNA as well as distinctive binding pattern similar to the reference indenoisoquinoline, indicating that the newly discovered targets are supposed to be promising candidates as Topo I inhibitors.

Keywords

Apoptosis; Benzothienopyran; Benzothienopyranopyrimidine; Cell cycle analysis; Cytotoxic agents; Molecular modeling; Topoisomerase inhibitors.

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