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Journal Article Epublish 7 citations

PubMed: 37954422 DOI: 10.1039/d3ra06189b

Novel 2-substituted-quinoxaline analogs with potential antiproliferative activity against breast cancer: insights into cell cycle arrest, topoisomerase II, and EGFR activity.

RSC Adv 13(47):33080-33095

Authors: Manar G Salem, Sara A Abu El-Ata, Elsherbiny H Elsayed, Suraj N Mali, Hussah Abdullah Alshwyeh, Ghassan Almaimani, Riyad A Almaimani, Hussain A Almasmoum, Najla Altwaijry, Ebtesam Al-Olayan, Essa M Saied, Mohamed F Youssef

Affiliations

  • Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Suez Canal University Ismailia 41522 Egypt.
  • Department of Chemistry, Faculty of Science, Port Said University Port Said Egypt.
  • Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology Ranchi 835215 India.
  • Department of Biology, College of Science, Imam Abdulrahman Bin Faisal University Dammam 31441 Saudi Arabia.
  • Basic & Applied Scientific Research Centre, Imam Abdulrahman Bin Faisal University PO Box 1982 Dammam 31441 Saudi Arabia.
  • Department of Surgery, Faculty of Medicine, Umm Al-Qura University Al Abdeyah, PO Box 7607 Makkah Saudi Arabia.
  • Department of Biochemistry, Faculty of Medicine, Umm Al-Qura University Al Abdeyah, PO Box 7607 Makkah Saudi Arabia.
  • Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Umm Al-Qura University Al Abdeyah, PO Box 7607 Makkah Saudi Arabia.
  • Department of Pharmaceutical Sciences, Princess Nourah Bint Abdulrahman University PO Box 84428 Riyadh 11671 Saudi Arabia.
  • Department of Zoology, College of Science, King Saud University Riyadh Saudi Arabia.
  • Department of Chemistry (Biochemistry Division), Faculty of Science, Suez Canal University Ismailia 41522 Egypt.
  • Institute for Chemistry, Humboldt Universität zu Berlin Brook-Taylor-Str. 2 12489 Berlin Germany.
  • Department of Chemistry (Organic Chemistry Division), Faculty of Science, Suez Canal University Ismailia 41522 Egypt.

Abstract

Breast cancer is a global health concern, with increasing disease burden and disparities in access to healthcare. Late diagnosis and limited treatment options in underserved areas contribute to poor outcomes. In response to this challenge, we developed a novel family of 2-substituted-quinoxaline analogues, combining coumarin and quinoxaline scaffolds known for their anticancer properties. Through a versatile synthetic approach, we designed, synthesized, and characterized a set of 2-substituted quinoxaline derivatives. The antiproliferative activity of the synthesized compounds was assessed toward the MCF-7 breast cancer cells. Our investigations showed that the synthesized compounds exhibit considerable antiproliferative activity toward MCF-7 cells. Notably, compound 3b, among examined compounds, displayed a superior inhibitory effect (IC = 1.85 ± 0.11 μM) toward the growth of MCF-7 cells compared to the conventional anticancer drug staurosporine (IC = 6.77 ± 0.41 μM) and showed minimal impact on normal cells (MCF-10A cell lines, IC = 33.7 ± 2.04 μM). Mechanistic studies revealed that compound 3b induced cell cycle arrest at the G1 transition and triggered apoptosis in MCF-7 cells, as evidenced by increasing the percentage of cells arrested in the G2/M and pre-G1 phases utilizing flow cytometric analysis and Annexin V-FITC/PI analysis. Moreover, compound 3b was found to substantially suppress topoisomerase enzyme activity in MCF-7 cells. Molecular modeling studies further supported the potential of compound 3b as a therapeutic candidate by demonstrating significant binding affinity to the active sites of both topoisomerase II and EGFR proteins. Taken together, the presented 2-substituted-quinoxaline analogues, especially compound 3b, show promise as potential candidates for the development of effective anti-breast cancer drugs.

MeSH

Cell Cycle, Pharmaceutical Preparations, Therapeutics, Breast Neoplasms, Quinoxalines, Dna Topoisomerases, Type Ii, Mcf-7 Cells

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