2. Academic Validation
  3. Design, synthesis, molecular modeling and anti-proliferative evaluation of novel quinoxaline derivatives as potential DNA intercalators and topoisomerase II inhibitors

Design, synthesis, molecular modeling and anti-proliferative evaluation of novel quinoxaline derivatives as potential DNA intercalators and topoisomerase II inhibitors

  • Eur J Med Chem. 2018 Jul 15:155:117-134. doi: 10.1016/j.ejmech.2018.06.004.
M K Ibrahim 1,  M S Taghour 1,  A M Metwaly 2,  A Belal 3,  A B M Mehany 4,  M A Elhendawy 5,  M M Radwan 5,  A M Yassin 6,  N M El-Deeb 6,  E E Hafez 7,  M A ElSohly 8,  I H Eissa 9
Affiliations

Affiliations

  • 1 Medicinal Chemistry Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, 11884, Egypt.
  • 2 Pharmacognosy Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, 11884, Egypt.
  • 3 Medicinal Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt.
  • 4 Zoology Department, Faculty of Science, Al-Azhar University, Cairo, 11884, Egypt.
  • 5 National Center for Natural Products Research, University of Mississippi, University, MS, 38677, USA.
  • 6 Biopharmaceutical Product Research Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications, Alexandria, Egypt.
  • 7 Department of Plant Protection and Biomolecular Diagnosis, ALCRI City of Scientific Research and Technological Applications, Alexandria, Egypt.
  • 8 National Center for Natural Products Research, University of Mississippi, University, MS, 38677, USA. Electronic address: mmelsohly@olemiss.edu.
  • 9 Medicinal Chemistry Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, 11884, Egypt. Electronic address: Ibrahimeissa@azhar.edu.eg.
PMID: 29885574 DOI: 10.1016/j.ejmech.2018.06.004
Abstract

New series of [1,2,4]triazolo [4,3-a]quinoxaline and bis([1,2,4]triazolo)[4,3-a:3',4'-c]quinoxaline derivatives have been designed, synthesized and biologically evaluated for their cytotoxic activities against three tumor cell lines (HePG-2, Hep-2 and Caco-2). Compounds 16e, 21, 25a and 25b exhibited the highest activities against the examined cell lines with IC50 values ranging from 0.29 to 0.90 μM comparable to that of doxorubicin (IC50 ranging from 0.51 to 0.73 μM). The most active members were further evaluated for their Topoisomerase II (Topo II) inhibitory activities and DNA intercalating affinities as potential mechanisms for their anti-proliferative activities. Interestingly, the results of Topo II inhibition and DNA binding assays were consistent with that of the cytotoxicity data, where the most potent anti-proliferative derivatives exhibited good Topo II inhibitory activities and DNA binding affinities, comparable to that of doxorubicin. Moreover, the most active compound 25a caused cell cycle arrest at G2/M phase and induced Apoptosis in Caco-2 cells. In addition, Furthermore, molecular docking studies were performed for the novel compounds against DNA-Topo II complex to investigate their binding patterns. Based on these studies, it was concluded that DNA binding and/or Topo II inhibition may contribute to the observed cytotoxicity of the synthesized compounds.

Keywords

Anticancer; DNA-Intercalator; Molecular docking; Quinoxaline derivatives; Topoisomerase II.

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