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

M K Ibrahim; M S Taghour; A M Metwaly; A Belal; A B M Mehany; M A Elhendawy; M M Radwan; A M Yassin; N M El-Deeb; E E Hafez; M A ElSohly; I H Eissa

doi:10.1016/j.ejmech.2018.06.004

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. Epub 2018 Jun 4.

Authors

M K Ibrahim¹, M S Taghour¹, A M Metwaly², A Belal³, A B M Mehany⁴, M A Elhendawy⁵, M M Radwan⁵, A M Yassin⁶, N M El-Deeb⁶, E E Hafez⁷, M A ElSohly⁸, I H Eissa⁹

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 16_e, 21, 25_a and 25_b 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 25_a 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.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
DNA / drug effects*
DNA Cleavage
DNA Topoisomerases, Type II / metabolism*
Dose-Response Relationship, Drug
Drug Design*
Humans
Models, Molecular
Molecular Structure
Quinoxalines / chemical synthesis
Quinoxalines / chemistry
Quinoxalines / pharmacology*
Structure-Activity Relationship
Topoisomerase II Inhibitors / chemical synthesis
Topoisomerase II Inhibitors / chemistry
Topoisomerase II Inhibitors / pharmacology*

Substances

Antineoplastic Agents
Quinoxalines
Topoisomerase II Inhibitors
DNA
DNA Topoisomerases, Type II