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Design and discovery of new 1,2,4‐triazolo[4,3‐ c ]quinazolines as potential DNA intercalators and topoisomerase II inhibitors
Author(s) -
Alesawy Mohamed S.,
AlKarmalawy Ahmed A.,
Elkaeed Eslam B.,
Alswah Mohamed,
Belal Ahmed,
Taghour Mohammed S.,
Eissa Ibrahim H.
Publication year - 2021
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.202000237
Subject(s) - cytotoxicity , topoisomerase , chemistry , dna , stereochemistry , intercalation (chemistry) , quinazoline , in vitro , docking (animal) , apoptosis , cell cycle , cell cycle checkpoint , mechanism of action , growth inhibition , biochemistry , medicine , inorganic chemistry , nursing
A new series of 1,2,4‐triazolo[4,3‐ c ]quinazoline derivatives was designed and synthesized as Topo II inhibitors and DNA intercalators. The cytotoxic effect of the new members was evaluated in vitro against a group of cancer cell lines including HCT‐116, HepG‐2, and MCF‐7. Compounds 14 c , 14 d , 14 e , 14 e , 15 b , 18 b , 18 c , and 19 b exhibited the highest activities with IC 50 values ranging from 5.22 to 24.24 µM. Furthermore, Topo II inhibitory activities and DNA intercalating affinities of the most promising candidates were evaluated as a possible mechanism for the antiproliferative effect. The results of the Topo II inhibition and DNA binding tests were coherent with that of in vitro cytotoxicity. Additionally, the most promising compound 18 c was analyzed in HepG‐2 cells for its apoptotic effect and cell cycle arrest. It was found that 18 c can induce apoptosis and arrest the cell cycle at the G2–M phase. Finally, molecular docking studies were carried out for the designed compounds against the crystal structure of the DNA−Topo II complex as a potential target to explore their binding modes. On the basis of these studies, it was hypothesized that the DNA binding and/or Topo II inhibition would participate in the noted cytotoxicity of the synthesized compounds.