Design and discovery of new 1, 2, 4‐triazolo[4, 3‐c]quinazolines as potential DNA intercalators and topoisomerase II inhibitors. Issue 3 (23rd November 2020)

• Record Type: Journal Article
• Authors: Alesawy, Mohamed S.; Al‐Karmalawy, Ahmed A.; Elkaeed, Eslam B.; Alswah, Mohamed; Belal, Ahmed; Taghour, Mohammed S.; Eissa, Ibrahim H.
• Is Part Of: Archiv der Pharmazie. Volume 354:Issue 3(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-11-23
• Subjects: anticancer -- DNA intercalator -- molecular docking -- 1, 2, 4‐triazolo[4, 3‐c]quinazoline -- topoisomerase II; Pharmaceutical chemistry -- Periodicals; Pharmacology -- Periodicals; 615.19
• DOI: 10.1002/ardp.202000237
• Languages: English
• ISSNs: 0365-6233

Abstract

Abstract: 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 IC50 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. Abstract : A new series of 1, 2, 4‐triazolo[4, 3‐ c ]quinazoline derivatives was designed and synthesized as topoisomerase II (Topo II) inhibitors and DNA intercalators, and their cytotoxic effect was evaluated in vitro. Compounds 14 c, 14 d, 14 e, 14 e, 15 b, 18 b, 18 c, and 19 b exhibited the highest activities. DNA binding and/or Topo II inhibition may contribute to the cytotoxicity of the synthesized compounds