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Synthesis and Biological Evaluation of 12-Aryl-11-Hydroxy-5,6-Dihydropyrrolo[2″,1″:3′,4′]Pyrazino[1′,2′:1,5]Pyrrolo[2,3-D]Pyridazine-8(9H)-One Derivatives As Potential Cytotoxic Agents Publisher



Barghi Lish A1 ; Foroumadi A2, 3 ; Kolvari E1 ; Safari F4
Authors
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Authors Affiliations
  1. 1. Department of Chemistry, Semnan University, Semnan, 35351-19111, Iran
  2. 2. Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, 1417614411, Iran
  3. 3. Drug Design and Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, 1417614411, Iran
  4. 4. Department of Biology, Faculty of Science, University of Guilan, Rasht, 4193833697, Iran

Source: ACS Omega Published:2023


Abstract

In the present paper, a facile and efficient synthetic procedure has been applied to obtain dihydrodipyrrolo[1,2-a:2′,1′-c]pyrazine-2,3-dicarboxylates (5a-s), which have subsequently gone through the cyclization in the presence of hydrazine hydrate to afford 12-aryl-11-hydroxy-5,6-dihydropyrrolo[2″,1″:3′,4′]pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-8(9H)-ones (7a-q). The molecular structures of these novel compounds were extensively examined through the analysis of spectroscopic data in combination with X-ray crystallography techniques. Following that, the in vitro cytotoxic activities of all derivatives against three human cancer cell lines (Panc-1, PC3, and MDA-MB-231) were comprehensively evaluated alongside the assessment on normal human dermal fibroblast (HDF) cells using the MTT assay. Among the compounds, the 3-nitrophenyl derivative (7m) from the second series showed the best antiproliferative activity against all tested cell lines, particularly against Panc-1 cell line, (IC50 = 12.54 μM), being nearly twice as potent as the standard drug etoposide. The induction of apoptosis and sub-G1 cell cycle arrest in Panc-1 cancer cells by compound 7m was confirmed through further assessment. Moreover, the inhibition of kinases and the induction of cellular apoptosis by compound 7m in Panc-1 cancer cells were validated using the Western blotting assay. © 2023 The Authors. Published by American Chemical Society.