2. Academic Validation
  3. In vitro cytotoxic activity of thiazole-indenoquinoxaline hybrids as apoptotic agents, design, synthesis, physicochemical and pharmacokinetic studies

In vitro cytotoxic activity of thiazole-indenoquinoxaline hybrids as apoptotic agents, design, synthesis, physicochemical and pharmacokinetic studies

  • Bioorg Chem. 2020 Jul;100:103951. doi: 10.1016/j.bioorg.2020.103951.
Eman A Fayed 1,  Yousry A Ammar 2,  Ahmed Ragab 3,  Nirvana A Gohar 4,  Ahmed B M Mehany 5,  Amel M Farrag 6
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo 11754, Egypt. Electronic address: alfayed_e@azhar.edu.eg.
  • 2 Department of Chemistry, Faculty of Science (Boys), Al-Azhar University, Cairo 11754, Egypt. Electronic address: yossry@yahoo.com.
  • 3 Department of Chemistry, Faculty of Science (Boys), Al-Azhar University, Cairo 11754, Egypt.
  • 4 Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, MTI University, Cairo, Egypt.
  • 5 Department of Zoology, Faculty of Science (Boys), Al-Azhar University, Cairo 11754, Egypt. Electronic address: amelfarrag@azhar.edu.eg.
  • 6 Department of Pharmaceutical Chemistry, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo 11754, Egypt. Electronic address: abelal_81@yahoo.com.
PMID: 32450392 DOI: 10.1016/j.bioorg.2020.103951
Abstract

In this study, anti-proliferative effects of twenty-seven indeno[1,2-b]quinoxalin-11-one derivatives were investigated in three human Cancer cell lines, namely: the colon Cancer cell line HCT-116, the liver Cancer cell line HepG-2, and the breast Cancer cell line MCF-7. Among them, 5, 6, 13, 14a, b and 15d-f derivatives displayed excellent anti-proliferative activities against the three tested cell lines compared to the reference standard Imatinib. Therefore, they were selected for further studies. First, to ensure the safety of our hits, investigation of the IC50 values on normal human cells (WI-38) was executed indicating that, they are highly selective (IC50 > 107 μM) in their cytotoxic effect. Second, the induction of Apoptosis by these active compounds was achieved by down-regulation of Bcl-2 and up-regulation of Bax and Caspase-3. Further investigations have shown that 14b and 15f, the most potent derivatives, induced cell cycle arrest at G2/M phase. Moreover, in silico evaluation of ADME properties indicated that all the potent compounds are orally bioavailable with no permeation to the blood brain barrier.

Keywords

BAX; Bcl-2 and Cancer Treatment; Caspase-3; Indeno[1,2-b]quinoxalin; Thiazole.

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