Design, synthesis and screening of 1, 2, 4-triazinone derivatives as potential antitumor agents with apoptosis inducing activity on MCF-7 breast cancer cell line

Islam Zaki; Mohammed K Abdelhameid; Ibrahim M El-Deen; Abdel Hady A Abdel Wahab; Abeer M Ashmawy; Khaled O Mohamed

doi:10.1016/j.ejmech.2018.07.003

Design, synthesis and screening of 1, 2, 4-triazinone derivatives as potential antitumor agents with apoptosis inducing activity on MCF-7 breast cancer cell line

Eur J Med Chem. 2018 Aug 5:156:563-579. doi: 10.1016/j.ejmech.2018.07.003. Epub 2018 Jul 7.

Authors

Islam Zaki¹, Mohammed K Abdelhameid², Ibrahim M El-Deen³, Abdel Hady A Abdel Wahab⁴, Abeer M Ashmawy⁴, Khaled O Mohamed⁵

Affiliations

¹ Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Port Said University, Port Said, Egypt.
² Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt. Electronic address: mohorganic@hotmail.com.
³ Chemistry Department, Faculty of Science, Port Said University, Port Said, Egypt.
⁴ Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt.
⁵ Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt.

PMID: 30025350
DOI: 10.1016/j.ejmech.2018.07.003

Abstract

Some triazinone derivatives are designed and synthesized as potential antitumor agents. Triazinone derivatives 4c, 5e and 7c show potent anticancer activity over MCF-7 breast cancer cells higher than podophyllotoxin (podo) by approximate 6-fold. DNA flow cytometry analysis for the compounds 3c, 4c, 5e, 6c and 7c show a potent inhibitory activity of cell proliferation and cell cycle arrest at G₂/M phase. Compounds 4c, 5e and 7c exhibit low to moderate β-tubulin polymerization inhibition percentage. Meanwhile, compound 6c displayed excellent β-tubulin percentage of polymerization inhibition equivalent to that exhibited by podo. In addition, compounds 4c, 5e and 7c show strong topoisomerase (topo) II inhibitory activity in nano-molar concentration, compared to known topo inhibitor as etoposide. Finally, apoptotic inducing activity over MCF-7 of compounds 4c, 5e, 6c and 7c is due to up-regulation of p53, increased Bax/Bcl-2 ratio and caspase3/7 levels 2-fold higher than podo.

Published by Elsevier Masson SAS.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects*
Breast Neoplasms / drug therapy*
Breast Neoplasms / metabolism
Drug Design*
Female
Humans
MCF-7 Cells
Topoisomerase II Inhibitors / chemical synthesis
Topoisomerase II Inhibitors / chemistry
Topoisomerase II Inhibitors / pharmacology
Triazines / chemical synthesis
Triazines / chemistry*
Triazines / pharmacology*
Tubulin / metabolism
Tubulin Modulators / chemical synthesis
Tubulin Modulators / chemistry
Tubulin Modulators / pharmacology

Substances

Antineoplastic Agents
Topoisomerase II Inhibitors
Triazines
Tubulin
Tubulin Modulators