2. Academic Validation
  3. Synthesis, antitumor evaluation and microarray study of some new pyrazolo[3,4-d][1,2,3]triazine derivatives

Synthesis, antitumor evaluation and microarray study of some new pyrazolo[3,4-d][1,2,3]triazine derivatives

  • Eur J Med Chem. 2017 Dec 1:141:603-614. doi: 10.1016/j.ejmech.2017.10.016.
Tamer Nasr 1,  Samir Bondock 2,  Mahmoud Youns 3,  Walid Fayad 4,  Wafaa Zaghary 5
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Helwan University, Egypt. Electronic address: tamerhefni@yahoo.com.
  • 2 Department of Chemistry, Faculty of Science, Mansoura University, Mansoura, Egypt; Department of Chemistry, Faculty of Science, King Khalid University, Abha, Saudi Arabia.
  • 3 Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Helwan University, Egypt.
  • 4 Drug Bioassay-Cell Culture Laboratory, Pharmacognosy Department, National Research Centre, Dokki, Giza, 12622, Egypt.
  • 5 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Helwan University, Egypt. Electronic address: wzaghary@yahoo.com.
PMID: 29107422 DOI: 10.1016/j.ejmech.2017.10.016
Abstract

Design and synthesis of new Anticancer scaffolds; pyrazolo[3,4-d][1,2,3]triazine derivatives, is a promising solution to overcome drug resistance problem. A series of (E)-2-cyano-N-(aryl)-3-methylthio-3-(substituted-amino)acrylamides 3a-e was synthesized and transformed to the 3-aminopyrazole derivatives 4a-e which were then transformed to the target pyrazolotriazinones 6a-e. All compounds were evaluated for their Anticancer activity against three different Cancer cell lines namely Huh-7, Panc-1 and CCRF. Compounds 3a, 3c, 6a and 6c showed excellent Anticancer activity against Huh-7 cell line (IC50: 4.93-8.84 μM vs doxorubicin 5.43 μM). Similarly, compounds 6a and 6d showed excellent activities against Panc-1 cells (IC50: 9.91 μM and 4.93 μM vs doxorubicin 6.90 μM). Caspase-Glo 3/7 assay was done and the results revealed that the pro-apoptotic activity of the target compounds could be due to the stimulation of caspases 3/7. Microarray experiment for Huh-7 cells treated with 6c was performed to search for Other molecular changes. SLC26A3, UGT1A1, UGT2B15, UGT2B7, DNASE1, MUCDH1 and UGT2B17 were among the up-regulated genes, while, GIP3, TAGL, THBS1, IFI27, FSCN1 and SOCS2 were among the most extensively down-regulated genes. These genes belong to Apoptosis, metabolism, cell cycle, tumor growth and suppressor genes. Finally, pyrazolo[3,4-d][1,2,3]triazine derivatives could be potent Anticancer drugs in the future.

Keywords

Anticancer; Apoptosis; Caspases 3/7; Microarray; Pyrazolo[3,4-d][1,2,3]triazine.

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