2. Academic Validation
  3. Design and synthesis of pyrazolo[3,4-d]pyrimidines: Nitric oxide releasing compounds targeting hepatocellular carcinoma

Design and synthesis of pyrazolo[3,4-d]pyrimidines: Nitric oxide releasing compounds targeting hepatocellular carcinoma

  • Bioorg Med Chem. 2017 Jun 15;25(12):2956-2970. doi: 10.1016/j.bmc.2017.03.002.
Yaseen A M M Elshaier 1,  Mohamed A Shaaban 2,  Mohammed K Abd El Hamid 2,  Mostafa H Abdelrahman 1,  Mahrous A Abou-Salim 3,  Sara M Elgazwi 4,  Fathi Halaweish 5
Affiliations

Affiliations

  • 1 Al-Azhar University, Faculty of Pharmacy, Pharmaceutical Organic Chemistry Department, Assiut 71524, Egypt.
  • 2 Cairo University, Faculty of Pharmacy, Pharmaceutical Organic Chemistry Department, Cairo 11562, Egypt.
  • 3 Al-Azhar University, Faculty of Pharmacy, Pharmaceutical Organic Chemistry Department, Assiut 71524, Egypt; South Dakota State University, Faculty of Science, Chemistry Department, Brookings, SD 57007, USA.
  • 4 South Dakota State University, Faculty of Science, Chemistry Department, Brookings, SD 57007, USA.
  • 5 South Dakota State University, Faculty of Science, Chemistry Department, Brookings, SD 57007, USA. Electronic address: fathi.halaweish@sdstate.edu.
PMID: 28487127 DOI: 10.1016/j.bmc.2017.03.002
Abstract

A new series of pyrazolo[3,4-d]pyrimidines tethered with nitric oxide (NO) producing functionality was designed and synthesized. Sulforhodamine B (SRB) Protein Assay revealed that NO releasing moiety in the synthesized compounds significantly decreased the cell growth more than the des-NO analogues. Compounds 7C and 7G possessing N-para-substituted phenyl group, released the highest NO concentration of 4.6% and 4.7% respectively. Anti-proliferative activity of synthesized compounds on HepG2 cell line identified compounds 7h, 7p, 14a and 14b as the most cytotoxic compounds in the series of IC50=3, 5, 3 and 5μM, respectively, compared to erlotinib as a reference drug (IC50=25μM). Flow cytometry studies revealed that 7h arrested the cells in G0/G1 phase of cell cycle while 7p arrested the cells in S phase. Moreover, docking study of the synthesized compounds on EGFR (PDB code: 1M17) and cytotoxicity study indicated that N-1 phenyl para substitution, pyrazole C-3 alkyl substitution and tethering the nitrate moiety through butyl group had a significant impact on the activity.

Keywords

EGFR; Hepatocellular carcinoma; Nitric oxide; Pyrazolo[3,4-d]pyrimidines.

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