2. Academic Validation
  3. Novel pyrazolopyrimidines: Synthesis, in vitro cytotoxic activity and mechanistic investigation

Novel pyrazolopyrimidines: Synthesis, in vitro cytotoxic activity and mechanistic investigation

  • Eur J Med Chem. 2017 Sep 29:138:565-576. doi: 10.1016/j.ejmech.2017.07.003.
Ghaneya S Hassan 1,  Doaa E Abdel Rahman 1,  Yassin M Nissan 2,  Esraa A Abdelmajeed 3,  Tamer M Abdelghany 4
Affiliations

Affiliations

  • 1 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr Elini St., Cairo 11562, Egypt.
  • 2 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr Elini St., Cairo 11562, Egypt. Electronic address: yassin.nissan@hotmail.com.
  • 3 National Cancer Institute, Cairo University, Fom Elkhalig, Kasr Elaini St., Cairo 11796, Egypt.
  • 4 Pharmacology and Toxicology Department, Faculty of Pharmacy, Al-Azhar University, Nasr City, Cairo 11787, Egypt.
PMID: 28704759 DOI: 10.1016/j.ejmech.2017.07.003
Abstract

A series of novel pyrazolo[3,4-d]pyrimidines bearing benzenesulfonamide moiety 5a-f, 6 and 7 were synthesized. Cytotoxic screening was conducted against MCF-7 and HepG2. 6-(4-Methoxyphenyl)-4-oxopyrazolopyrimidine derivative 5e and 4-imino-6-oxopyrazolopyrimidine derivative 6 revealed potent cytotoxic activity with IC50 1.4 μM (MCF-7) and 0.4 μM (HepG2), respectively compared to that of doxorubicin, (IC50 = 1.02 μM and 0.9 μM, respectively). Compounds 5e and 6 were subjected to cell cycle analysis and Apoptosis assay after 24 h and 48 h treatment. Compound 5e arrested cell at G1 phase, while 6 arrested cell at S and G2/M phases, respectively. The apoptotic effect of both compounds were evidenced by pre G1 Apoptosis as its percentage increased by time (7.38%, 11.61%) and (13.92%, 16.71%), respectively. Apoptosis induction capability was confirmed by the effect on early and late Apoptosis and augmentation of Caspase-3 level. Furthermore, compound 6 inhibited CDK2 Enzyme with IC50 = 0.19 μM and increased levels of its regulators, P21 and P27 by 10.06% and 8.5%, respectively. Moreover, a molecular docking study of compound 6 on CDK2 Enzyme was adopted to explore binding interaction with amino acid residues of its active site.

Keywords

Apoptosis; CDK2 inhibitor; Cytotoxicity; Pyrazolopyrimidines.

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