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.
Subject(s)
Antineoplastic Agents/pharmacology , Carcinoma, Hepatocellular/drug therapy , Liver Neoplasms/drug therapy , Nitric Oxide Donors/pharmacology , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Cell Cycle/drug effects , Cell Proliferation/drug effects , Drug Design , Hep G2 Cells , Humans , Liver/drug effects , Liver/metabolism , Liver/pathology , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Models, Molecular , Nitric Oxide Donors/chemical synthesis , Nitric Oxide Donors/chemistry , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/chemistryABSTRACT
A series of new 1-aryl-4-benzylidenehydrazinyl-3-methylsulphanyl-pyrazolo[3,4-d]pyrimidines 6a-p was synthesized. The cytotoxic activity of the newly synthesized compounds against human breast cancer cell line, MCF7 was investigated. Most of the test compounds showed potent antitumor activity comparable to that of doxorubicin. The 1-phenyl series (6a-i) exhibited better antitumor activity than 1-(4-methoxyphenyl) series (6j-p). 4-[2-(4-Fluorobenzylidene)hydrazinyl]-3-(methylsulphanyl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine (6d) was the most active compound in this study with IC(50) equal to 7.5 nM.
Subject(s)
Antineoplastic Agents/chemical synthesis , Pyrazoles/chemical synthesis , Pyrimidines/chemical synthesis , Adenocarcinoma/drug therapy , Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Cell Line, Tumor , Cell Survival/drug effects , Doxorubicin/pharmacology , Drug Design , Female , Humans , Inhibitory Concentration 50 , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Structure-Activity RelationshipABSTRACT
A new series of pyrazolo[3,4-d]pyrimidines has been synthesized. The new compounds were tested for their antitumor activity on 60 different cell lines, and some of the compounds were found to have potent antitumor activity. In particular, 2-hydroxybenzaldehyde [1-(4-chlorophenyl)-3-methyl-1H-pyrazolo-[3,4-d]pyrimidin-4-yl]hydrazone (VIIa) was found to be the most effective among the other derivatives, showing IC50 values of 0.326 to 4.31 µM on 57 different cell lines.