Synthesis, COX-2 inhibition and metabolic stability studies of 6-(4-fluorophenyl)-pyrimidine-5-carbonitrile derivatives as anticancer and anti-inflammatory agents

摘要

In continuation of previous work on cyanopyrimidine derivatives for cancer and inflammation, eighteen novel amino containing cyanopyrimidine derivatives (4a-p) bearing secondary or tertiary amines and alkyl-thio substitution were synthesized by Biginelli condensation reaction followed by nucleophilic substitution reaction. Two compounds 4 g (NSC: 795,754) and 4o (NSC: 798,988) showed excellent anticancer potency against most of the cell lines. Compound 4 g was selected for five dose-assays and the result of tested compound was given by three response parameters i.e. GI(50), TGI and LC50 for each cell line. Compound 4 g exhibited superior anticancer activity against ovarian cancer with GI(50)-value of 0.33 mu M and selectivity index of 4.84 in comparison to 5-fluoro uracil (5-FU) which exhibited GI(50)-value 4.43 mu M. During in-vivo anti-inflammatory study, compound 4 g exhibited 87 % inhibition of inflammation at 3 h which was found superior to the standard drugs ibuprofen (78 %) and celecoxib (52 %). The compounds 4 g and 4o exhibiting both anticancer and anti-inflammatory potential were further studied for their biological target studies and in-vitro metabolic stability assessment. The result showed that compounds 4 g and 4o displaying broad anticancer activity were more selective towards COX-2 as compared to COX-1.