Chronic inflammation is a vital factor in the pathogenesis of several diseases including periodontitis, neurodegenerative disorders and endometriosis. Long term prevalence of chronic inflammation has also been found to culminate into cancer. The classic anti-inflammatory drugs, namely, NSAIDS and COXIBS are known to cause undesirable side effects including gastro intestinal disturbances and cardiovascular complications respectively. Hence, inhibition of PGE2 which is the product of the downstream enzymes of the prostaglandin pathway offers promising hopes to identify a successful anti-inflammatory drug that is devoid of side effects. The involvement of PGE2 in the augmentation of inflammatory responses and proliferation of cancer has been well established in previous studies. Hence, inhibiting the production of PGE2 also offers a solution to inflammation induced cancer.
In this thesis work, computational and experimental approach was followed in identifying potential candidates against inflammation. Two models, PhM-PP and PhM-Alk, has been developed using known anti-inflammatory molecules. Three novel scaffolds, viz., isocoumarin derivatives, phytochemicals (present in medicinal plants and herbs) and tyrosine derivatives were found to map onto both the models. Hence they were explored further for anti-inflammatory and anti-cancer activities in vitro. These compounds were found to be good inhibitors of both PGE2 production and mRNA expression of inflammatory enzymes, specifically COX-2 and mPGES1. They also exhibited preliminary anti-cancer abilities including the inhibition of proliferation of cancer cells, cell cycle arrest, changes in cell morphology and mRNA expression of cancer markers and inflammatory cytokines. Finally, the transcriptional regulation of mPGES1 gene was investigated as a novel strategy for drug discovery. In this regard, the presence of three c-Myc binding sites in the mPGES1 promoter was identified and it was also found that the c-Myc is a positive regulator of mPGES1 gene.
This study has identified lead compounds that could be developed further as anti-inflammatory and anti-cancer drugs.