SAR Studies on the Inhibitors for the Treatment of Inflammatory Diseases

Abstract

Inflammation is defensive host response that occurs from infection and injury and the inflammatory process is the pivotal physiological response of our body and essential part of the human physiology. Due to the mechanistic relationship between chronic diseases and inflammation, a better understanding for the molecular mechanism of chronic inflammation could attenuate cellular inflammation pathways. Under inflammatory pathways, the impetus of proinflammatory mediators usually caused by the increased expression of transcriptional factors which is also a potential targets in the development of novel and effective anti-inflammatory therapeutics. Among others, we are interested in the Nuclear Factor Kappa-B (NF-κB) which is reported as a major mediator that regulates inflammatory gene expression and also decrease the prevalence of inflammation responses. To suppress the inflammatory activity, inhibitors that could selectively target this protein are needed. We therefore, chose the natural product cerulenin which has been studied widely because of its antifungal and antibacterial properties, for designing inhibitors. In light of the interesting inhibitory properties displayed by cerulenin for fatty acid synthase (FASN), we were keen to explore the possible binding mode of this natural product with a view to design various derivatives that would be amicable to synthetic manipulation in order to enable SAR studies. Potent analogues of cerulenin, with various chain lengths and substitutions, are synthesized and evaluated for their ability to inhibit NF-κB enhanceosome. Taken together, by identifying target protein with constructed inhibitors derived from cerulenin might give revolutionary effect on discovering new therapeutic agents.