Design and biological evaluation of Inhibitors of Critical Target Proteins as Antiproliferative Agents

The cell cycle is divided into four distinct phases (m, gl, s, g2) and is co-operatively regulated by a family of cyclin-dependent kinases (cdk 1-9) whose activities require binding of a cyclin protein and atp for activation. they are a family of serine theronine kinases, which catalyse the phosphorylation of cellular substrates utilising atp as a phosphate donor. in cancer cell lines, cdk-related mechanisms are deregulated leading to increased cell divisions. hence, they are promising targets for the design and development of anti proliferative drugs. many currently available cdk inhibitors are purine derivatives by virtue of their structural analogy to atp, by competitively binding at the atp site. hymenialdisine, an abundant metabolite of certain marine sponges and kenpaullone, have been identified as potent and novel cdk inhibitors. co-crystalization of these inhibitors with cdk2 has identified that the pyrroloazepinone structure in hymenialdisine forms three hydrogen bonds with active site, which contributes to its increased potency over kenpaullone (forms two hydrogen bonds). the novel scaffold identified by these compounds provides an interesting lead for drug development, the seven membered lactam ring provides structure activity relationships which are important in cdk inhibition and differ from purine based cdks inhibitors that block cell division. this project aims to develop the synthesis of novel kenpaullone and hymenialdisine analogues with the ability to mimic the hydrogen bonding of these compounds to the cdk active site and exploration of additional substrate-enzyme interactions. in addition to the synthesis of the basic scaffold, a number of derivatives have been prepared to test structure activity relationships but because of the confidentiality of the work no more details can be given here.