Research Projects

Bergamotane sesquiterpenes are a class of uncommon fungal secondary metabolites having a unique bi/tri or tetracyclic framework in their structure. To date, close to 100 such bergamotane sesquiterpenes have been isolated and structurally characterized (with proper stereochemical assignments). Among them poly-oxygenated bergamotane sesquiterpenes are structurally novel as during the biosynthesis (FPP-pathway by terpene cyclase enzyme) several enzymatic oxygenation occurs (catalyzed by P-450 dependent oxygenase) and provide [5,5]-oxaspirolactone embedded in the core sesquiterpene framework. Such [5,5]-oxaspirolactone containing bergamotane sesquiterpenes are topologically distinct (cyclic connectivity) and having mostly tetracyclic framework with a strained bicyclic [3,1,1] heptane and an all carbon quaternary stereocenter in their structural unit. Almost 20 such [5,5]-oxaspirolactone containing bergamotane sesquiterpenes have been isolated and found to possess significant biological activity such as pancreatic lipase inhibition (anti-obesity agent) and α-glucosidase inhibition (anti-diabetic; potential type II diabetes drug), in addition, they also exhibit cytotoxic effects on various cancerous cell lines. Representative examples of few bergamotane sesquiterpenes bearing [5,5]-oxaspirolactones are presented in Figure-1. Purpurolides A-F exhibit potent pancreatic lipase inhibition activity and hence might have a promising role as drug candidates for the treatment of anti-obesity disorders. Purpurolide D (IC50 value = 1.22 μM is more potent than anti-obesity drug Kaemferol with IC50 = 1.50 μM) and other structural congeners act as covalent inhibitors of pancreatic lipase and hence prevent the conversion of triglycerides (from diet) into free fatty acids and maintain the caloric intake and weight management. Expansolides A-D exhibit excellent inhibitory activity against α-glucosidase enzyme, and might act as lead candidates in diabetes-2 management by slowing down carbohydrate metabolism (expansolide C & D with IC50 = 0.5 mM is much potent than the commercially available drug acarbose with IC50 = 1.9 mM). In this current proposal, we would like to embark on a unified asymmetric total synthesis of such bergamotane sesquiterpenes with [5,5]-oxaspirolactones through the strategic exploration of novel spirocyclization method to access substantial amount of those compounds for further biological assay in pursuit of new anti-obesity and anti-diabetic drug candidate.7 In the first part of the proposal we aim to develop simple precursor (common feedstock material) based approach to access advanced intermediates through a strategy (transformation guided) driven pathway. The advanced intermediates will then be assembled through the cascade spirocyclization method en-route to the total synthesis of the target natural products. In the later part of the proposal the synthesized bergamotane sesquiterpene based [5,5]-oxaspirolactones (Figure-1) will be tested for their potency against α-glucosidase and pancreatic lipase inhibition so that potential lead molecules can be subjected to further in-vitro and in-vivo activity studies. For the pancreatic lipase inhibition assay “resorufin coupled artificial substrate” based spectrophotometric assay method will be implemented. For α-glucosidase inhibition assay spectrophotometric assay method with “PNP-glucopyranoside” based method will be employed. Structure activity relationship analysis will be then adopted to identify lead fragments or pharmacophores in those bergamotane sesquiterpenes. The active fragment based analogues of such [5,5]-oxaspirolactones will then be synthesized and evaluated for potential inhibitory activity towards pancreatic lipase and alpha-glucosidase inhibition through in-vitro assay methods.