650 research outputs found
Design, synthesis and biological evaluation of indanesulfonamides as carbonic anhydrase IX inhibitors
Investigation of the function of delta-cadinene synthase with aza-analogues and site directedmutagenesis
Terpenes are one of the most structurally varied families of natural products with extraordinary chemical properties that have been exploited for numerous applications. Sesquiterpene synthases are a family of metal-dependent enzymes that catalyse the cyclisation of farnesyl diphosphate (FDP) into a myriad of complex C15-isoprenoid hydrocarbons, the sesquiterpenes. δ-Cadinene synthase (DCS) from Gossypium arboreum (cotton tree) catalyses the formation of δ-cadinene (DCN), a bicyclic intermediate in the biosynthesis of important phytoalexins such us gossypol.
Two mechanistic proposals have been made for the formation of δ-cadinene: a 1,10-ring closure mechanism leading to the key intermediate germacradienyl cation, or a 1,6-ring closure leading to thealpha-bisabolyl carbocation. Previous investigation with fluorinated FDP analogues were in partial agreement with both scenarios and hence it was not possible to distinguish unambiguously between the two possible cyclisation reactions.
To investigate the catalytic mechanism of DCS, enantiopure samples of the azaanalogues of alpha-bisabolyl cation and germacradienyl cation were needed. These compounds are designed as stable structural and electrostatic mimics of the putative short-lived carbocationic intermediates generated by terpene synthases, and hence often act as potent reversible competitive inhibitors (low Ki) of these
enzymes.
Here, the enantioselective total synthesis of R- and S- aza-analogues of the alpha-bisabolyl cation are described as well as the partial racemic synthesis of azagermacradienyl
cation. Both enantiomers of aza-bisabolyl cation were goodmimics of α-bisabolene. They were competitive inhibitors of DCS, providing evidence for a
1,6-cyclisation closure.
The second part of the project involved the investigation of the role of tryptophan 279 for the desolvation of the active site of DCS and therefore for the formation of
DCN. Seven mutants of W279 were created. The data obtained showed that W279 is essential to prevent water from entering the active site and form the hydroxylate
terpenoid germacradien-4-ol (GD4ol). Mutagenesis studies yielded a mutant, W279A, capable of making GD4ol as the sole product
THIOSEMICARBAZONES AS INHIBITORS OF TRYPTOPHAN 2,3-DIOXYGENASE (TDO), AN EMERGING TARGET FOR CANCER TREATMENT
A dual thromboxane inhibitor and thromboxane receptor antagonist prevents pig myocardial infarction induced by coronary thrombosis
peer reviewe
Design, synthesis and biological evaluation of indanesulfonamides as carbonic anhydrase IX inhibitors
Novel Inhibitors of Indoleamine 2,3-Dioxygenase (IDO), a Target for Anti-Cancer Immunotherapy
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