6784-45-8Relevant articles and documents
Characterization of the first naturally thermostable terpene synthases and development of strategies to improve thermostability in this family of enzymes
Styles, Matthew Q.,Nesbitt, Edward A.,Marr, Scott,Hutchby, Marc,Leak, David J.
, p. 1700 - 1711 (2017)
The terpenoid family of natural products is being targeted for heterologous microbial production as a cheaper and more reliable alternative to extraction from plants. The key enzyme responsible for diversification of terpene structure is the class-I terpene synthase (TS), and these often require engineering to improve properties such as thermostability, robustness and catalytic activity before they are suitable for industrial use. Improving thermostability typically relies on screening a large number of mutants, as there are no naturally thermostable TSs described upon which to base rational design decisions. We have characterized the first examples of natural TSs exhibiting thermostability, which catalyse the formation of the sesquiterpene τ-muurolol at temperatures up to 78 °C. We also report an enzyme with a kcat value of 0.95 s?1 at 65 °C, the highest kcat recorded for a bacterial sesquiterpene synthase. In turn, these thermostable enzymes were used as a model to inform the rational engineering of another TS, with the same specificity but low sequence identity to the model. The newly engineered variant displayed increased thermostability and turnover. Given the high structural homology of the class-I TS domain, this approach could be generally applicable to improving the properties of other enzymes in this class. Database: Model data are available in the PMDB database under the accession number PM0080780.
A mild method for the replacement of a hydroxyl group by halogen: 3. the dichotomous behavior of α-haloenamines towards allylic and propargylic alcohols
Munyemana, Fran?ois,Patiny, Luc,Ghosez, Léon
, (2021/06/07)
A study of the deoxyhalogenation of allylic and propargylic alcohols with tetramethyl-α-halo-enamines is reported. Primary allylic and primary and secondary propargylic alcohols gave the corresponding halides in high yields. Secondary allylic and propargylic alcohols yielded the corresponding secondary halides but the reaction also produced some rearranged primary halides (I > Br > Cl). The reactions with tertiary allylic and tertiary propargylic alcohols gave several products and was therefore of little synthetic value. However, the addition of triethylamine to the reaction mixture or the use of lithium alkoxide instead of alcohol brought about a major change of the course of the reaction which led to amides carrying an allyl or an allenyl group at C2. This was shown to result from a Claisen-Eschenmoser rearrangement of an intermediate α-allyloxy- or propargyloxy-enamine.
Repositioning Salirasib as a new antimalarial agent
Porta, Exequiel O. J.,Bofill Verdaguer, Ignasi,Perez, Consuelo,Banchio, Claudia,Ferreira De Azevedo, Mauro,Katzin, Alejandro M.,Labadie, Guillermo R.
, p. 1599 - 1605 (2019/09/30)
Malaria is a serious tropical disease that kills thousands of people every year, mainly in Africa, due to Plasmodium falciparum infections. Salirasib is a promising cancer drug candidate that interferes with the post-translational modification of Ras. This S-farnesyl thiosalicylate inhibits isoprenylcysteine carboxyl methyltransferase (ICMT), a validated target for cancer drug development. There is a high homology between the human and the parasite enzyme isoforms, in addition to being a druggable target. Looking to repurpose its structure as an antimalarial drug, a collection of S-substituted derivatives of thiosalicylic acid were prepared by introducing 1,2,3-triazole as a diversity entry point or by direct alkylation of the thiol. We further investigated the in vitro toxicity of FTS analogues to Plasmodium falciparum in the asexual stages and in Vero cells. An antiplasmodial activity assay was performed using a simple, high-sensitivity methodology based on nanoluciferase (NLuc)-transfected P. falciparum parasites. The results showed that some of the analogs were active at low micromolar concentration, including Salirasib. The most potent member of the series has S-farnesyl and the 1,2,3-triazole moiety substituted with phytyl. However, the compound substituted with methyl-naphthyl shows promising physicochemical and activity values. The low cytotoxicity in eukaryotic cells of the most active analogs provided good therapeutic indices, being starting-point candidates for future antimalarial drug development.
Concise synthesis of artemisinin from a farnesyl diphosphate analogue
Tang, Xiaoping,Demiray, Melodi,Wirth, Thomas,Allemann, Rudolf K.
, p. 1314 - 1319 (2017/09/30)
Artemisinin is one of the most potent anti-malaria drugs and many often-lengthy routes have been developed for its synthesis. Amorphadiene synthase, a key enzyme in the biosynthetic pathway of artemisinin, is able to convert an oxygenated farnesyl diphosphate analogue directly to dihydroartemisinic aldehyde, which can be converted to artemisinin in only four chemical steps, resulting in an efficient synthetic route to the anti-malaria drug.
