2592-18-9Relevant articles and documents
Synthesis of the 26-Membered Core of Thiopeptide Natural Products by Scalable Thiazole-Forming Reactions of Cysteine Derivatives and Nitriles
Johnson, Trevor C.,Christy, Mitchell P.,Siegel, Dionicio
, p. 498 - 508 (2021)
The increased resistance of bacteria to clinical antibiotics is one of the major dilemmas facing human health and without solutions the problem will grow exponentially worse. Thiopeptide natural products have shown promising antibiotic activities and provide an opportunity for the development of a new class of antibiotics. Attempts to directly translate these compounds into human medicine have been limited due to poor physiochemical properties. The synthesis of the core structure of the 26-membered class of thiopeptide natural products is reported using chemistry that enables the synthesis of large quantities of synthetic intermediates and the common core structure. The use of cysteine/nitrile condensation reactions followed by oxidation to generate thiazoles has been key in enabling large academic scale reactions that in many instances avoided chromatography further aiding in accessing large amounts of key synthetic intermediates.
Accessing HIV-1 Protease Inhibitors through Visible-Light-Mediated Sequential Photocatalytic Decarboxylative Radical Conjugate Addition-Elimination-Oxa-Michael Reactions
Bhattacharyya, Aditya,Krolo, Tomislav,Reiser, Oliver
supporting information, p. 6283 - 6287 (2021/08/23)
A photocatalytic decarboxylative radical conjugate addition-elimination-oxa-Michael reaction of hydroxyalkylated carboxylic acids with cyclopentenones is developed to construct diverse cyclopentanonyl-fused functionalized 5-7 membered cyclic ethers. The stereoselective synthetic strategy is amenable to substructural variation, establishing a direct total synthetic route to two diastereomers of C3-amino cyclopentyltetrahydrofuranyl-derived potent HIV-1 protease inhibitors with low nanomolar IC50 values.
Optimization of globomycin analogs as novel gram-negative antibiotics
Braun, Marie-Gabrielle,Burdick, Daniel J.,Castanedo, Georgette M.,Chen, Yi-Chen,Cheng, Yun-Xing,Cheong, Jonathan,Daniels, Blake,Deshmukh, Gauri,Fu, Yuhong,Garland, Keira,Gibbons, Paul,Gloor, Susan L.,Hanan, Emily J.,Hua, Rongbao,Kapadia, Sharookh B.,Labadie, Sharada,Liu, Xiongcai,Pantua, Homer,Pastor, Richard,Stivala, Craig,Xu, Min,Xu, Yiming,Zheng, Hao
supporting information, (2020/08/13)
Discovery of novel classes of Gram-negative antibiotics with activity against multi-drug resistant infections is a critical unmet need. As an essential member of the lipoprotein biosynthetic pathway, lipoprotein signal peptidase II (LspA) is an attractive target for antibacterial drug discovery, with the natural product inhibitor globomycin offering a modestly-active starting point. Informed by structure-based design, the globomycin depsipeptide was optimized to improve activity against E. coli. Backbone modifications, together with adjustment of physicochemical properties, afforded potent compounds with good in vivo pharmacokinetic profiles. Optimized compounds such as 51 (E. coli MIC 3.1 μM) and 61 (E. coli MIC 0.78 μM) demonstrate broad spectrum activity against gram-negative pathogens and may provide opportunities for future antibiotic discovery.
