312962-11-1Relevant academic research and scientific papers
Thermal proteome profiling efficiently identifies ribosome destabilizing oxazolidinones
N?cker, Christina,Kaiser, Nadine,Foley, Daniel,Sievers, Sonja,Janning, Petra,Waldmann, Herbert,Laraia, Luca
, (2021/04/22)
Identifying the targets of bioactive small molecules is a challenging endeavor for which no general solution currently exists. Classical affinity purification experiments suffer from the need to functionalise a bioactive compound and link it to a solid support, which may interfere with target binding. A modern mass spectrometry-based proteomics technique that has partially circumvented this problem is thermal proteome profiling (TPP), which determines the effect of an unmodified small molecule on the thermal stability of the whole proteome simultaneously. Here, we use TPP to identify the mode-of-action of a newly-discovered autophagy inhibitor based on oxazolidinones often employed as chiral auxiliaries. Surprisingly, a significant portion of all ribosomal proteins were found to be destabilized by the inhibitor, highlighting the utility of this technology for determining a challenging mode-of-action.
Total synthesis of (-)-salicylihalamide.
Fuerstner,Dierkes,Thiel,Blanda
, p. 5286 - 5298 (2007/10/03)
A concise total synthesis of the potent cytotoxic marine natural products salicylihalamide A and B (la, b) is reported. Key steps of our approach were the asymmetric hydrogenation reactions of beta-keto esters 18 and 32 catalyzed by [((S)-BINAP)Ru-Cl2]2. NEt3 and the cyclization of the macrolide core by ring closing olefin metathesis (RCM) using the "second-generation" ruthenium carbene complex 24 as the catalyst which bears an imidazol-2-ylidene ligand. The EIZ ratio obtained in this macrocyclization reaction was determined by the protecting groups at the remote phenolic OH group of the cyclization precursor. The elaboration of the resulting cycloalkene 37 into the final target involved a CrCl2-mediated synthesis of vinyliodide 49 which, after deprotection, did undergo a copper-catalyzed cross-coupling process with the (Z,Z)-configurated carboxamide 42 to form the labile enamide moiety of 1. Compound 42 was derived from a palladium-catalyzed Negishi coupling between butynylzinc chloride and 3-iodoacrylate 39 followed by a Lindlar reduction of enyne 40 thus obtained and a final aminolysis of the ester group.
Asymmetric synthesis of the fully functional macrolide core of salicylihalamide: remote control of olefin geometry during RCM.
Fuerstner,Thiel,Blanda
, p. 3731 - 3734 (2007/10/03)
A catalysis-based approach to the core region 24 of the antitumor agents salicylihalamides A and B is reported. Key steps are two asymmetric hydrogenations of beta-keto esters 13 and 16 catalyzed by [(R)-BINAP.RuCl(2)](2).NEt(3) and an RCM-based macrocyclization effected by the NHC-containing ruthenium carbene 21. The stereochemical outcome of the latter reaction is controlled by remote substituents on the phenolic OH group of the cyclization precursor 23.
