14565-11-8Relevant articles and documents
Investigation of (S)-(-)-acidomycin: A selective antimycobacterial natural product that inhibits biotin synthase
Bockman, Matthew R.,Engelhart, Curtis A.,Cramer, Julia D.,Howe, Michael D.,Mishra, Neeraj K.,Zimmerman, Matthew,Larson, Peter,Alvarez-Cabrera, Nadine,Park, Sae Woong,Boshoff, Helena I. M.,Bean, James M.,Young, Victor G.,Ferguson, David M.,Dartois, Veronique,Jarrett, Joseph T.,Schnappinger, Dirk,Aldrich, Courtney C.
, p. 598 - 617 (2019)
The synthesis, absolute stereochemical configuration, complete biological characterization, mechanism of action and resistance, and pharmacokinetic properties of (S)-(-)-acidomycin are described. Acidomycin possesses promising antitubercular activity against a series of contemporary drug susceptible and drug-resistant M. tuberculosis strains (minimum inhibitory concentrations (MICs) = 0.096-6.2 μM) but is inactive against nontuberculosis mycobacteria and Gram-positive and Gram-negative pathogens (MICs > 1000 μM). Complementation studies with biotin biosynthetic pathway intermediates and subsequent biochemical studies confirmed acidomycin inhibits biotin synthesis with a Ki of approximately 1 μM through the competitive inhibition of biotin synthase (BioB) and also stimulates unproductive cleavage of S-adenosyl-l-methionine (SAM) to generate the toxic metabolite 5′-deoxyadenosine. Cell studies demonstrate acidomycin selectively accumulates in M. tuberculosis providing a mechanistic basis for the observed antibacterial activity. The development of spontaneous resistance by M. tuberculosis to acidomycin was difficult, and only low-level resistance to acidomycin was observed by overexpression of BioB. Collectively, the results provide a foundation to advance acidomycin and highlight BioB as a promising target.
Asymmetric Synthesis of Chiral 1,3-Dimethyl Units Through a Double Michael Reaction of Nitromethane and Crotonaldehyde Catalyzed by Diphenylprolinol Silyl Ether
Hayashi, Yujiro,Toda, Shunsuke
, p. 442 - 448 (2019)
An efficient synthetic route to install chiral 1,3-dimethyl units through a double Michael reaction of crotonaldehyde and nitromethane catalyzed by diphenylprolinol silyl ether is developed. Either 1,3- syn - or 1,3- anti -dimethyl units are obtained selectively depending on the enantiomer of the diphenylprolinol silyl ether catalyst used. The side chain of pneumocandin B 0 is synthesized enantioselectively by using the present method as a key step.
Stereoselective synthesis of MaR2n-3 DPA
S?nderskov, Jeanne,Tungen, J?rn E.,Palmas, Francesco,Dalli, Jesmond,Serhan, Charles N.,Stenstr?m, Yngve,Vidar Hansen, Trond
, (2020)
The first total synthesis of the n-3 docosapentaenoic derived oxygenated product MaR2n-3 DPA has been achieved. The 13R and 14S stereogenic centers were introduced using 2-deoxy-D-ribose in a chiral pool strategy. The geometry of the Z,E,E-triene moiety was prepared using highly E-selective Wittig- and Takai-olefination reactions as well as the Z-stereoselective Lindlar reduction. LC/MS-MS data of synthetic MaR2n-3 DPA matched data for the biosynthetic formed product that enabled the configurational assignment of this oxygenated natural product to be (7Z,9E,11E,13R,14S,16Z,19Z)-13,14-dihydroxydocosa-7,9,11,16,19-pentaenoic acid.
Total synthesis of the lipid mediator PD1n-3 DPA: Configurational assignments and anti-inflammatory and pro-resolving actions
Aursnes, Marius,Tungen, J?rn E.,Vik, Anders,Colas, Romain,Cheng, Chien-Yee C.,Dalli, Jesmond,Serhan, Charles N.,Hansen, Trond V.
supporting information, p. 910 - 916 (2014/05/20)
The polyunsaturated lipid mediator PD1n-3 DPA (5) was recently isolated from self-resolving inflammatory exudates of 5 and human macrophages. Herein, the first total synthesis of PD1n-3 DPA (5) is reported in 10 steps and 9% overall yield. These efforts, together with NMR data of its methyl ester 6, confirmed the structure of 5 to be (7Z,10R,11E,13E,15Z,17S,19Z)-10,17- dihydroxydocosa-7,11,13,15,19-pentaenoic acid. The proposed biosynthetic pathway, with the involvement of an epoxide intermediate, was supported by results from trapping experiments. In addition, LC-MS/MS data of the free acid 5, obtained from hydrolysis of the synthetic methyl ester 6, matched data for the endogenously produced biological material. The natural product PD1 n-3 DPA (5) demonstrated potent anti-inflammatory properties together with pro-resolving actions stimulating human macrophage phagocytosis and efferocytosis. These results contribute new knowledge on the n-3 DPA structure-function of the growing numbers of specialized pro-resolving lipid mediators and pathways.
