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    Home > Science: pleuroutilins simple synthesis to promote antibiotic research

    Science: pleuroutilins simple synthesis to promote antibiotic research

    • Last Update: 2017-11-03
    • Source: Internet
    • Author: User
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    Tricyclic diterpenoid fungal metabolite (+) - pluromutilin (1) has become the starting material for the development of new antibiotics The semisynthetic modification of its functional group on C14 provides the first derivative suitable for human use C12 is derived to synthesize 12 EPI pluromutilins with broad-spectrum antibacterial activity, especially for Gram-negative pathogens In view of the inherent limitations of semi synthesis, if the derivative structure of (+ - pluromutilin (1) can be fully controlled, it will provide an opportunity to develop derivatives with better antibacterial activity Pleuroutilins and 12 EPI pluromutilins are promising antibiotic species (source: Science) diterpenoid fungal metabolites (+ - pluromutilin (1) mainly inhibit the growth of Gram-positive pathogens (GPPS) Because of its unique mechanism of action, the resistance of pathogen to (+ - pluromutilin (1) is not easy to produce, and it shows the minimum cross resistance with existing antibiotics The pharmacological characteristics of the derivatives of (-) - pluromutilin (1) have been studied extensively The main interaction between ribosome binding and(+) - pluromutilin (1) is from its core tricycle, and most of the semi synthesis work is focused on the modification of its C14 side chain More than 3000 C14 derivatives have been synthesized These efforts eventually led to the approval of postapamulin (3) in 2007 for the treatment of local methicillin resistant Staphylococcus aureus (MRSA) infection and the development of lefamulin for the treatment of acquired bacterial pneumonia Although the stereoselective synthesis of conjugated fragments (source: Science) has made progress in the treatment of GPP, the lack of antibiotics for the treatment of Gram-negative pathogens (GNP) is still a global health problem All kinds of C14 modified pleuroutilins have little inhibitory effect on Gram-negative bacteria In order to find a new derivative method and obtain the pluromutilins derivatives with GNP activity, Seth B herzon from Yale University has developed a new and more convenient synthesis method to synthesize (+ - pluromutilin (1), and with this method, more unique derivatives can also be synthesized After a large number of experiments, two fragments of compound 4 and 5 were used At first, compound 5 will undergo nucleophilic addition reaction to compound 4 after lithium ionization, and then use acid treatment to obtain diketone compound 7 The high electrophilicity of N-Boc is the key factor for this reaction After that, alkyne aldehyde compound 8 was obtained by three-step reaction, and then fragment connection was carried out for the second time This reaction is the reductive cyclization of terminal alkynes and aldehydes, which has not been used before After screening, the research team finally realized the selective cyclization of exo by using the Ni / IPR catalytic system reported by montogomery et al In addition, good yield and chiral selectivity were obtained, and the compound 9 with 8-membered ring was synthesized Compound 9, as a common intermediate, can be used for chiral selective reduction of diketone, and then combined with the rearrangement of organic zinc reagent to synthesize a variety of derivatives On the other hand, the reaction of two keto carbonyls of compound 9 with metal Na can yield (+ - 12 EPI mutilin (13), although the yield and chiral selectivity are relatively general Then compounds 13 can be used as intermediates to synthesize (+ - pluromutilin (1), 12 epi - pluromutilins (3), and compounds 14 of C11, C12 epimer Synthesis of (+ - 12 EPI pluromutiln (29), (+) - pluromutilin (1), (+) - 11,12-di-epipleurumutilin (32) (source: Science) through the methods outlined in this paper, to create other derivatives with optimized structure, these derivatives can further solve the inherent constraints of semi synthesis method, and can obtain shorter and higher output routes The recent success in the development of synthesis routes of tetracycline and macrolide antibiotics shows the potential of total synthesis of new clinical antimicrobial candidates Paper link: http://science.sciencemag.org/content/356/6341/956 brief introduction of scientific research team: http://
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