Diazo Reagents with Small Steric Footprints for Simultaneous Arming/SAR Studies of Alcohol-Containing Natural Products via O–H Insertion

Natural products are essential tools for basic cellular studies leading to the identification of medically relevant protein targets and the discovery of potential therapeutic leads. The development of methods that enable mild and selective derivatization of natural products continues to be of signif...

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Published inACS chemical biology Vol. 6; no. 11; pp. 1175 - 1181
Main Authors Chamni, Supakarn, He, Qing-Li, Dang, Yongjun, Bhat, Shridhar, Liu, Jun O, Romo, Daniel
Format Journal Article
LanguageEnglish
Published United States American Chemical Society 18.11.2011
Subjects
Alcohols - chemistry
Azo Compounds - chemical synthesis
Azo Compounds - chemistry
Azo Compounds - pharmacology
Biological Products - chemical synthesis
Biological Products - chemistry
Biological Products - pharmacology
Humans
Hydrocarbons, Fluorinated - chemistry
Interleukin-2 - antagonists & inhibitors
Interleukin-2 - chemistry
Molecular Conformation
Stereoisomerism
Structure-Activity Relationship
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Summary:Natural products are essential tools for basic cellular studies leading to the identification of medically relevant protein targets and the discovery of potential therapeutic leads. The development of methods that enable mild and selective derivatization of natural products continues to be of significant interest for mining their information-rich content. Herein, we describe novel diazo reagents for simultaneous arming and structure–activity relationship (SAR) studies of alcohol-containing natural products with a small steric footprint, namely, an α-trifluoroethyl (HTFB) substituted reagent. The Rh(II)-catalyzed O–H insertion reaction of several natural products, including the potent translation inhibitor lactimidomycin, was investigated, and useful reactivity and both chemo- and site (chemosite) selectivities were observed. Differential binding to the known protein targets of both FK506 and fumagillol was demonstrated, validating the advantage of the smaller steric footprint of α-trifluoroethyl derivatives. A p-azidophenyl diazo reagent is also described that will prove useful for photoaffinity labeling of low affinity small molecule protein receptors.
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ISSN:1554-8929
1554-8937
DOI:10.1021/cb2002686