ABSTRACT
FR901464 is a natural product that exhibits antiproliferative activity at single-digit nanomolar concentrations in cancer cells. Its tetrahydropyran-spiroepoxide covalently binds the spliceosome. Through our medicinal chemistry campaign, we serendipitously discovered that a bromoetherification formed a tetrahydrofuran. The tetrahydrofuran analog was three orders of magnitude less potent than the corresponding tetrahydropyran analogs. This study shows the significance of the tetrahydropyran ring that presents the epoxide toward the spliceosome.
Subject(s)
Epoxy Compounds , Furans , Pyrans , Spiro Compounds , Humans , Cell Line, Tumor , Epoxy Compounds/chemical synthesis , Epoxy Compounds/pharmacology , Furans/chemical synthesis , Furans/pharmacology , Pyrans/chemical synthesis , Pyrans/pharmacology , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacologyABSTRACT
Hydrogen peroxide (H2 O2 ) mediates the biology of wound healing, apoptosis, inflammation, etc. H2 O2 has been fluorometrically imaged with protein- or small-molecule-based probes. However, only protein-based probes have afforded temporal insights within seconds. Small-molecule-based electrophilic probes for H2 O2 require many minutes for a sufficient response in biological systems. Here, we report a fluorogenic probe that selectively undergoes a [2,3]-sigmatropic rearrangement (seleno-Mislow-Evans rearrangement) with H2 O2 , followed by acetal hydrolysis, to produce a green fluorescent molecule in seconds. Unlike other electrophilic probes, the current probe acts as a nucleophile. The fast kinetics enabled real-time imaging of H2 O2 produced in endothelial cells in 8 seconds (much earlier than previously shown) and H2 O2 in a zebrafish wound healing model. This work may provide a platform for endogenous H2 O2 detection in real time with chemical probes.
Subject(s)
Fluorescent Dyes/chemistry , Hydrogen Peroxide/chemistry , Acetals/chemistry , Animals , Disease Models, Animal , Endothelial Cells/cytology , Endothelial Cells/metabolism , HeLa Cells , Humans , Hydrogen Peroxide/metabolism , Hydrolysis , Mice , Microscopy, Fluorescence , Molecular Conformation , Optical Imaging , Oxidation-Reduction , RAW 264.7 Cells , Selenium/chemistry , Wounds and Injuries/diagnostic imaging , Zebrafish/metabolismABSTRACT
Meayamycin B is currently the most potent modulator of the splicing factor 3b subunit 1 and used by dozens of research groups. However, current supply for this natural product analogue is limited because of the lengthy synthetic scheme. Here, we report a more concise, more cost-effective, and greener synthesis of this compound by developing and employing a novel asymmetric reduction of a prochiral enone to afford an allylic alcohol with high enantioselectivity. In addition to this reaction, this synthesis highlights a scalable Mukaiyama aldol reaction, Nicolaou-type epoxide opening reaction, stereoselective Corey-Chaykovsky-type reaction, and a modified Horner-Wadsworth-Emmons Z-selective olefination. We also discuss a Z-E isomerization during the α,ß-unsaturated amide formation. The new synthesis of meayamycin B consists of 11 steps in the longest linear sequence and 24 total steps.