ABSTRACT
A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. A basic nitrogen within the tether linking the aniline nitrogen atom to a tetrahydroindolone moiety allowed access to compounds with good physical properties. Important structure-activity relationship information was obtained from this series which led to the discovery of a soluble and stable compound which is potent in an Hsp90 binding and cell-proliferation assay.
Subject(s)
Antineoplastic Agents/chemistry , Benzamides/chemistry , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Benzamides/chemical synthesis , Benzamides/pharmacology , Binding Sites , Cell Line, Tumor , Cell Proliferation , Computer Simulation , Crystallography, X-Ray , Drug Design , HSP90 Heat-Shock Proteins/metabolism , Humans , Protein Binding , Structure-Activity RelationshipABSTRACT
Redox isomerization is a synthetically important process because it creates two new functional groups in the product, among which is the isomerization of propargylic alcohols to conjugated enones. Although E-enones have been prepared by this approach, Z-enones could not be accessed. We previously reported DABCO-catalyzed E-selective isomerization of electron-deficient propargylic alcohols to enones and its mechanism. Based on this mechanism, we have now developed the first Z-selective redox isomerization of electron-deficient propargylic alcohol to enone using sodium bicarbonate as a catalyst.
Subject(s)
Alcohols/chemistry , Isatin/analogs & derivatives , Isatin/chemistry , Sodium Bicarbonate/chemistry , Alkenes/chemistry , Catalysis , Dimethyl Sulfoxide , Electrons , Indicators and Reagents , Isomerism , Magnetic Resonance Spectroscopy , Organophosphonates/chemistry , Spectrophotometry, Infrared , StereoisomerismABSTRACT
We have developed highly stereoselective methods to isomerize electron-deficient propargylic alcohols to E-enones under mild conditions (EWG = electron-withdrawing group). Among weak bases we screened, catalytic (10-20 mol %) 1,4-diazabicyclo[2.2.2]octane (DABCO) was found to be effective in most cases. When the substrate is conjugated with an amide, the addition of sodium acetate catalyzed the isomerization.
ABSTRACT
[reaction: see text] Since the discovery of organic base-catalyzed isomerization of gamma-hydroxy-alpha,beta-acetylenic esters to gamma-oxo-alpha,beta-trans-alkenyl esters in 1949, the mechanism has not been elucidated. This study shows that the mechanism involves cumulene formation, protonation with the conjugate acid of the amine, and protonation of the resulting allenol with water.
