ABSTRACT
A hypervalent iodine(III)-mediated cross-dehydrogenative coupling reaction for the direct formation of C-C, C-N, and C-O bonds in dihydroquinazolines has been developed. This one-pot method allows for the synthesis of C4-disubstituted dihydroquinazolines as well as C4-spirolactam, spirolactone, and spiroindene dihydroquinazolines in moderate to high yields.
ABSTRACT
Aggregates or oligomeric forms of many intrinsically disordered proteins (IDPs), including α-synuclein, are hallmarks of neurodegenerative diseases, like Parkinson's and Alzheimer's disease, and key contributors to their pathogenesis. Due to their disordered nature and therefore lack of defined drug-binding pockets, IDPs are difficult targets for traditional small molecule drug design and are often referred to as "undruggable". The 20S proteasome is the main protease that targets IDPs for degradation and therefore small molecule 20S proteasome enhancement presents a novel therapeutic strategy by which these undruggable IDPs could be targeted. The concept of 20S activation is still relatively new, with few potent activators having been identified thus far. Herein, we synthesized and evaluated a library of dihydroquinazoline analogues and discovered several promising new 20S proteasome activators. Further testing of top hits revealed that they can enhance 20S mediated degradation of α-synuclein, the IDP associated with Parkinson's disease.
Subject(s)
Intrinsically Disordered Proteins/antagonists & inhibitors , Parkinson Disease/drug therapy , Proteasome Endopeptidase Complex/metabolism , Quinazolines/pharmacology , alpha-Synuclein/antagonists & inhibitors , Dose-Response Relationship, Drug , Humans , Intrinsically Disordered Proteins/metabolism , Molecular Structure , Parkinson Disease/metabolism , Quinazolines/chemical synthesis , Quinazolines/chemistry , Structure-Activity Relationship , alpha-Synuclein/metabolismABSTRACT
A multicomponent tandem assembly procedure for the synthesis of diverse C4-quaternary 3,4-dihydroquinazolines from amides, amines, and ketones has been developed. The one-pot reaction involves successive triflic anhydride mediated amide dehydration, ketimine addition, and Pictet-Spengler-like cyclization processes and affords products in up to 92% yield. Conversion of 3,4-dihydroquinazolines to the corresponding 1,4-dihydroquinazolines via a two-step N1 dealkylation and regioselective N3 functionalization protocol, including computational rationale for the observed regioselectivity, is also described.
Subject(s)
Amines , Ketones , Amides , Cyclization , StereoisomerismABSTRACT
A one-pot three-component tandem reaction involving a key Pictet-Spengler-like annulation step has been developed, providing an efficient method for the synthesis of 3,4-dihydroquinazolines in moderate to good yields from amides, aldehydes, and amines. The multicomponent triflic anhydride mediated reaction tolerates the installation of numerous functional groups, affording extensive diversity about the heterocyclic scaffold.
Subject(s)
Furans/chemistry , Quinazolines/chemical synthesis , Sulfonamides/chemistry , Aldehydes/chemistry , Amides/chemistry , Amines/chemistry , CyclizationABSTRACT
A series of α-alkoxy carbamates that cleave under mild conditions to release alcohols has been synthesized through a multicomponent process. The relationship between structural features in these compounds and the rate of alcohol release in the presence of basic hydrogen peroxide has been studied. The preparation of carbamates that cleave under other conditions has been demonstrated.
Subject(s)
Alcohols/chemistry , Carbamates/chemical synthesis , Carbamates/chemistry , Hydrogen Peroxide/chemistry , Molecular StructureABSTRACT
This review highlights the broad range of science that has arisen from the isolation of pederin, the mycalamides, theopederins, and onnamides, and psymberin. Specific topics include structure determination, biological activity, synthesis, and analog preparation and analysis.
