ABSTRACT
We report herein that the oroidin-derived alkaloids palau'amine (1), dibromophakellin (2), and dibromophakellstatin (3) inhibit the proteolytic activity of the human 20S proteasome as well as the (i)20S immunoproteasome catalytic core. Palau'amine is found to prevent the degradation of ubiquitinylated proteins, including IκBα, in cell culture, which may be indicative of the potential mechanism by which these agents exhibit their exciting cytotoxic and immunosuppressive properties.
Subject(s)
Alkaloids/pharmacology , Guanidines/pharmacology , Heterocyclic Compounds, 4 or More Rings/pharmacology , Imidazoles/pharmacology , Proteasome Inhibitors , Pyrroles/pharmacology , Spiro Compounds/pharmacology , Alkaloids/chemistry , Guanidines/chemistry , HeLa Cells , Heterocyclic Compounds, 4 or More Rings/chemistry , Humans , Imidazoles/chemistry , Microscopy, Confocal , NF-kappa B/metabolism , Proteasome Endopeptidase Complex/chemistry , Pyrroles/chemistry , Spiro Compounds/chemistry , StereoisomerismABSTRACT
The sponge-derived alkaloid dibromoagelaspongin was prepared from a dihydrooroidin derivative by exploiting the Pummerer reaction twice in succession. Oxidative cyclization of the substrate's pyrrole-2-carboxamide function into the imidazole moiety was achieved in a regiospecific manner to establish both C-N bonds to C(6) of the target.
Subject(s)
Alkaloids/chemical synthesis , Pyrroles/chemical synthesis , Alkaloids/chemistry , Cyclization , Imidazolines/chemistry , Oxidation-Reduction , Pyrroles/chemistry , Stereoisomerism , Substrate SpecificityABSTRACT
The sponge metabolite dibromoagelaspongin was synthesized in 16 steps from imidazole. The route features two successive oxidative cyclizations with complete control of regiochemistry to deliver the unusual triaminomethane core of the target. These oxidative cyclizations likely resulted from Pummerer-like processes on the imidazole-2-sulfoxide (sulfide) precursors.
Subject(s)
Pyrroles/chemical synthesis , Alkaloids/chemical synthesis , Cyclization , Guanidines/chemical synthesis , Imidazoles/chemistry , Oxidation-Reduction , Stereoisomerism , Sulfides/chemistry , Sulfoxides/chemistryABSTRACT
The syntheses of (+/-)-dibromophakellstatin and, from this species, (+/-)-dibromophakellin are described. Oxidative cyclization of a phenylthiolated dihydrooroidin derivative triggered by a Pummerer reaction constitutes the key step in this biomimetic approach to this family of marine alkaloids.
Subject(s)
Alkaloids/chemical synthesis , Chemistry, Organic/methods , Imidazoles/chemical synthesis , Piperazines/chemical synthesis , Alkaloids/chemistry , Cyclization , Imidazoles/chemistry , Molecular Structure , Piperazines/chemistry , StereoisomerismABSTRACT
The solution-phase synthesis of a discovery library of 178 tricyclic pyrrole-2-carboxamides was accomplished in nine steps and seven purifications starting with three benzoyl-protected amino acid methyl esters. Further diversity was introduced by two glyoxaldehydes and 41 primary amines. The combination of Pauson-Khand, Stetter, and microwave-assisted Paal-Knorr reactions was applied as a key sequence. The discovery library was designed with the help of QikProp 2.1, and physicochemical data are presented for all pyrroles. Library members were synthesized and purified in parallel and analyzed by LC/MS. Selected compounds were fully characterized.
Subject(s)
Amides/chemical synthesis , Carboxylic Acids/chemistry , Heterocyclic Compounds, 3-Ring/chemical synthesis , Pyrroles/chemistry , Pyrroles/chemical synthesis , Combinatorial Chemistry Techniques , Computational Biology , Computer Simulation , Gas Chromatography-Mass Spectrometry , Molecular Structure , Pharmaceutical Preparations , StereoisomerismABSTRACT
Cascade reactions of internal and terminal alkynes, zirconocene hydrochloride, dimethylzinc, and phosphinoyl imines (prepared in one step from aldehydes and diphenylphosphinoyl amide) lead to allylic phosphinoyl amides after aqueous workup. Microwave acceleration allows the completion of this one-pot reaction sequence in 10 min. These allylic amides can be converted into a variety of derivatives, including carbamates and sulfonamides, or reacted prior to workup with diiodomethane to give novel C-cyclopropylalkylamides. A solution-phase "libraries from libraries" approach was used to generate an intermediate 20-member library which was subsequently expanded to a 100-member library by a series of N-functionalizations. The biological activity was evaluated in an assay for competitive binding to the estrogen receptor (ERalpha), revealing three potent lead compounds of a new structural type.
