ABSTRACT
The role of the C(8) gem-dimethyl group in the A-ring of bryostatin 1 has been examined through chemical synthesis and biological evaluation of a new analogue. Assays for biological function using U937, K562, and MV4-11 cells as well as the profiles for downregulation of PKC isozymes revealed that the presence of this group is not a critical determinant for the unique pattern of biological activity of bryostatin.
Subject(s)
Antineoplastic Agents/chemical synthesis , Bryostatins/chemical synthesis , Protein Kinase C/antagonists & inhibitors , Antineoplastic Agents/pharmacology , Bryostatins/pharmacology , Cell Adhesion/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Down-Regulation , Humans , Isoenzymes/antagonists & inhibitors , Isoenzymes/metabolism , Molecular Structure , Protein Kinase C/metabolism , Structure-Activity Relationship , Tetradecanoylphorbol Acetate/pharmacologyABSTRACT
A close structural analogue of bryostatin 1, which differs from bryostatin 1 only by the absence of the C(30) carbomethoxy group (on the C(13) enoate of the B-ring), has been prepared by total synthesis. Biological assays reveal a crucial role for substitution in the bryostatin 1 A-ring in conferring those responses which are characteristic of bryostatin 1 and distinct from those observed with PMA.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Bryostatins/chemistry , Phorbol Esters/chemistry , Antineoplastic Agents/pharmacology , Bryostatins/chemical synthesis , Bryostatins/pharmacology , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Molecular Structure , Phorbol Esters/pharmacology , Structure-Activity RelationshipABSTRACT
The total synthesis of the farnesyltransferase inhibitor kurasoin A has been achieved using a novel asymmetric phase-transfer-catalyzed glycolate alkylation reaction. 2,5-Dimethoxyacetophenone 7 with cinchonidinium catalyst 9(10 mol %) and hydroxide base with pivaloyl benzyl bromide 8 provided S-alkylation product 10 in high yield (80-99%) and excellent enantioselectivity. Baeyer-Villiger oxidation, Weinreb amide formation, and benzyl Grignard addition to the TES-ether 17 gave the protected target. Lithium hydroxide and peroxide generated kurasoin A ([alpha](D) +8.4 degrees ) without isomerization.
Subject(s)
Indoles/chemical synthesis , Ketones/chemistry , Phenols/chemical synthesis , Alkylation , Catalysis , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Farnesyltranstransferase/antagonists & inhibitors , Hydroxylation , Indoles/chemistry , Molecular Structure , Phenols/chemistry , Substrate SpecificityABSTRACT
[Reaction: see text]. Asymmetric glycolate alkylation using a protected acetophenone surrogate under solid-liquid phase-transfer conditions is a new approach to the synthesis of 2-hydroxy esters and acids. Diphenylmethyloxy-2,5-dimethoxyacetophenone 1 with a trifluorobenzyl cinchonidinium bromide catalyst 9 (10 mol %) and cesium hydroxide provided S-alkylation products 2 at -35 degrees C in high yield (80-99%) and with excellent enantioselectivities using a wide range of electrophiles (80-90% ee). Alkylated products were elaborated to useful alpha-hydroxy intermediates 3 using bis-TMS peroxide Baeyer-Villiger conditions and selective transesterification reactions. The ester products have been enantioenriched by simple recrystallization from ether to give a single isomer (99% ee). A tight ion-pair model is proposed for the observed S-stereoinduction that includes van der Waals contacts between the extended enolate and the isoquinoline of the catalyst. To demonstrate the utility of the new methodology, the anti-diabetes drug (-)-ragaglitazar 24 was synthesized in six steps from a key 2-alkoxy-3-p-phenoxypropionic acid 26 that was made using PTC glycolate alkylation.
Subject(s)
Glycolates/chemistry , Oxazines/chemical synthesis , Phenylpropionates/chemical synthesis , Acetophenones/chemistry , Alkylation , Catalysis , Crystallization , Esters/chemistry , Oxazines/chemistry , Phenylpropionates/chemistry , StereoisomerismABSTRACT
[reaction: see text] Asymmetric surrogate glycolate alkylation has been performed under phase-transfer conditions. Diphenylmethyloxy-2,5-dimethoxyacetophenone with trifluorobenzyl cinchonidinium catalyst and cesium hydroxide provided alkylation products at -35 degrees C in high yield (80-99%) and with excellent enantioselectivities (90:10 to 95:5). Useful alpha-hydroxy products were obtained using bis-TMS peroxide Baeyer-Villiger conditions and selective transesterification. The intermediate aryl ester can be obtained with >99% ee after a single recrystallization. A tight ion-pair model for the observed (S)-stereoinduction is proposed.
