ABSTRACT
A polymer-supported route for the synthesis of sphingosine derivatives is presented based on the C-acylation of polymeric phosphoranylidene acetates with an Fmoc-protected amino acid. The approach enables the flexible variation of the sphingosine tail through a deprotection-decarboxylation sequence followed by E-selective Wittig olefination cleavage. d-Erythro-sphingosine analogs have been synthesized by diastereoselective reduction of the keto group employing LiAlH(O-tBu)3 as reducing agent. The effect of ceramides and keto-ceramides on the proliferation of three cancer cell lines HEP G-2, PC-12 and HL-60 was investigated and a ceramide containing an aromatic sphingosine tail was identified as being most active.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Ceramides/chemistry , Ceramides/pharmacology , Polymers/chemistry , Sphingosine/analogs & derivatives , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Ceramides/chemical synthesis , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HL-60 Cells , Hep G2 Cells , Humans , Molecular Structure , Sphingosine/chemical synthesis , Sphingosine/chemistry , Sphingosine/pharmacology , Structure-Activity RelationshipABSTRACT
Novel syntheses of peptidyl ketones and peptidyl diketones on polymer support are described. Peptidyl phosphoranylidene acetates were prepared via C-acylation of polymer-supported phosphorus ylides. Selective alkylation of the ylide carbon with various alkyl halides, such as methyl iodide and benzyl bromide was established. Peptidyl diketones were obtained by oxidative cleavage. Peptidyl ketones were furnished by hydrolysis of the peptidyl phosphorus ylides under either basic or acidic conditions.
Subject(s)
Ketones/chemistry , Peptides/chemistry , Phosphorus/chemistry , Acylation , Alkylation , Hydrolysis , Ketones/chemical synthesis , Molecular Structure , Oxidation-Reduction , Peptides/chemical synthesisABSTRACT
C-Acylations of polymer-supported 2-phosphoranylidene acetates ("linker reagents") with protected amino acids yielded 2-acyl-2-phosphoranylidene acetates as flexible intermediates for the C-terminal variation of carboxylic acids: peptidyl-2,3-diketoesters, peptidyl vinyl ketones, peptidyl-2-ketoaldehydes, and 1,3-diamino-2-hydroxy-propanes were obtained as products. [reaction: see text]
