ABSTRACT
Bioactivity guided fractionation of Echiochilon fruticosum Desf. (Boraginaceae) butanolic extract biautography assay against fungi led to the isolation of a new bioactive alkaloid, named saoussanabiloïde (1). Its structure was established on the basis of spectroscopic measurements, IR, MS and 2D NMR using COSY, HMQC and HMBC experiments. The strongest inhibitory effect of the butanolic extract, from fractions derived from the crude extract and saoussanabiloïde (1), were observed against Fusarium oxysporum f. sp. niveum.
Subject(s)
Alkaloids/isolation & purification , Alkaloids/pharmacology , Antifungal Agents/isolation & purification , Antifungal Agents/pharmacology , Boraginaceae/chemistry , Fusarium/drug effects , Plant Extracts/pharmacology , Alkaloids/chemistry , Antifungal Agents/chemistry , Magnetic Resonance Spectroscopy , Microbial Sensitivity Tests , Molecular Structure , Plant Extracts/chemistry , Plant Extracts/isolation & purification , TunisiaABSTRACT
The general concept of tethered combinatorial libraries of compounds in which two pharmacophores are found is described. In particular, an improved method for the solid-phase synthesis of bicyclic guanidines from reduced N-acylated dipeptides, and its use in the synthesis of urea-linked bicyclic guanidines, is described. The exhaustive reduction of glutamine-containing resin-bound N-acylated dipeptides, using borane-THF, generated compounds containing three secondary amines and one primary amine. Following selective trityl protection of the primary amine, treatment of the three secondary amines with thiocarbonyldiimidazole (CSIm2) and mercuric acetate (Hg(OAc)2) generated the resin-bound bicyclic guanidines. Following trityl deprotection, an Fmoc-amino acid was coupled. Upon removal of the Fmoc protecting group, the resulting primary amine was treated with hexyl isocyanate to generate the urea-linked bicyclic guanidines. The desired products were cleaved from the resin using hydrogen fluoride. The selection of building blocks and characterization of controls for the synthesis of a combinatorial library is discussed.
Subject(s)
Bridged Bicyclo Compounds/chemical synthesis , Guanidines/chemical synthesis , Urea/chemistry , Combinatorial Chemistry TechniquesABSTRACT
An efficient method for the solid-phase synthesis of bis-heterocyclic compounds from resin-bound orthogonally protected lysine is presented. The initial reaction step involves the exhaustive reduction of resin-bound tetra-amides using borane-THF, followed by cyclization of the resulting tetra-amine with either carbonyldiimidazole, thiocarbonyldiimidazole, or oxalyldiimidazole to generate resin-bound bis-cyclic ureas, bis-cyclic thioureas, and bis-cyclic diketopiperazines, respectively. Cleavage from the solid support using hydrogen fluoride, followed by extraction and lyophilization, yields the desired bis-heterocyclic compounds in excellent yield and high purity.
Subject(s)
Heterocyclic Compounds/chemical synthesis , Lysine/analogs & derivatives , Lysine/chemical synthesis , Acylation , Combinatorial Chemistry Techniques , Cyclization , Resins, PlantABSTRACT
The development of soluble mixture-based heterocyclic combinatorial libraries derived from amino acids and peptides is described. Starting with a "toolbox" of various chemical transformations, including alkylations, reductions, acylations, and the use of a variety of bifunctional reagents, the "libraries from libraries" concept has been expanded to encompass the development of more than fifty positional scanning combinatorial libraries each composed of tens of thousands of low molecular weight acyclic and heterocyclic compounds.
Subject(s)
Peptide Biosynthesis , Peptides/chemistry , Peptides/chemical synthesis , Combinatorial Chemistry Techniques , Guanidine/chemistry , Lysine/chemistry , Models, Chemical , Peptide Library , Thiourea/chemistryABSTRACT
The exhaustive reduction of resin-bound tripeptides with borane afforded three secondary amines and one primary amine. The treatment of the solid-support polyamines with thiocarbonyldiimidazole afforded, following cleavage of the solid support, the corresponding bis-cyclic thiourea in good purity and yield.
Subject(s)
Imidazoles/chemical synthesis , Oligopeptides/chemistry , Imidazoles/chemistrySubject(s)
Chemistry, Organic , Peptide Library , Drug Design , Guanidines , Models, Chemical , Organic Chemistry PhenomenaABSTRACT
Modified dipeptides have been used successfully for the generation of a variety of small organic and heterocyclic combinatorial libraries, including linear urea, polyamine, hydantoin, thiohydantoin, cyclic urea, cyclic thiourea and bicyclic guanidine. The synthesis and screening results for a number of these libraries are described. The solid phase synthesis of heterocyclic compounds such as diazepine and thiomorpholinone are also described.
Subject(s)
Chemistry, Organic/methods , Databases as Topic , Dipeptides/chemical synthesis , Drug Design , Heterocyclic Compounds/chemical synthesis , Peptide Library , Peptides/chemical synthesis , Dipeptides/chemistry , Heterocyclic Compounds/chemistry , Indicators and Reagents , Molecular Conformation , Molecular Structure , Peptides/chemistry , Protein Conformation , Structure-Activity RelationshipABSTRACT
Pseudo-prolines (psi Pro) are introduced as a temporary protection technique for serine, threonine and cysteine side chains in standard Fmoc/tBu solid-phase peptide synthesis (SPPS). The incorporation of these novel building blocks into a growing peptide chain proceeds by means of the coupling of preformed, suitably protected psi Pro dipeptides. For the example of representative model peptides used in protein de novo design, the potential of psi Pro to solubilize otherwise sparingly or completely insoluble peptides is demonstrated. Because of their intrinsic propensity for preventing peptide aggregation and beta-sheet formation, pseudo-prolines offer new possibilities for accessing large peptides by convergent strategies and chemoselective ligation techniques.
