ABSTRACT
A heterotropic ternary complex was obtained from a photochromic dithienylethene derivative bearing pyridyl groups (1), a chiral tetrasubstituted ferrocene as a scissoring component bearing two pyridyl and free-base porphyrin groups (3*), and a biaryl derivative as an intermediately bridging component bearing four zinc porphyrin handles (2). The three components are connected together via bidentate coordination bonds and mechanically interconnected. Exposure of the ternary complex to UV or visible light allowed for the isomerization of 1. This configurational change gave rise to an angular motion of 2, resulting in a scissoring motion of 3*. In the absence of 2, the isomerization of 1 does not lead to any defined motions of 3*. Thus, the heterotropic ternary complex may be regarded as a prototype of "molecular reacher" for remote manipulation of molecular events.
Subject(s)
Macromolecular Substances/chemistry , Porphyrins/chemistry , Pyridines/chemistry , Zinc/chemistry , Circular Dichroism , Ethylenes/chemistry , Ferrous Compounds/chemistry , Isomerism , Metallocenes , Models, Molecular , Molecular Conformation , Signal TransductionABSTRACT
The design and synthesis of a novel piperidine series of farnesyltransferase (FTase) inhibitors with reduced potential for metabolic glucuronidation are described. The various substitution and exchange of the phenyl group at the C-2 position of the previously described 2-(4-hydroxy)phenyl-3-nitropiperidine 1a (FTase IC(50)=5.4nM) resulted in metabolically stable compounds with potent FTase inhibition (14a IC(50)=4.3nM, 20a IC(50)=3.0nM, and 50a IC(50)=16nM). Molecular modeling studies of these compounds complexed with FTase and farnesyl pyrophosphate are also described.
Subject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Drug Design , Enzyme Inhibitors/pharmacology , Glucuronides/metabolism , Piperidines/chemical synthesis , Animals , Crystallography, X-Ray , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Mice , Microsomes, Liver/metabolism , Models, Molecular , Molecular Structure , Piperidines/chemistry , Piperidines/pharmacology , Protein Prenylation , Rats , Structure-Activity RelationshipABSTRACT
The reactions of several aryl-, furanyl-, and vinyl-substituted sulfilimines with dichloroketene proceeded at 25 degrees C to yield thioalkyl-substituted gamma-lactams. The overall process involves nucleophilic addition of the nitrogen atom of the sulfilimine onto the highly electrophilic dichloroketene to first generate a zwitterionic intermediate. A subsequent [3,3]-sigmatropic rearrangement is followed by intramolecular trapping of the Pummerer cation by the amido anion to furnish the observed gamma-lactam product. Incorporation of donor groups on the aromatic ring of the sulfonyl functionality had little effect when aryl-substituted sulfilimines were used but exhibited a major effect on the efficiency of the reaction with furanyl-substituted systems. The placement of an electron donor group (i.e., OMe) on the sulfonyl aryl group enhances the nucleophilicity of the amido anion contained within the sulfonium ion intermediate and facilitates the rate of the 3,3-sigmatropic rearrangement. Styryl-substituted sulfilimines cyclize in a stereospecific manner and produce a 3:2-mixture of gamma-lactams and the isomeric imino-lactone system. The heavily functionalized gamma-lactams are easily converted to a variety of nitrogen containing substrates. The vinyl sulfilimine cyclization method was applied to the total synthesis of the Calabar alkaloid (+/-)-desoxyeseroline.
Subject(s)
Dichloroethylenes/chemistry , Indoles/chemical synthesis , Sulfur Compounds/chemistry , Vinyl Compounds/chemistry , Cyclization , Indoles/chemistry , Molecular StructureABSTRACT
The reactions of several aryl-, furanyl-, and vinyl substituted sulfilimines with dichloroketene proceeded at 25 degrees C to yield thioalkyl substituted gamma-lactams which, in turn, were converted to a variety of nitrogen-containing substrates. [reaction: see text]
Subject(s)
Dichloroethylenes/chemistry , Lactams/chemical synthesis , Sulfur Compounds/chemistry , Vinyl Compounds/chemistry , Catalysis , Indicators and Reagents , Molecular Structure , StereoisomerismABSTRACT
Complete reversal of diastereoselectivity was observed in the SmI(2)-promoted ketyl-olefin coupling cyclizations of the hydroxy ketone or aldehyde and its acetate. For example, the stereodivergent synthesis of the epimeric five-membered-ring alcohols 2 and 4 has been accomplished through the SmI(2)-induced ketyl-olefin coupling cyclizations of the delta-hydroxy ketone 1 and delta-acetoxy ketone 3.
ABSTRACT
A novel piperidine series of farnesyltransferase (FTase) inhibitors is described. Systematic medicinal chemistry studies starting with the lead compound, discovered from a 5-nitropiperidin-2-one combinatorial library, resulted in a potent series of novel FTase inhibitors. We found that all of four substituents of the piperidine core played an important role for FTase inhibition. A 10-fold increase in potency was observed by changing the piperidine-2-one core to the corresponding piperidine core. This class of compounds was found to inhibit farnesyltransferase in a Ras competitive manner. Optical resolution of several potent inhibitors revealed that the (+)-enantiomers showed potent farnesyltransferase inhibition. (+)-8 inhibited FTase with an IC(50) of 1.9 nM.
Subject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Piperidines/chemical synthesis , Alkyl and Aryl Transferases/chemistry , Animals , Cattle , Chromatography, High Pressure Liquid , Combinatorial Chemistry Techniques , Crystallography, X-Ray , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Farnesyltranstransferase , Humans , Kinetics , Magnetic Resonance Spectroscopy , Piperidines/chemistry , Piperidines/pharmacology , Stereoisomerism , Structure-Activity Relationship , Tumor Cells, Cultured , ras Proteins/metabolismABSTRACT
[structure: see text] UCS1025A and B, novel pentacyclic polyketides with an unprecedented furopyrrolizidine skeleton, were isolated from the fungus Acremonium sp. KY4917. The structures and stereochemistry were elucidated by a combination of two-dimensional NMR and X-ray crystallographic analysis. UCS1025A showed unique chemical equilibria involving three tautomeric isomers and exhibited antimicrobial activity and antiproliferative activity against human tumor cell lines.
