ABSTRACT
A family of image contrast agent conjugates designed to undergo enzymatic activation has been synthesized. The agents underwent activation both with enzymatically active prostate specific antigen (PSA) and alpha-chymotrypsin, releasing free fluorophore via cleavage of a three-component system. A hexapeptide derivative showed exclusive activation by PSA and constitutes a method for tracking PSA activity in vitro.
Subject(s)
Contrast Media/chemistry , Prostate-Specific Antigen/chemistry , Chymotrypsin/chemistry , Enzyme Activation , Magnetic Resonance Spectroscopy , Spectrometry, Mass, Electrospray IonizationABSTRACT
[structure: see text] The viability of proteins as targets of thermally and photoactivated enediynes has been confirmed at the molecular level. Model studies using a labeled substrate confirmed the efficacy of atom transfer from diyl radicals produced from enediynes to form captodatively stabilized carbon centered aminoacyl radicals, which then undergo either fragmentation or dimerization. To exploit this finding, a family of enediynes was developed using an intramolecular coupling strategy. Derivatives were prepared and used to target specific proteins, showing good correlation between affinity and photoinduced protein degrading activity. The findings have potential applications in the design of artificial chemical proteases and add to our understanding of the mechanism of action of the clinically important enediyne antitumor antibiotics.
Subject(s)
Alkenes/chemical synthesis , Alkynes/chemical synthesis , Muramidase/chemistry , Photosensitizing Agents/chemical synthesis , Receptors, Estrogen/chemistry , Serum Albumin, Bovine/chemistry , Alkenes/chemistry , Alkenes/radiation effects , Alkynes/chemistry , Alkynes/radiation effects , Animals , Binding Sites , Cattle , Humans , Molecular Structure , Muramidase/metabolism , Photochemistry , Photosensitizing Agents/chemistry , Photosensitizing Agents/radiation effects , Receptors, Estrogen/metabolism , Serum Albumin, Bovine/metabolism , Structure-Activity RelationshipABSTRACT
A family of differentially substituted poly(ethyleneglycol) building blocks has been assembled from commercially available material. Their utility is demonstrated by formation of amino acid conjugates, image contrast agents, gold nanoparticles, and functional antibody conjugates. Application in the cellular trafficking of antitumoral agent conjugates is expected.
Subject(s)
Polyethylene Glycols/chemistry , Amino Acids/chemistry , Animals , Antibodies/chemistry , Antineoplastic Agents/pharmacokinetics , Binding Sites , Biological Transport , Goats , Immunoglobulin G , Polyethylene Glycols/pharmacokineticsABSTRACT
A family of image contrast agent conjugates designed to undergo enzymatic activation has been synthesized. The agents underwent activation both with enzymatically active prostate specific antigen and alpha-chymotrypsin, releasing free fluorophore via cleavage of a three-component system.
Subject(s)
Contrast Media/chemistry , Contrast Media/metabolism , Prostate-Specific Antigen/metabolismABSTRACT
Twenty two analogues of SB-203207 have been prepared by total synthesis, and evaluated as inhibitors of a range of tRNA synthetases. Changes to the bicyclic core, removing either the terminal amino substituent or the sulfonyl group from the side chain, and altering either the carbon skeleton or stereochemistry of the isoleucine residue, decreases the potency of inhibition of isoleucyl tRNA synthetase. Substituting the isoleucine residue with other amino acids produces inhibitors of the corresponding synthetases. In particular, a methionine derivative is 50-100 times more potent against methionyl tRNA synthetase than against any of the corresponding isoleucyl, leucyl, valyl, alanyl and prolyl synthetases.
Subject(s)
Indenes/chemical synthesis , Indenes/pharmacology , Isoleucine-tRNA Ligase/antagonists & inhibitors , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , Amino Acids/chemistry , Amino Acyl-tRNA Synthetases , Animals , Inhibitory Concentration 50 , Liver/enzymology , Rats , Staphylococcus aureus/enzymology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The stereochemistry of the indium-promoted reaction of allyl bromide with alpha-thia (PhS and MeS), disubstituted alpha-amino (Bn(2)N, Me(2)N, isoindolyl), and protected alpha-amino aldehydes (Ac and Boc) in water has been evaluated. The reactions involving the sulfur derivatives are minimally diastereoselective, indicating that the allylindium reagent is not thiophilic. Chelation is not observed and pi-facial discrimination is achieved via Felkin-Ahn transition states under the steric control of the substituents. The Garner aldehyde is also anti-diastereoselective. Interestingly, N-acetylmannosamine is appreciably responsive to chelation control and is capable of generating 90% of the syn beta-amino alcohol when reacted in a 0.5 M NH(4)Cl solution. While the alpha-dibenzylamino substituent is too bulky to enter into complexation, the alpha-dimethylamino group is not and can lead to high levels (99%) of syn diastereomer. The size of other neighboring substituents does have an impact on pi-facial discrimination in these systems and can erode the stereoselectivity accordingly.
