ABSTRACT
The synthesis of a series of 1,2,4-oxadiazole analogs is discussed along with their ZAP-70 SH2 inhibitory activity. The tyrosine moiety in the original series has been replaced with nonpeptidic functional groups without a substantial loss of binding affinity.
Subject(s)
Enzyme Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , src Homology Domains , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Fluorescence Polarization , Protein Binding , ZAP-70 Protein-Tyrosine KinaseABSTRACT
A series of 1,2,4-oxadiazole analogues has been shown to be potent and selective SH2 inhibitors of the tyrosine kinase ZAP-70, a potential therapeutic target for immune suppression. These compounds typically are 200-400-fold more potent than the native, monophosphorylated tetrapeptide sequences. When compared with the high-affinity zeta-1-ITAM peptide (Ac-NQL-pYNELNLGRREE-pYDVLD-NH(2), wherein pY refers to phosphotyrosine) some of the best 1,2, 4-oxadiazole analogues are approximately 1 order of magnitude less active. This series of compounds displays an unprecedented level of selectivity over the closely related tyrosine kinase Syk, as well as other SH2-containing proteins such as Src and Grb2. Gel shift studies using a protein construct consisting only of C-terminal ZAP-70 SH2 demonstrate that these compounds can effectively engage this particular SH2 domain.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Oxadiazoles/chemical synthesis , Protein-Tyrosine Kinases/antagonists & inhibitors , src Homology Domains , Enzyme Inhibitors/chemistry , Enzyme Precursors/antagonists & inhibitors , Intracellular Signaling Peptides and Proteins , Models, Molecular , Oxadiazoles/chemistry , Structure-Activity Relationship , Syk Kinase , ZAP-70 Protein-Tyrosine KinaseABSTRACT
The structure-activity relationships (SAR) of a novel class of Src SH2 inhibitors are described. Variation at the pY+1 and pY+3 side chain positions using 2,4- and 2,5-substituted thiazoles and 1,2,4-oxadiazoles as scaffolds resulted in inhibitors that bound as well as the standard tetrapeptide Ac-pYEEI-NH2.
Subject(s)
Thiazoles/chemistry , Thiazoles/pharmacology , src Homology Domains , Structure-Activity RelationshipABSTRACT
Novel anions that contain one molecule each of C60 and the polycyclic aromatic hydrocarbon coronene are generated in the gas phase by electron attachment desorption chemical ionization. Collision-induced dissociation reveals that these cluster ions are loosely bonded. Fragmentation of the mass-selected cluster anion yields, as the only products, the intact radical anions of the constituent molecules, namely, the C60 radical anion and the coronene radical anion, in almost identical relative abundances. This result is interpreted as evidence that the cluster ion can be considered as the anion radical of one molecule solvated by the other molecule. The known very high electron affinity of C60 (2.66 eV) and the comparable degree to which C60 and the PAH compete for the electron suggests that dissociation may be controlled by the electron affinity of a portion of the C60 surface, that is, in this case the kinetic method yields information on the local electron affinity of C60. The electron affinity of the bowl-shaped compound corannulene is estimated for the first time to be 0.50 ± 0.10 eV by the kinetic method by using a variety of reference compounds. Unlike coronene, corannulene reacts with C -⢠(60) in the gas phase to form a covalently bonded, denydrogenated cluster ion. Support for the concept of "local" electron affinity of C60 comes from a theoretical calculation on the electronic structure of C60 anions, which shows evidence for localization of the charge in the C60 molecule. The possibility of electron tunneling in the C60-coronene system is discussed as an alternative explanation for the unusual observation of equal abundances of C60 anions and coronene anions upon dissociation of the corresponding cluster ion.
