FR131535, a novel water-soluble echinocandin-like lipopeptide: synthesis and biological properties.

The synthesis and biological properties of a novel water-soluble echinocandin-like lipopeptide, FR131535, are described. This compound displayed potent in vitro and in vivo antifungal activities. The hemolytic activity of FR901379 was reduced by replacing the acyl side chain. This compound showed good water-solubility, comparable to the natural product FR901379.

Carbon-11 labeled ethionine and propionine as tumor detecting agents.

To develop 18F-fluoroalkyl derivatives of methionine (MET) as a tumor detecting agent by mean of clinical PET, a pilot study assessing the potential of their parent compounds, 11C-labeled ethionine (11C-ETH) and propionine (11C-PRO), was performed. 11C-ETH and 11C-PRO were prepared by the reaction of L-homocysteine thiolactone and corresponding 11C-alkyl iodides. After i.v. injection of a mixture of 3H-MET. 14C-ETH and 11C-PRO into mice bearing FM3A mammary carcinoma, the highest FM3A uptake was found in 14C-ETH, followed by 3H-MET and 11C-PRO, while the FM3A-to-brain and FM3A-to-muscle ratios were nearly the same for all three compounds. The FM3A uptake of 14C-ETH and 11C-PRO were nearly equal or slightly higher than the liver uptake. In the pancreas, liver, FM3A and brain tissues, incorporation of 14C-ETH into acid-precipitable materials was much lower than that of 3H-MET, whereas no incorporation of 11C-PRO was found. Brain uptake of all three compounds was significantly reduced by carrier MET-loading (5 min p.i.) or by cycloheximide treatment to inhibit protein synthesis (60 min p.i.), whereas the FM3A uptake was not affected. Incorporation of 14C-ETH into acid-precipitable materials was inhibited by the cycloheximide. The results suggest that 11C-labeled ETH has a similar potential for tumor detection by PET as 11C-MET, and that 11C-PRO has similar properties to those of other artificial amino acids. The development of 18F-fluoroalkyl derivatives of MET is of interest as the next step.

Specific interactions outside the proline-rich core of two classes of Src homology 3 ligands.

Two dodecapeptides belonging to distinct classes of Src homology 3 (SH3) ligands and selected from biased phage display libraries were used to investigate interactions between a specificity pocket in the Src SH3 domain and ligant residues flanking the proline-rich core. The solution structures of c-Src SH3 complexed with these peptides were solved by NMR. In addition to proline-rich, polyproline type II helix-forming core, the class I and II ligands each possesses a flanking sequence that occupies a large pocket between the RT and n-Src loops of the SH3 domain. Structural and mutational analyses illustrate how the two classes of SH3 ligands exploit a specificity pocket on the receptor differently to increase binding affinity and specificity.

Identification of osteopontin in human dental calculus matrix.

Osteopontin is a prominent non-collagenous component of bone matrix, although it is expressed in several other tissues. Recently, osteopontin was reported to be involved in urinary stone formation and atherosclerotic lesions of the aorta, suggesting that it may be a key protein associated with these types of pathological mineralization. In this study, whether or not human dental calculus contains osteopontin was investigated by immunoblotting and immunohistochemical analyses. After extraction of calculus proteins with EDTA and separation of the proteins by electrophoresis, immunoblotting analysis revealed the presence of osteopontin. Two forms of osteopontin appeared at 61 and 68 kDa on 10% polyacrylamide gel and the proteins were digested with thrombin, a highly specific protease. Moreover, immunohistochemical analysis revealed that osteopontin was localized in dental calculus adherent to tooth roots. These findings indicate that osteopontin is, in fact, present in human dental calculus and may be involved in calculus formation as the stone matrix.