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.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Activation of cytoplasmic serine/threonine kinase Raf-1, an important effector of Ras, requires direct binding to Ras. The yeast two-hybrid screening system used for identification of inhibitors of Ras/Raf-1 interaction showed radicicol to be an inhibitor. Radicicol has been shown to induce morphological reversion of transformed cells. Immunoprecipitation with an anti-Ras antibody revealed that the in vivo Ras/Raf-1 binding in v-Ha-ras-transformed cells was also blocked by low concentrations of radicicol (0.1 approximately 1 microg/ml), while degradation of Raf-1 was induced at concentrations higher than 2 microg/ml. However, in vitro binding of glutathion S-transferase-fused Ras to a maltose binding protein-fused RIP3 containing the Ras-binding domain (RBD) of Raf-1 was not inhibited by radicicol. Similar two-hybrid assays with several truncated forms of Raf-1 showed that both the conserved serine/threonine-rich domain (CR2) and the C-terminal protein kinase domain (CR3) were required for the full inhibition by radicicol. These results suggest that radicicol interacts directly or indirectly with the region except with RBD of Raf-1, thereby inhibiting a conformational change of Raf-1 prerequisite for binding to Ras.

of our screening for suppressors of glutamate-toxicity tc ameliorate and/or overcome brain ischemic injury using neuronal hybridoma N18-RE-105 cells as an in vitrc model, we isolated espicufolin (1, Fig. 1). In this paper, we report the fermentation, isolation and structure determination of 1. The espicufolin producing organism, identified as Streptomyces sp. cu39, was cultivated in the medium consisting of glucose 2.5%, soybean meal 1.5%, dried yeast 0.2% and CaCO3 0.4% at 27°C for 5days. The mycelial acetone extract was concentrated to a small volume and the aqueous residue was extracted with EtOAc. The solvent layer was dried over Na2SO4 and concentrated to give an oily residue. This material was applied to a silica gel column packed with CHC13MeOH (50: 1) and eluted with the same solvent system. The combined active eluate was then subjected to preparative silica gel TLC developed with CHCl3-MeOH (50: 1). Further purification by a Sephadex LH-20 column (CHC13-MeOH, 1 : 1) gave a crude sample of1. Finally, 1 was purified by HPLC using a PEGASIL ODS column (Senshu-Pak, i.d. 20 x 250mm, 85% MeOH) as a yellow powder.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.