1091-85-6Relevant academic research and scientific papers
Synthesis of the Rheb and K-Ras4B GTPases
Chen, Yong-Xiang,Koch, Sebastian,Uhlenbrock, Katharina,Weise, Katrin,Das, Debapratim,Gremer, Lothar,Brunsveld, Luc,Wittinghofer, Alfred,Winter, Roland,Triola, Gemma,Waldmann, Herbert
, p. 6090 - 6095 (2010)
Now available! Farnesylated and carboxymethylated Rheb (see picture) and K-Ras4B GTPases were synthesized in useful amounts by a combination of expressed protein ligation and solid-phase lipopeptide synthesis. The functionality of the proteins was proven by biochemical, biophysical, and cell-based investigations.
Naphthalenylsulfonyl-hydantoins as aldose reductase inhibitors
Malamas, MS,Sestanj, K,Millen, J
, p. 369 - 374 (1991)
Accumulation of intracellular sorbitol, formed from glucose by aldose reductase, is believed to play an important role in the development of certain chronic complications of diabetes mellitus.Several 1-(naphthalenylsulfonyl)hydantoins inhibit aldose reductase isolated from bovine lens in vitro, and decrease galactitol formation in sciatic nerves of galactosemic rats in vivo.The 5-bromo analogue (entry 12, table I) was found to be the most orally active aldose reductase inhibitor of this series with an ED50 value of 8.1 mg/kg po.The 1-(naphthalenylsulfonyl)-2-thiohydantoin analogues with the exception of entry 11 (table I) which showed good in vivo activity, were either inactive or had only marginal activity.
Module assembly for protein-surface recognition: Geranylgeranyltransferase I bivalent inhibitors for simultaneous targeting of interior and exterior protein surfaces
Machida, Shinnosuke,Usuba, Kakeru,Blaskovich, Michelle A.,Yano, Akiko,Harada, Kazuo,Sebti, Said M.,Kato, Nobuo,Ohkanda, Junko
supporting information; experimental part, p. 1392 - 1401 (2009/04/07)
Synthetic chemical probes designed to simultaneously targeting multiple sites of protein surfaces are of interest owing to their potential application as site specific modulators of protein-protein interactions. A new approach toward bivalent inhibitors of mammalian type I geranylgeranyltransferase (GGTase I) based on module assembly for simultaneous recognition of both interior and exterior protein surfaces is reported. The inhibitors synthesized in this study consist of two modules linked by an alkyl spacer; one is the tetrapeptide CVIL module for binding to the interior protein surface (active pocket) and the other is a 3,4,5-alkoxy substituted benzoyl motif that contains three aminoalkyl groups designed to bind to the negatively charged protein exterior surface near the active site. The compounds were screened by two distinct enzyme inhibition assays based on fluorescence spectroscopy and incorporation of a [ 3H]-labeled prenyl group onto a protein substrate. The bivalent inhibitors block GGTase I enzymatic activity with Ki values in the submicromolar range and are approximately one order of magnitude and more than 150 times more effective than the tetrapeptide CVIL and the methyl benzoate derivatives, respectively. The bivalent compounds 6 and 8 were shown to be competitive inhibitors, suggesting that the CVIL module anchors the whole molecule to the GGTase I active site and delivers the other module to the targeting protein surface. Thus, our module-assembly approach resulted in simultaneous multiple-site recognition, and as a consequence, synergetic inhibition of GGTase I activity, thereby providing a new approach in designing protein-surface-directed inhibitors for targeting protein-protein interactions.
Protease inhibitors - Part 5. Alkyl/arylsulfonyl- and arylsulfonylureido-/arylureido- glycine hydroxamate inhibitors of Clostridium histolyticum collagenase
Scozzafava, Andrea,Supuran, Claudiu T.
, p. 299 - 307 (2007/10/03)
Reaction of alkyl/arylsulfonyl halides with glycine afforded a series of derivatives which were first N-benzylated by treatment with benzyl chloride, and then converted to the corresponding hydroxamic acids with hydroxylamine in the presence of carbodiimide derivatives. Other derivatives were obtained by reaction of N-benzyl-glycine with aryl isocyanates, arylsulfonyl isocyanates or benzoyl isothiocyanate, followed by conversion of their COOH group into the CONHOH moiety, as mentioned above. The 90 new compounds reported here were assayed as inhibitors of the Clostridium histolyticum collagenase (EC 3.4.24.3), a zinc enzyme which degrades triple helical regions of native collagen. The prepared hydroxamate derivatives were generally 100-500 times more active than the corresponding carboxylates. In the series of synthesized hydroxamates, substitution patterns leading to the best inhibitors were those involving perfluoroalkylsulfonyl- and substituted- arylsulfonyl moieties, such as pentafluorophenylsulfonyl, 3- and 4- carboxyphenylsulfonyl-, 3-trifluoromethyl-phenylsulfonyl or 1- and 2-naphthyl among others. Thus, it seems that similarly to the matrix metalloproteinase (MMP) hydroxamate inhibitors, Clostridium histolyticum collagenase inhibitors should incorporate hydrophobic moieties at the P1, and P2, sites, whereas the α-carbon substituent may be a small and compact moiety (such as H. for the Gly derivatives reported here). Such compounds might lead to the design of collagenase inhibitor-based drugs useful as anti-cancer, anti-arthritis or anti-bacterial agents for the treatment of corneal keratitis. (C) 2000 Editions scientifiques et medicales Elsevier SAS.
