19255-49-3Relevant academic research and scientific papers
Molecular boxes derived from crown ethers and nucleotide bases: Probes for Hoogsteen vs Watson-Crick H-bonding and other base-base interactions in self-assembly processes
Schall, Otto F.,Gokel, George W.
, p. 6089 - 6100 (1994)
Bibracchial lariat ethers based upon 4,13-diaza-18-crown-6 having -(CH2)3- sidearms terminated in adenine or thymine have been prepared and characterized. The three structures are as follows: adenine-(CH2)3-〈N18N〉- (CH2)3-adenine (A-O-A), thymine-(CH2)3-〈N18N〉-(CH2) 3-thymine (T-O-T), and adenine-(CH2)3-〈N18N〉- (CH2)3-thymine (A-O-T). Association of the nucleotide bases was expected to afford molecular boxes or other aggregates that would be stabilized by interactions between or among the nucleotide bases. These compounds have been studied in solution by 1H-NMR spectroscopy and by vapor pressure osmometry to determine the extent of association as well as what interactions occur between the bases. The 1H-NMR solution studies involved both temperature and concentration dependence and NOE studies. Several lines of evidence make clear that association does occur in CDCl3 with an association constant for A-O-A with T-O-T of 855 M-1. Both intra- and intermolecular H-bonding interactions are detected. Hoogsteen binding modes appear to play a very important role in these flexible systems. The A-O- A·T-O-T box may also comprise a ditopic receptor system in which the sides of the box are Ade::Thy pairs and the ends are crown ethers. We have studied such systems in the presence of decanediyldiammonium and dodecanediyldiammonium salts and report evidence for a ternary induced-fit receptor complex.
Peptidyl α-ketoamides with nucleobases, methylpiperazine, and dimethylaminoalkyl substituents as calpain inhibitors
Ovat, Asli,Li, Zhao Zhao,Hampton, Christina Y.,Asress, Seneshaw A.,Fernández, Facundo M.,Glass, Jonathan D.,Powers, James C.
supporting information; experimental part, p. 6326 - 6336 (2010/10/20)
A series of peptidyl α-ketoamides with the general structure Cbz-l-Leu-d,l-AA-CONH-R were synthesized and evaluated as inhibitors for the cysteine proteases calpain I, calpain II, and cathepsin B. Nucleobases, methylpiperazine, and dimethylaminoalkyl groups were incorporated into the primed region of the inhibitors to generate compounds that potentially cross the blood-brain barrier. Two of these compounds (Cbz-Leu-d,l-Abu-CONH-(CH 2)3-adenin-9-yl and Cbz-Leu-d,l-Abu-CONH-(CH 2)3-(4-methylpiperazin-1-yl) have been shown to have useful concentrations in the brain in animals. The best inhibitor for calpain I was Cbz-Leu-d,l-Abu-CONH-(CH2)3-2-methoxyadenin-9-yl (Ki = 23 nM), and the best inhibitor for calpain II was Cbz-Leu-d,l-Phe-CONH-(CH2)3-adenin-9-yl (Ki = 68 nM). On the basis of the crystal structure obtained with heterocyclic peptidyl α-ketoamides, we have improved inhibitor potency by introducing a small hydrophobic group on the adenine ring. These inhibitors have good potential to be used in the treatment of neurodegenerative diseases.
Cocrystal structures of primed side-extending α-ketoamide inhibitors reveal novel calpain-inhibitor aromatic interactions
Qian, Jin,Cuerrier, Dominic,Davies, Peter L.,Li, Zhaozhao,Powers, James C.,Campbell, Robert L.
experimental part, p. 5264 - 5270 (2009/07/09)
Calpains are intracellular cysteine proteases that catalyze the cleavage of target proteins in response to Ca2+ signaling. When Ca2+ homeostasis is disrupted, calpain overactivation causes unregulated proteolysis, which can contribute to diseases such as postischemic injury and cataract formation. Potent calpain inhibitors exist, but of these many cross-react with other cysteine proteases and will need modification to specifically target calpain. Here, we present crystal structures of rat calpain 1 protease core (μI-II) bound to two α-ketoamide-based calpain inhibitors containing adenyl and piperazyl primed-side extensions. An unexpected aromatic-stacking interaction is observed between the primed-side adenine moiety and the Trp298 side chain. This interaction increased the potency of the inhibitor toward μI-II and heterodimeric m-calpain. Moreover, stacking orients the adenine such that it can be used as a scaffold for designing novel primed-side address regions, which could be incorporated into future inhibitors to enhance their calpain specificity.
Syntheses and coordination chemistry of aminomethylphosphine derivatives of adenine
Zhang, Qingzhi,Hua, Guoxiong,Bhattacharyya, Pravat,Slawin, Alexandra M. Z.,Woollins, J. Derek
, p. 2426 - 2437 (2007/10/03)
Two aminomethylphosphane derivatives of adenine 9-(2-{bis[(diphenylphosphanyl)methyl]amino}ethyl)adenine (La) and 9-(3-{bis[(diphenylphosphanyl)methyl]amino}propyl)adenine (Lb) were synthesised. Oxidation of La and Lb with H2O2, elemental sulfur or elemental selenium led to the corresponding oxidized products 4a/b-6a/b. Both La and Lb behave as didentate ligands towards late transition metals. Reaction of La or Lb with [MX2(cod)] (M = Pd, Pt; X = Cl, Me) gave chelate complexes 7a/b-10a/b. Reaction of La or Lb with [AuCl(tht)] of [{RuCl(μ-Cl)(p-MeC6H4iPr)}2] gave the didentate bridging complexes 11a/b and 12a. All compounds have been fully characterised by microanalysis, IR, 1H and 31P{1H} NMR spectroscopy, and EI/CI/FAB mass spectrometry. 1H{31P} NMR and 1H-13C correlation experiments were used to confirm the spectral assignments where necessary. Two compounds were structurally characterised by X-ray crystallographic analysis. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.
