R. Curtis Haltiwanger

Potent and Selective Nonpeptide Inhibitors of Caspases 3 and 7 Inhibit Apoptosis and Maintain Cell Functionality

Caspases have been strongly implicated to play an essential role in apoptosis. A critical question regarding the role(s) of these proteases is whether selective inhibition of an effector caspase(s) will prevent cell death. We have identified potent and selective non-peptide inhibitors of the effector caspases 3 and 7. The inhibition of apoptosis and maintenance of cell functionality with a caspase 3/7-selective inhibitor is demonstrated for the first time, and suggests that targeting these two caspases alone is sufficient for blocking apoptosis. Furthermore, an x-ray co-crystal structure of the complex between recombinant human caspase 3 and an isatin sulfonamide inhibitor has been solved to 2.8-Å resolution. In contrast to previously reported peptide-based caspase inhibitors, the isatin sulfonamides derive their selectivity for caspases 3 and 7 by interacting primarily with the S2 subsite, and do not bind in the caspase primary aspartic acid binding pocket (S1). These inhibitors blocked apoptosis in murine bone marrow neutrophils and human chondrocytes. Furthermore, in camptothecin-induced chondrocyte apoptosis, cell functionality as measured by type II collagen promoter activity is maintained, an activity considered essential for cartilage homeostasis. These data suggest that inhibiting chondrocyte cell death with a caspase 3/7-selective inhibitor may provide a novel therapeutic approach for the prevention and treatment of osteoarthritis, or other disease states characterized by excessive apoptosis.

Aziridine-mediated asymmetric synthesis of quaternary β-amino acids using 2H-azirine 2-carboxylate esters

Regioselective hydrogenation of enantiopure 3-substituted and 3,3-disubstituted aziridine 2-carboxylate esters affords β-amino acids and quaternary β-amino acids, respectively, in good yield. The aziridines are prepared via an aza-Darzens reaction of α-bromoenolates with enantiopure sulfinimines (N-sulfinyl imines) and by addition of Grignard reagents to 2H-azirine 2-carboxylate esters.

STRUCTURAL STUDIES OF N-N-BIS(DICHLOROPHOSPHINO) PHENYLAMINES

Abstract The structural characterization of PhN(PCl2)2 and m-MeC6H4N(PCl2)2 in solution by 31P NMR spectroscopy and of PhN(PCl2)2 in the solid by single crystal X-ray analysis is reported. PhN(PCl2)2 adopts a C2v conformation in the solid, in which the phosphorus lone pair electrons are eclipsed and both trans to the Ph group. The C2v conformation assignment for PhN(PCl2)2 and m-MeC6H4N(PCl2)2 is consistent with the low temperature 31P NMR spectral data. PhN(PCl2)2 crystallizes in space group P21, a=6.360(2) A, b=25.618(11) A, c=7.146(2) A, β=90.62(2) deg, Z=4, with two independent molecules per unit cell. The structure was solved and refined by direct methods to R=0.058 and Rw=0.078 for 671 independent reflections. Mean distances (A) and angles (deg) are: P-Cl, 2.036(13); P - N, 1.69(3);

Artabotrine: A novel bioactive alkaloid from Artabotrys zeylanicus

Abstract The structure of artabotrine, an unprecedented bioactive N-methoxylated alkaloid from Artabotrys zeylanicus, has been deduced as N-methoxynorcepharadione A (1) from spectral data and single crystal X-ray analysis. The known oxoaporphine alkaloid, atherospennidine (2), was also isolated and shown to be active in a mechanism-based yeast bioassay.

Design of a potent and orally active nonpeptide platelet fibrinogen receptor (GPIIb/IIIa) antagonist.

The direct design of the potent nonpeptide platelet fibrinogen receptor (GPIIb/IIIa) antagonist, 8-[[[4- (aminoiminomethyl)phenyl]amino]carbonyl]-2,3,4,5-tetrahydro-3-oxo- 4- (2-phenylethyl)-1H-1,4-benzodiazepine-2-acetic acid, (3) (SB 207448), based on the structure and conformation of the potent and highly constrained cyclic peptide antagonist SK&F 107260 (2), has been reported [Ku et al., J. Am. Chem. Soc. 1993, 115, 8861]. While 3 displayed in vivo activity in the conscious dog following intravenous administration, it was not active following intraduodenal administration; activity was measured with an ex vivo platelet aggregation assay. The secondary amide in 3 was N-methylated in the expectation of increased absorption and bioavailability. The resulting tertiary amide, 4 (SB 208651), also showed high binding affinity for human GPIIb/IIIa and potent antiaggregatory activity in human platelet-rich plasma. Most importantly, 4 was active in vivo following intravenous and intraduodenal administration. Comparison of the iv and id inhibition curves suggests an apparent bioavailability of approximately 10%. Thus, 4 represents the first orally active compound in this series of potent, nonpeptide fibrinogen receptor antagonists.

Facile biocatalytic reduction of the carbon–carbon double bond of 5-benzylidenethiazolidine-2,4-diones. Synthesis of (±)-5-(4-{2-[methyl(2-pyridyl)amino]ethoxy}benzyl)thiazolidine-2,4-dione (BRL 49653), its (R)-(+)-enantiomer and analogues

A novel biotransformation system for the reduction of carbon-carbon double bonds in 5-benzylidenethiazolidine-2, 4-diones, to give the corresponding 5-benzylthiazolidine-2, 4-diones, using whole cells of red yeasts is described. These reduced compounds, which are recovered in good yield, are of potential use in the treatment of non-insulin dependent diabetes mellitus. The mild reaction conditions developed allow reduction of 5-benzylidenethiazolidine-2, 4-diones containing other functionalities which are not compatible with alternative reduction methods. The biocatalytic reduction is enantioselective and the synthesis of R-(+)-5-(4-{2-[methyl(2-pyridyl)amino]ethoxy}benzyl)thiazolidine-2, 4-dione by Rhodotorula rubra CBS 6469 and structure confirmation by X-ray crystallography is detailed. Optimisation of reaction conditions (including immobilisation) for these whole cell reduction systems is described.

Evolution of the boulder model for the molecular origins of the polarization in ferroelectric liquid crystals

Abstract Development of a model relating the structure of FLC molecules to the sign and magnitude of the macroscopic ferroelectric polarization P exhibited by the supramolecular assembly in the C* phase is clearly an important and interesting goal. We have reported on our own simple stereochemical model for the molecular origins of P, which is based upon the concept that the sign and magnitude of P in FLCs can be understood in terms of a kind of molecular recognition occurring in the phase. Herein we present an overview of research aimed at testing this model by design, synthesis and characterization of FLC components with predictable properties.

Synthetic analogues of SB-219383. Novel C-glycosyl peptides as inhibitors of tyrosyl tRNA synthetase

Novel inhibitors of bacterial tyrosyl tRNA synthetase have been synthesised in which the cyclic hydroxylamine moiety of SB-219383 is replaced by C-pyranosyl derivatives. Potent and selective inhibition of bacterial tyrosyl tRNA synthetase was obtained.

Phenylbutyrates as potent, orally bioavailable vitronectin receptor (integrin αvβ3) antagonists

In our continuing efforts to identify small molecule vitronectin receptor antagonists, we have discovered a series of phenylbutyrate derivatives, exemplified by 16, which have good potency and excellent oral bioavailability (approximately 100% in rats). This new series is derived conceptually from opening of the seven-membered ring of SB-265123.

Asymmetric Diels-Alder reactions with sulfines derived from proline

A partir de s-proline, synthese dalcoxymethyl-2 pyrrolidides dacide α-sulfinyl alcanesulfoniques. La cycloaddition de ces sulfines et de dimethyl-2,3 butadiene-1,3 conduit aux alcoxymethyl-2 pyrrolidides de S-oxydes dacides dihydro-3,6 dimethyl-4,5 thiopyrannesulfoniques-2