Cyclic peptide-polymer complexes and their self-assembly.

The efficient synthesis of novel chiral cyclic peptides cyclo[NHCHX-CH=CHCH(2)CO(NHCH(2)CH=CHCH(2)CO)(2)] designed to develop hydrogen-bonding interactions with suitable polymers is described. Complexation of a carboxylic acid derivatized cyclic peptide 2 (X = CH(2)OCOCH(2)CH(2)CO(2)H) capable of self-assembling as "endless" tubes, with poly(vinyl alcohol) (PVA) led to a vast weak-interaction network, in which the cyclopeptide developed extensive hydrogen-bonding interactions with the hydroxyl groups of PVA through not only the carboxylic acid, but also its ester carbonyl and amide groups. In aqueous solution, the peptide/PVA complexes self-assemble into long-grain ricelike aggregates compatible with the stacking of cyclic peptides through intercycle hydrogen bonds. Upon casting on silicon wafer, the anisotropic aggregates can coalesce to form filaments tens of micrometers long. The study demonstrates that complexing functionalized cyclic peptides with polymers through hydrogen bonding is a useful approach for using polymers to mediate the self-assembly and self-organization of cyclic peptides.

Novel tricyclic inhibitors of IkappaB kinase.

The design and synthesis of a novel series of oxazole-, thiazole-, and imidazole-based inhibitors of IkappaB kinase (IKK) are reported. Biological activity was improved compared to the pyrazolopurine lead, and the expedient synthesis of the new tricyclic systems allowed for efficient exploration of structure-activity relationships. This, combined with an iterative rat cassette dosing strategy, was used to identify compounds with improved pharmacokinetic (PK) profiles to advance for in vivo evaluation.

New access to indolizidine and pyrrolizidine alkaloids from an enantiopure proline: total syntheses of (-)-lentiginosine and (1R,2R,7aR)-dihydroxypyrrolizidine.

A new approach to the synthesis of indolizidine and pyrrolizidine skeletons is reported. (-)-Lentiginosine and (1R,2R,7aR)-dihydroxypyrrolizidine have both been synthesized in 13 steps from di-O-isopropylidene-d-mannitol. The common key intermediate is (-)-dihydroxyproline benzyl ester 10.

Reliability and validity of static knee strength measurements obtained with a chair-fixed dynamometer in subjects with hip or knee arthroplasty.

OBJECTIVES: To evaluate the reliability (intertrial, interevaluator) and the concurrent validity of strength measurements obtained with a chair-fixed dynamometer and to recommend a clinical protocol that minimizes standard error of measurement (SEM). DESIGN: Within-session repeated measures of maximal static strength of knee flexors and extensors at 30 degrees and 60 degrees of flexion on the chair-fixed and Cybex dynamometers. SETTING: Ambulatory physiotherapy department of a rehabilitation hospital. PARTICIPANTS: Convenience sample of 50 subjects with total hip (n=25) or knee (n=25) arthroplasty. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Reliability was quantified by indices of dependability and corresponding SEMs estimated with the generalizability theory, whereas coefficients of correlation were used to assess the validity. RESULTS: Indices of dependability confirmed excellent intertrial (0.98-1.00) and a very good interevaluator (.92-.99) reliability for the strength measures obtained for different movements and positions. An average of 3 trials minimized the magnitude of the SEMs (>2 Nm for all measurements). When comparing the strength values obtained with the Cybex dynamometer to those measured with the chair-fixed dynamometer, strongest relations were attained when the tested knee was positioned at 60 degrees compared with 30 degrees for subjects with a total knee (.78-.92 vs .87-.93) or hip (.73-.85 vs .86-.91) arthroplasty. CONCLUSIONS: A clinical protocol averaging 3 trials with the knee positioned at 60 degrees after a familiarization period, both for knee flexors and extensors, performed by a trained therapist is recommended to minimize measurement errors on strength values measured with the chair-fixed dynamometer.

Stereoselective synthesis of 3-hydroxyproline benzyl esters from N-protected beta-aminoaldehydes and benzyl diazoacetate.

The synthesis of a series of 3-hydroxyproline benzyl esters from alpha-alkyl and alpha-alkoxy N-protected aminoaldehydes with benzyl diazoacetate is described. Aldehydes with alpha-alkyl substituents afforded prolines as a single diastereomer with a trans-cis relative configuration in 14-77%. An alpha-tert-butyldimethylsilyloxy aminoaldehyde afforded a proline as a single diastereomer with a trans-trans relative configuration in 37% yield.

Stereoselective synthesis of tetrahydropyrans via formal [4 + 2]-cycloaddition: a comparison of allylsilane and crotylsilane.

The reaction of a series of beta-(triethylsilyloxy)aldehydes with several allylsilanes and crotyldimethylphenylsilane is described. Aldehydes possessing an alpha-stereocenter afforded tetrahydropyrans as mixtures of two diastereomers with allylsilane, but only a single diastereomer was observed in the case of crotylsilanes. The reaction time for crotylsilanes was longer than that for allylsilanes likely due to the increased steric hindrance. Allylsilanes afforded tetrahydropyrans in 34-67% yields, and crotylsilanes provided products in 0-62% yields.