Regioselective Synthesis of Hamilton-Receptor-Fullerene Oligo-Adducts for the Supramolecular Binding of Cyanuric Derivatives.

A new concept for the regioselective synthesis of Hamilton-receptor and cyanurate-functionalized oligo adducts of the fullerene C60 was developed. Based on an in-situ deprotection and click-post-functionalization approach with novel azido precursors, the corresponding fullerene hexakis-adducts with octahedral addition patterns and up to twelve Hamilton-receptor/cyanurate moieties surrounding the fullerene sphere were synthesized. The versatility of this approach was further demonstrated by the synthesis of Hamilton-receptor/cyanurate functionalized fullerene mono-adducts, which are not accessible by direct cyclopropanation. Several fullerene target compounds were purified by simple washing procedures of the solid crude reaction mixture without the need for chromatography. The resulting fullerene mono- and hexakis-adducts were fully characterized and their supramolecular properties were investigated by NMR-spectroscopy and isothermal titration calorimetry (ITC).

Sequential Tether-Directed Synthesis of New [3 : 2 : 1] Hexakis-Adducts of C60 with a Mixed Octahedral Addition Pattern.

A new concept for the regioselective synthesis of [3 : 2 : 1] hexakis-adducts of fullerene C60 was developed. Based on sequential tether-directed remote functionalizations, chiral [3 : 2] pentakis-adducts with an incomplete octahedral addition pattern were synthesized via stepwise cyclopropanation of C60 with suitable macrocyclic tri- and bifunctional cyclomalonate tethers. The four resulting stereoisomers were isolated using chiral HPLC. The corresponding pairs of enantiomers show mirror image behavior in their CD-spectra. The pentakis-adducts served as suitable building blocks for the spatially controlled synthesis of mixed hexakis-adducts. Implementation of functional group-bearing monomalonates afforded octahedral [3 : 2 : 1] hexakis-adducts suitable for the construction of larger molecular and supramolecular fullerene architectures in excellent yield.

3-Fluoro-2,4-dioxa-3-phosphadecalins as inhibitors of acetylcholinesterase. A reappraisal of kinetic mechanisms and diagnostic methods.

A systematic survey of the acetylcholine-mimetic 2,4-dioxa-3-phosphadecalins as irreversible inhibitors of acetylcholinesterase revealed hitherto overlooked properties as far as the kinetic mechanisms of interaction are concerned. As a support to past and future work in this field, we describe the kinetics of eight reaction schemes that may be found in irreversible enzyme modification and compare them with two mechanism of reversible, slow-binding inhibition. The relevant kinetic equations and their associated graphical representations are given for all mechanisms, and concrete examples illustrate their practical use. Since irreversible inhibition is a time-dependent phenomenon, kinetic analysis is greatly facilitated by fitting the appropriate integrated rate equations to reaction-progress curves by nonlinear regression. This primary scrutiny provides kinetic parameters that are indispensable tools for diagnosing the kinetic mechanism and for calculating inhibition constants. Numerical integration of sets of differential equations is an additional useful investigation tool in critical situations, e.g., when inhibitors are unstable and/or act as irreversible modifiers only temporarily.

Synthesis and characterization of the enantiomerically pure cis- and trans-2,4-dioxa-3-fluoro-3-phosphadecalins as inhibitors of acetylcholinesterase.

The title compounds, the P(3)-axially- and P(3)-equatorially-substituted cis- and trans-configured 3-fluoro-2,4-dioxa-3-phosphadecalin 3-oxides (=3-fluoro-2,4-dioxa-3-phosphabicyclo[4.4.0]decane 3-oxides) have been prepared (ee>99%) and fully characterized. The compounds are irreversible inhibitors of acetylcholinesterase, and both the kinetic data and the mechanisms of the inhibition are determined by a novel enzyme-kinetic approach that is described in the preceding report. The inhibitors display pronounced stereoselectivity, and several of them are significantly stronger than diisopropyl fluorophosphate that is generally used as a potent standard.

Synthesis and structure-activity relationship of 7-azaindole piperidine derivatives as CCR2 antagonists.

The synthesis and structure-activity relationship of a series of 7-azaindole piperidine derivatives are described. SAR studies led to the discovery of the potent CCR2 antagonists displaying IC(50) values in the nanomolar range. The representative compound 15 showed reasonable P450 and pharmacokinetics profile.

Substituted dipiperidine alcohols as potent CCR2 antagonists.

The synthesis and biological evaluation of a series of substituted dipiperidine alcohols are described. Structure-activity relationship studies led to the discovery of potent CCR2 antagonists displaying IC(50) values in the nanomolar or subnanomolar range. The cinnamoyl compounds had higher binding affinities than the corresponding urea analogs.

Synthesis, structure-activity relationship and in vivo antiinflammatory efficacy of substituted dipiperidines as CCR2 antagonists.

A series of substituted dipiperidine compounds have been synthesized and identified as selective CCR2 antagonists. Combining the most favorable substituents led to the discovery of remarkably potent CCR2 antagonists displaying IC50 values in the nanomolar range. Compound 7a had outstanding selectivity over CCR1, CCR3, CCR4, CCR5, CCR6, CCR7, and CCR8 and showed excellent efficacy in adjuvant-induced arthritis model, collagen-induced arthritis model, and allergic asthma model.

Synthesis and biological evaluation of phenyl piperidine derivatives as CCR2 antagonists.

A series of phenyl piperidine derivatives possessing potent and selective CCR2 antagonist activity is reported. Structure-activity relationship (SAR) studies have established that incorporation of a second ring system adjacent to the aryl piperidine plays an important role in determining the CCR2 potency. Both a second piperidine ring and a 1,3-substituted cyclopentylamine have been probed as linkers. For the cyclopentylamine series, the 1S,3R-configuration exhibits much higher affinity for hCCR2 than the 1R,3S-configuration. Compound 3g shows good selectivity over CCR1, CCR3, 5-HT and has an excellent P450 profile.

Potent and selective CC-chemokine receptor-2 (CCR2) antagonists as a potential treatment for asthma.

A number of compounds bearing a quaternary ammonium moiety were found to be antagonists with nanomolar binding affinity for the chemokine receptor-2. The structure-activity relationships in the series are described herein along with some detailed characterization of the interesting compounds.

What influences self-perception of health in the elderly? The role of objective health condition, subjective well-being and sense of coherence.

The study examines in what way objective health-related variables interfere with psychic health and personality factors in explaining self-perception of health in the elderly. Two hundred and sixty-one patients aged 60 and older of an internal medicine hospital previously examined between 1994 and 1997 were once more contacted five years later. One hundred and sixty-four patients could not be included in the present investigation because of death, dementia, or severe physical illness. Of the 97 patients eligible for this second investigation, 74 agreed to participate. They were investigated extensively by means of psychometric scales and diagnostic interviews. A positive selection effect could be found for the sample of the present investigation with regard to age and health-related variables. Subjective evaluation of health correlated highly with the self-evaluation scales that recorded subjective well-being (life satisfaction, anxiety, and depression), and with the sense of coherence, but not substantially with objective health-related variables. A backward regression resulted in an adjusted R2 = 0.33 for the three retained variables "subjective physical complaints", "sense of coherence" and "self-evaluated depression" which rendered the same variance clarification of subjective health as did the model including all variables. Since the elderly represent the majority of patients treated in general hospitals and as subjective health and subjective physical complaints influence frequency of medical consultations and health care utilization, this is an important issue for consultation-liaison-psychiatry and health policy.

Synthesis and structure-activity relationships of 3,5-diarylisoxazoles and 3,5-diaryl-1,2,4-oxadiazoles, novel classes of small molecule interleukin-8 (IL-8) receptor antagonists.

A novel series of 3,5-diarylisoxazole and 3,5-diaryl-1,2,4-oxadiazole IL-8 inhibitors has been identified. These compounds exhibit activity in an IL-8 binding assay as well as in a functional assay of IL-8 induced elastase release from neutrophils. In addition, one of the compounds exhibits oral activity in a rat adjuvant arthritis model.

Ageing styles: subjective well-being and somatic complaints in inpatients aged >/=60 years.

BACKGROUND: Recent gerontological research shows a high variability in the elderly population. The aim of the present study is to investigate by means of cluster analysis, as to whether different 'ageing styles' can be identified in a sample of cognitively not impaired older persons, and to assess discrepancies between self-rated and expert-rated psychological and physical health. METHOD: 243 patients aged 60 years and older in a general hospital were investigated using a clinical psychiatric interview, expert ratings, and self-report scales after extensive internal medical diagnostic evaluation. RESULTS: Five clusters, representing significantly different 'ageing styles' with regard to subjective well-being and subjective physical complaints, could be identified. Two clusters, which together constituted 57% of the sample, represented quite positive and desirable ageing styles. In two clusters (altogether 23% of the sample), there was a discrepancy between medical findings and subjective physical complaints. CONCLUSIONS: These findings support the notion of high variability in the elderly and the existence of subgroups, which show a discrepancy between subjective assessment of well-being and expert assessment of psychological and physical health and impairment. The recording of subjectively perceived physical complaints should, therefore, be part of the evaluation of older peoples' subjective well-being.

Subjective body complaints as an indicator of somatization in elderly patients.

The authors examined the correlation of subjective body complaints (measured by the Giessen Subjective Complaints List) with sociodemographic data, objective health measures, measures of subjective well-being, and clinicians' ratings of somatization and psychological impairment in 251 cognitively unimpaired general hospital inpatients aged >/=60 years. The level of subjective body complaints correlated most highly with self-assessed life satisfaction and age-related changes and with the clinicians' rating of somatization. The results suggest that the level of subjective body complaints is determined by subjective well-being rather than by objective health measures, and thus subjective body complaints may be an indicator of somatization in elderly inpatients.