ABSTRACT
An efficient synthesis of (S)- or (R)-3-(benzyloxy-methyl)-cyclopent-3-enol was developed by appling an enzyme-catalyzed kinetic-resolution approach. This procedure allowed the syntheses of the enantiomeric building blocks (S)- and (R)-cyclopentenol with high optical purity (>98 % ee). In contrast to previous approaches, the key advantage of this procedure is that the resolution is done on the level of enantiomers that only contain one stereogenic center. Owing to this feature, it was possible to chemically convert the enantiomers into each other. By using this route, the starting materials for the syntheses of carbocyclic D- and L-nucleoside analogues were readily accessible. 3',4'-Unsaturated D- or L-carbocyclic nucleosides were obtained from the condensation of various nucleobases with (S)- or (R)-cyclopentenol. Functionalization of the double bond in 3'-deoxy-3',4'-didehydro-carba-D-thymidine led to a variety of new nucleoside analogues. By using the cycloSal approach, their corresponding phosphorylated metabolites were readily accessable. Moreover, a new synthetic route to carbocyclic 2'-deoxy-nucleosides was developed, thereby leading to D- and L-carba-dT. D-Carba-dT was tested for antiviral activity against multidrug-resistance HIV-1 strain E2-2 and compared to the known antiviral agent d4T, as well as L-carba-dT. Whilst L-carba-dT was found to be inactive, its D-analogue showed remarkably high activity against the resistant virus and significantly better than that of d4T. However, against the wild-type virus strain NL4/3, d4T was found to be more-active than D-carba-dT.
Subject(s)
Anti-HIV Agents/chemical synthesis , Cyclopentanes/chemical synthesis , HIV Reverse Transcriptase/antagonists & inhibitors , Nucleosides/chemical synthesis , Reverse Transcriptase Inhibitors/chemical synthesis , Anti-HIV Agents/pharmacology , Catalysis , Cell Line , Cell Survival/drug effects , Cyclization , Cyclopentanes/pharmacology , Drug Resistance, Multiple, Viral , HIV Reverse Transcriptase/chemistry , HIV-1/drug effects , Humans , Inhibitory Concentration 50 , Kinetics , Nucleosides/pharmacology , Pancreatin/chemistry , Pancreatin/metabolism , Reverse Transcriptase Inhibitors/pharmacology , Stavudine/pharmacology , Stereoisomerism , Virus Replication/drug effectsABSTRACT
BACKGROUND AND AIM: Cholesterol gallstone disease is caused by both genetic and environmental factors (e.g., deranged motility of the gallbladder wall). Recently, a single nucleotide polymorphism (SNP) of the vasoactive intestinal peptide receptor 1 (VIPR1) gene has been linked to late onset of achalasia, a lower esophagus dysmotility disorder. As VIPR1 is expressed in the gallbladder wall as well, and patients with achalasia exhibit extraesophageal motility disorders, the influence of VIPR1 SNP on cholelithiasis was investigated. METHODS: We analyzed 254 gallstone-free controls (confirmed by ultrasound, age 21-78 years, 88% women, BMI 16-43 kg/m²) and 226 individuals from 107 families with gallstones (age 24-80 years, 87% women, BMI 17-55 kg/m²). All individuals were genotyped for the VIPR1 rs437876 SNP (intron 4) with PCR-based 5'-nuclease and fluorescence detection assays (TaqMan). We performed nonparametric linkage (NPL) analysis in affected sib-pairs (ASP), association tests, and regression analyses. RESULTS: Controls were significantly younger (P < 0.01) and leaner than ASP and cases (P < 0.01), and both age as well as BMI significantly increased the risk of developing gallstones (P < 0.001). Allele frequencies were in line with database entries and no deviation from Hardy-Weinberg equilibrium was detected. Neither allele and genotype distributions nor NPL scores or the restriction of analysis to individuals older than 50 years provided evidence for association or linkage of the VIPR1 SNP and cholelithiasis. CONCLUSION: The VIPR1 polymorphism, previously linked to gastrointestinal dysmotility disorders, does not represent a common risk factor for gallstones in the general or in an elderly population.
