SYNTHESIS AND NMR-ANALYSIS OF TRICYCLIC NUCLEOSIDES

Two anomeric tricyclic nucleosides have been synthesised from diacetone-D-glucose using oxidation, stereoselective Grignard-addition of a vinyl-group, a stereoselective dihydroxylation followed by a tandem ring closing reaction, and finally a nucleobase coupling. The main β-configured product was examined and its configuration confirmed using NMR-spectroscopy in connection to ab initio calculations. The preferred conformation of this tricyclic nucleoside was described.     

Juniperanol: First total synthesis and evaluation in Type 2 Diabetes disease

The first total synthesis of juniperanol, the tricyclic sesquiterpenoid enantiomer of α-cedrol is described. The synthesis relies on stereoselective gold-catalyzed Ohloff-type propargylic ester rearrangement performed on a 10 g scale, and a carbocationic cascade in the presence of acetyl methanesulfonate. The ability of juniperanol to interfere in glucose processes in different cell types is described.     

Tricyclic ureas: A new class of HIV-1 protease inhibitors

A new class of tricyclic ureas containing a conformationally constrained proline was designed with the aid of molecular modeling. Efficient stereoselective intermolecular pinacol coupling represented the highlight of the synthesis. These rigid cyclic ureas are active towards HIV-1 protease, with 9 being the most potent compound (Ki = 9 nM) despite interacting with only three side chain binding pockets of HIV protease.     

En route to sugar-alkaloid conjugates

After stereoselective addition of N-iodosuccinimide to glycals subsequent dehalogenation results in formation of N-glycopyranosyl succinimides. By UV irradiation both azepindiones and preferentially [5.3.1.0^2,6] tricyclic oxalactams could be obtained. Their transformation into a number of novel sugar conjugates resembling some prominent alkaloid N-pyrrol components by thiation and reduction is reported.     

Phosphorylation of ganciclovir phosphonate by cellular GMP kinase determines the stereoselectivity of anti-human cytomegalovirus activity

A racemic mixture of ganciclovir phosphonate was resolved by stereoselective phosphorylation using GMP kinase. The R-enantiomer of ganciclovir phosphonate was active against human cytomegalovirus but the S-enantiomer was less active. We show that enantiomeric selectivity of antiviral for ganciclovir phosphonate was conferred by stereoselective phosphorylations by mammalian enzymes, not by stereoselective inhibition of DNA polymerase from human cytomegalovirus.     

Intestinal absorption and metabolism of chlorpheniramine enantiomers in rat

Chlorpheniramine (CPAM) is a chiral antihistaminic drug commercialized as a racemic mixture. The intestinal absorption and metabolism of CPAM have been investigated in rat using in vivo (oral and IV administration), in situ (intestinal loop model), and in vitro (everted sac model) experiments. Oral and IV administrations of 20 mg/kg of the racemic mixture show that the pharmacokinetics of CPAM are stereoselective, with higher AUCs for the (+)-S-enantiomer compared to its antipode. The monodesmethyl metabolite (DCPM) was quantifiable in blood and its pharmacokinetics are stereoselective after oral but not after IV administration. Experiments using intestinal loops and everted sacs showed that the absorption is not stereoselective and that in vivo stereoselective formation of DCPM is presumably due to stereoselective hepatic metabolism. Moreover, the in vitro and in situ absorption of CPAM are not modified by modulators of P-glycoprotein and cytochromes P450 (cyclosporin A, ketoconazole).     

Stereoselective binding and degradation of sulbenicillin in the presence of human serum albumin

Binding of sulbenicillin (SBPC) isomers to human serum albumin (HSA) was stereoselective. There were at least two classes of binding sites on HSA for SBPC isomers. At the stereoselective high affinity site, binding was in favor of R-SBPC, the binding constant of R-SBPC being approximately 2.3-fold greater than that of S-SBPC. By using site marker ligands, it was revealed that the stereoselective site was Site I (warfarin binding site). Affinity for the low affinity (nonstereoselective) site was similar for the diastereomers, approximately 7--30-fold lower than for the stereoselective site. R-SBPC and S-SBPC appeared to displace each other competitively at both binding sites. On the other hand, R-SBPC was degraded much faster than S-SBPC in the presence of HSA, with a degradation rate constant approximately 7-fold greater for R-SBPC than for S-SBPC. The degradation of R-SBPC was inhibited in the presence of warfarin and dependent on the concentration of R-SBPC bound to Site I. The results demonstrate that Site I is responsible for the stereoselective degradation.     

Stereoselective binding of carbenicillin epimers to human serum albumin

Binding of carbenicillin (CBPC) epimers to human serum albumin (HSA) was found to be stereoselective. Epimer-epimer interaction was also observed in the binding to HSA. There were at least three binding sites on HSA for CBPC epimers, one of which (stereoselective site) was more in favor of S-CBPC than R-CBPC. At the stereoselective site, the binding constant of S-CBPC was approximately 4-fold greater than that of R-CBPC. The affinities to other binding sites (non-stereoselective sites) were similar between the epimers, and the affinity of S-CBPC of the non-stereoselective sites was much smaller than that for the stereoselective site. R-CBPC and S-CBPC appeared to displace each other at all the binding sites, i.e., the binding of the epimers was competitive at the non-stereoselective sites as well as at the stereoselective site. By using site marker ligands, it was revealed that CBPC epimers may bind to Site I (warfarin binding site), but not to Site II (diazepam binding site). A binding model with an assumption of competitive interactions at all the binding sites simulated the binding characteristics of CBPC epimers fairly well. © 1996 Wiley-Liss, Inc.     

Substrate specificity and stereoselectivity of hydrolytic enzymes from Brevibacterium imperiale B222

Four different hysrolytic enzymes were isolated and partially purified from Brevibacterium imperiale B222 cells. The stereoselectivity of each enzyme was assayed by using the nitrile, amide and esters derivatives of 2-aryloxypropionic acid. Within the cellular pool of hydrolytic enzymes, a non-stereoselective nitrile hydratase, a stereoselective amidase and two partially stereoselective esterases of opposite enantiomeric preference were found. Correspondence to: D. Bianchi     

Selective serotonin reuptake inhibitors: meta-analysis of efficacy and acceptability.

OBJECTIVE--To examine the evidence for using selective serotonin reuptake inhibitors instead of tricyclic antidepressants in the first line treatment of depression. DESIGN--Meta-analysis of 63 randomised controlled trials comparing the efficacy and acceptability of selective serotonin reuptake inhibitors with those of tricyclic and related antidepressants. MAIN OUTCOME MEASURES--Improvement in mean scores on Hamilton depression rating scale for 53 randomised controlled trials. Pooled drop out rates from the 58 trials which reported drop out by treatment group. RESULTS--Among the 20 studies reporting standard deviation for the Hamilton score no difference was found in efficacy between serotonin reuptake inhibitors and tricyclic and related antidepressants (standardised mean difference 0.004, 95% confidence interval -0.096 to 0.105). The difference remained insignificant when the remaining 33 studies that used the 17 item and 21 item Hamilton score were included by ascribing weighted standard deviations. The odds ratio for drop out rate in patients receiving serotonin reuptake inhibitors compared with those receiving tricyclic antidepressants was 0.95 (0.86 to 1.07). Similar proportions in both groups cited lack of efficacy as the reason for dropping out but slightly more patients in the tricyclic group cited side effects (18.8% v 15.4% in serotonin reuptake group). CONCLUSIONS--Routine use of selective serotonin reuptake inhibitors as the first line treatment of depressive illness may greatly increase cost with only questionable benefit.     

Fluoxetine and suicide: a meta-analysis of controlled trials of treatment for depression.

OBJECTIVE--A comprehensive meta-analysis of clinical trial data was performed to assess the possible association of fluoxetine and suicidality (suicidal acts and ideation). DESIGN--Retrospective analysis of pooled data from 17 double blind clinical trials in patients with major depressive disorder comparing fluoxetine (n = 1765) with a tricyclic antidepressant (n = 731) or placebo (n = 569), or both. MAIN OUTCOME MEASURES--Multiple data sources were searched to identify patients with suicidal acts. Suicidal ideation was assessed with item 3 of the Hamilton depression rating scale, which systematically rates suicidality. Emergence of substantial suicidal ideation was defined as a change in the rating of this item from 0 or 1 at baseline to 3 or 4 during double blind treatment; worsening was defined as any increase from baseline; improvement was defined as a decrease from baseline at the last visit during the treatment. RESULTS--Suicidal acts did not differ significantly in comparisons of fluoxetine with placebo (0.2% v 0.2%, p = 0.494, Mantel-Haenszel adjusted incidence difference) and with tricyclic antidepressants (0.7% v 0.4%, p = 0.419). The pooled incidence of suicidal acts was 0.3% for fluoxetine, 0.2% for placebo, and 0.4% for tricyclic antidepressants, and fluoxetine did not differ significantly from either placebo (p = 0.533, Pearson''s chi 2) or tricyclic antidepressants (p = 0.789). Suicidal ideation emerged marginally significantly less often with fluoxetine than with placebo (0.9% v 2.6%, p = 0.094) and numerically less often than with tricyclic antidepressants (1.7% v 3.6%, p = 0.102). The pooled incidence of emergence of substantial suicidal ideation was 1.2% for fluoxetine, 2.6% for placebo, and 3.6% for tricyclic antidepressants. The incidence was significantly lower with fluoxetine than with placebo (p = 0.042) and tricyclic antidepressants (p = 0.001). Any degree of worsening of suicidal ideation was similar with fluoxetine and placebo (15.4% v 17.9%, p = 0.196) and with fluoxetine and tricyclic antidepressants (15.6% v 16.3%, p = 0.793). The pooled incidence of worsening of suicidal ideation was 15.3% for fluoxetine, 17.9% for placebo, and 16.3% for tricyclic antidepressants. The incidence did not differ significantly with fluoxetine and placebo (p = 0.141) or tricyclic antidepressants (p = 0.542). Suicidal ideation improved significantly more with fluoxetine than with placebo (72.0% v 54.8%, p less than 0.001) and was similar to the improvement with tricyclic antidepressants (72.5% v 69.8%, p = 0.294). The pooled incidence of improvement of suicidal ideation was 72.2% for fluoxetine, 54.8% for placebo, and 69.8% for tricyclic antidepressants. The incidence with fluoxetine was significantly greater than with placebo (p less than 0.001) and did not differ from that with tricyclic antidepressants (p = 0.296). CONCLUSIONS--Data from these trials do not show that fluoxetine is associated with an increased risk of suicidal acts or emergence of substantial suicidal thoughts among depressed patients.     

17,20-lyase inhibitors. Part 4: design, synthesis and structure-activity relationships of naphthylmethylimidazole derivatives as novel 17,20-lyase inhibitors

A novel series of naphthylmethylimidazole derivatives and related compounds have been investigated as selective 17,20-lyase inhibitors. Optimization of the substituent at the 6-position on the naphthalene ring was performed to yield a methylcarbamoyl derivative, which exhibited potent inhibitory activity against human 17,20-lyase and promising selectivity (>200-fold) for 17,20-lyase over CYP3A4. Further modifications of the methylcarbamoyl derivative led to the discovery of the corresponding tricyclic compound, which showed highly potent activity against human 17,20-lyase (IC(50) 19 nM) and good selectivity (>1000-fold) for inhibition of 17,20-lyase over CYP3A4. Additional biological evaluation revealed that the tricyclic compound had potent in vivo efficacy in monkeys and favorable pharmacokinetic profiles when administered in rats. Asymmetric synthesis of the selective tricyclic inhibitor was also achieved using a chiral α-hydroxy ketone.     

Antisera Raised Against the Drug Imipramine

Antisera against 2-aminoimipramine covalently coupled to albumin have been raised in two rabbits. Both antisera bind imipramine and related tricyclic compounds as if to a single class of sites with high affinity and high titres. Displacement/inhibition assays showed that the affinities of various tricyclic compounds for the antisera showed a good correlation with the affinities of these drugs for the tricyclic antidepressant inhibitory sites on plasma-membrane 5-hydroxytryptamine carriers of human platelets and rat brain cortex. 5-Hydroxytryptamine and 5-hydroxytryptamine-uptake-selective drugs did not inhibit [3H]imipramine binding to antisera. The anti-imipramine antibodies were purified using imipramine-Sepharose affinity chromatography and were shown to be IgG class by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and protein A-Sepharose precipitation.     

Exploring a pocket for polycycloaliphatic groups in the CXCR3 receptor with the aid of a modular synthetic strategy

A CXCR3 pocket capable of accommodating polycycloaliphatics was explored using a modular synthetic strategy. The systematic studies reveal that the tricyclic 2-adamantane and bicyclic (iso)bornyl group are efficiently recognized by CXCR3.     

Stereoselective determination and pharmacokinetics of dihydropyridines: an updated review

All dihydropyridines, except nifedipine, have at least one chiral center, and their pharmacokinetics and clinical effects differ from one enantiomer to another. Chiral separation methods for dihydropyridines using chromatographic techniques are discussed. The stereoselective pharmacokinetics of dihydropyridine calcium antagonists were reviewed in detail in 1995. The present review article updates the methods for the stereoselective determination of dihydropyridines using chromatographic techniques and summarizes the pharmacokinetics of the dihydropyridines, including the newest drugs under development.     

Stereoselective synthesis of 1'-functionalized-4'-thionucleosides

Stereoselective functionalization of the 1'-position of 4'-thionucleosides was achieved using a stereoselective S(N)2 reaction controlled by 5-membered ring coordination.     

Thrombomodulin induction in cultured human endothelial cells by 9-cis-locked retinoic acid analogues

9-cis-Retinoic acid (RA) analogues devised to lock the 9-cis double bond by ring formation were synthesized using two stereoselective carbon-carbon bond formation reactions as key steps. The palladium-mediated Suzuki reaction was adopted to construct a 7E-double bond (RA numbering) and the Horner-Emmons olefination was employed for stereoselective 11E-double bond (RA numbering) formation. The synthesized 9-cis-RA analogues that are locked by five-membered ring systems (cyclopentene, dihydrofuran, and dihydrothiophene) were shown to have comparable thrombomodulin induction activities to that of 9-cis RA. Conformational analysis of these compounds showed their similarity to 9-cis RA in the spatial orientation of the side chain and the terminal carboxy group.     

Stereoselective synthesis of novel 4'-branched and bicyclo[3.1.0]hexane-templated nucleoside

The racemic and stereoselective synthesis of a novel nucleoside 4'-branched and bicyclo[3.1.0]hexane templated nucleoside 15 was accomplished using a [3,3]-sigmatropic rearrangement, an intramolecular carbene cycloaddition reaction and a Curtius rearrangement as the key reactions.     

Resolution of (RS)-proglumide using lipase from Candida cylindraceae

Proglumide is used in the treatment of neuropathic pain. It acts by inhibiting peptide cholecystokinin (CCK). Neural injury produces an elevation in plasma CCK. Proglumide has been also shown to augment the analgesic effect of sustained release morphine in neuropathic pain. Currently proglumide is administered as a racemic mixture. In the present study, an attempt is made to separate the racemic mixture of the drug using lipase obtained from Candida cylindracea by stereoselective esterification. Enzymatic stereoselective esterification was carried out in organic solvents. The resolution was studied using a chromatographic column with a chiral support and mass spectrometry. The reaction conditions for stereoselective esterification including amount of substrate, amount of enzyme, alcohol, solvent and temperature were optimised during the present investigation. Butanol and hexanol were found to be suitable for formation of S and R esters, respectively. Hexane was the best solvent for esterification and the optimum temperature was found to be 30 degreesC.     

New potential calcium channel modulators: design and synthesis of compounds containing two pyridine, pyrimidine, pyridone, quinoline and acridine units under microwave irradiation

The synthesis of bifunctional pyridine, pyrimidine, pyridone, quinoline and acridine derivatives was investigated using dialdehyde as a precursor. A rapid and efficient method was developed for the synthesis of a range of bifunctional monocyclic, bicyclic and tricyclic products related to 1,4-DHPs with the aim of finding new classes of biologically active compounds.