Is the required therapeutic effect always achieved by racemic switch of proton-pump inhibitors?

Many of the drugs currently used in medical practice are racemates. The enantiomers of a racemic drug differ in pharmacodynamics and/or pharmacokinetics, thus in some cases it is preferable to develop pure enantiomers by racemic switch. In a recent study by Pai et al, dexrabeprazole [R(+)-rabeprazole] (10 mg) was found to be more effective than rabeprazole (20 mg) in the treatment of gastroesophageal reflux disease. We read with great interest in this study and discussed whether such racemic switch would be applicable to other proton-pump inhibitors (PPIs). A literature review indicates that stereoselective pharmacokinetics, rather than stereoselective pharmacological activity, is the main cause of differences in clinical efficacy between pure enantiomer and racemic PPI. Racemic switches of PPI provide the therapeutic advantages such as reducing metabolic load on the body, simplifying pharmacokinetics, providing benefit to the non-responders to standard dose of racemate, more homogenous response to treatment and better efficacy with equal safety. Further studies in quantitative structure-activity relationships (QSARs) are needed to address the fact that the preferred enantiomer of PPI is not always in the same absolute configuration, i.e., S-form is for omeprazole, pantoprazole and tenatoprazole whereas R-form is for lansoprazole and rabeprazole.

Chiral metabolism of propafenone in rat hepatic microsomes treated with two inducers

AIM: To study the influence of inducers of drug metabolism enzyme, beta-naphthoflavone (BNF) and dexamethasone (DEX), on the stereoselective metabolism of propafenone in the rat hepatic microsomes. METHODS: Phase I metabolism of propafenone was studied using the microsomes induced by BNF and DEX and the non-induced microsome was used as the control. The enzymatic kinetics parameters of propafenone enantiomers were calculated by regress analysis of Eadie-Hofstee Plots. Propafenone enantiomer concentrations were assayed by a chiral HPLC. RESULTS: The metabolite of propafenone, N-desalkylpropafenone, was found after incubation of propafenone with the rat hepatic microsomes induced by BNF and DEX. In these two groups, the stereoselectivity favoring R(-) isomer was observed in metabolism at low substrate concentrations of racemic propafenone, but lost the stereoselectivity at high substrate concentrations. However, in control group, no stereoselectivity was observed. The enzyme kinetic parameters were: (1) K(m). Control group: R(-) 83+/-6, S(+) 94+/-7; BNF group: R(-) 105+/-6, S(+)128+/-14; DEX group: R(-) 86+/-11, S(+) 118+/-16; (2)V(max). Control group: R(-) 0.75+/-0.16, S(+) 0.72+/-0.07; BNF group: R(-) 1.04+/-0.15, S(+)1.07+/-14; DEX group: R(-) 0.93+/-0.06, S(+) 1.04+/-0.09; (3)Cl(int). Control group: R(-) 8.9+/-1.1, S(+) 7.6+/-0.7; BNF group: R(-) 9.9+/-0.9, S(+)8.3+/-0.7; DEX group: R(-) 10.9+/-0.8, S(+) 8.9+/-0.9. The enantiomeric differences in K(m) and Cl(int) were both significant, but not in V(max), in BNF and DEX group. Whereas enantiomeric differences in three parameters were all insignificant in control group. Furthermore, K(m) and V(max) were both significantly less than those in BNF or DEX group. In the rat liver microsome induced by DEX, nimodipine (NDP) decreased the stereoselectivity in propafenone metabolism at low substrate concentration. The inhibition of NDP on the metabolism of propafenone was stereoselective with R(-)-isomer being impaired more than S(+)-isomer. The inhibition constant (Ki) of S(+)- and R(-)-propafenone, calculated from Dixon plots, was 15.4 and 8.6 mg x L(-1), respectively. CONCLUSION: CYP1A subfamily(induced by BNF) and CYP3A4 (induced by DEX) have pronounced contribution to propafenone N-desalkylation which exhibited stereoselectivity depending on substrate concentration. The molecular base for this phenomenon is the stereoselectivity in affinity of substrate to the enzyme activity centers instead of at the catalyzing sites.

Assessment and Comparison of in vitro Immunoregulatory Activity of Three Astaxanthin Stereoisomers

In recent years,the immune-modulatory role of all-trans astaxanthin from different pigment sources has been studied.It was reported that all-trans astaxanthin might exist as three stereoisomers,and the composition of all-trans stereoisomers in natural materials differs from that of synthetic products.However,the different biological effects of various all-trans stereoisomers still remain unclear.In the present study,we evaluated the bioactivity of three astaxanthin stereoisomers,(3S,3'S)-trans-,(3R,3'R)-transand meso-trans-astaxanthin,in regulating cell-mediated immune response using mice lymphocytes and peritoneal exudates cells(PECs) systems.After the treatment with three astaxanthin stereoisomers(20 μmol L-1),the lymphocyte proliferation capacity,neutral red phagocytosis of PECs and natural killer(NK) cell cytotoxic activity were comparatively assessed.The results showed that all three astaxanthin stereoisomers significantly promoted lymphocyte proliferation,phagocytic capacity of PECs,and cytotoxic activity of NK cells.Moreover,the(3S,3'S)-trans-astaxanthin exhibited a much higher response than others.

Enumeration of Stereoisomers of Chiral and Achiral Derivatives of Monocyclic Cycloalkanes Having Heteromorphous Alkyl Substituents with Distinct Length <i>k</i>

A combinatorial method based on the determination of the averaged weight of permutations controlling the chirality/achirality fittingness of 2n substitution sites of the monocyclic cycloalkane allows to obtain generalized functional equations for direct enumeration of enantiomers pairs and achiral skeletons of any derivatives of monocyclic cycloalkanes having heteromorphic alkyl substituents with the distinct length k with the empirical formula , wherein at least two alkyl groups??of the distinct size ?each. ?is the number of alkyl radicals ?of the system??verifying the relation . The integer sequences of enantiomer pairs and achiral skeletons are given for substituted derivatives of monocyclic cycloalkane for n = 3, 4 and k = 3, 4, 5. The composite stereoisomerism of this particular compound is also highlighted.

Stereoselective metabolic disruption of cypermethrin by remolding gut homeostasis in rat

Cypermethrin(CYP), a prototypical synthetic pyrethroid, reportedly causes metabolic disruption, while its stereoselective impact remains elusive. This study initially revealed that only α-CYP caused significant weight loss at 8.5 mg/(kg·day) in rats. All three CYP isomers caused the accumulation of hepatic glycogen, and hyperlipemia phenotype as the increment of total triglyceride. Rats treated with α-CYP had markedly high blood glucose levels and homeostasis model assessment of insulin resistance index. The systematic inflammation of θ-CYP group rats was evidenced by high lipopolysaccharide-binding protein levels and abnormalities of leukocytes indices. By examining the gut microbiome, we found thatα-CYP-treated rats had low contents of Firmicutes and high levels of Verrucomicrobia while Elusimicrobia was enriched in the β-CYP group. The increasing alpha diversity in the θ-CYP group may be due to the dominance of pathogenic bacteria and the increase of probiotics to counteract adverse effects. Exclusively, the α-CYP group enriched total short-chain fatty acids(SCFAs), whereas most SCFAs depleted in the θ-CYP group. The correlation analysis further found Firmicutes, an energy storage modulator, was positive to body weight(BW),while SCFAs exerted the opposite, confirming the low BW in α-CYP. Blood glucose that correlated well with SCFAs and Verrucomicrobia can be accounted for the discrepancy betweenα-CYP and θ-CYP. Overall, the three isomers exerted stereoselective glycolipid disruption in rats, and gut homeostasis acted as vital indicators.

Antiviral stereoisomers of 3,5-bis(2-hydroxybut-3-en-1-yl)-1,2,4-thiadiazole from the roots of Isatis indigotica

Four stereoisomers of 3,5-bis（2-hydroxybut-3-en-1-yl）-l,2,4-thiadiazole, named insatindigothiadia- zoles A-D （1a-1d）, were isolated from the roots oflsatis indigotica. Their structures were determined by spectroscopic analysis; specifically, the absolute configurations were assigned by using the MPA determination rule based on △δrs values of MPA esters, and supported by electronic CD （ECD） calculations. Proposed biosynthetic pathways and preliminary investigations of the biological activities of la-1d against influenza virus A （H3N2）, Coxsackie virus B3, and/or HSV-1 are also discussed.

First Synthesis and Characterization of Stereoisomers of Choleretic Drug Dihydroxydibutylether

Dihydroxydibutylether （DHBE） is a choleretic drug used for the treatment of gallstone and hepatic disorders due to its choleretic activity and hepatoprotective action. The drug is a mixture of three regioisomers. The main re- gioisomer 3-（3-hydroxylbutoxy）-1-butanol （III） contains four stereoisomers, including （R）-3-（（R）-3-hydroxyl- butoxy）-1-butanol （IIIa）, （R）-3-（（S）-3-hydroxylbutoxy）-1-butanol （IIIh）, （S）-3-（（R）-3-hydroxylbutoxy）-1-butanol （Ille） and （S）-3-（（S）-3-hydroxylbutoxy）-1-butanol （IIId）. In this paper, the four stereoisomers are synthesized separately for the first time.

Bistachybotrysins D and E,one stereoisomeric pair of cytotoxic phenylspirodrimane dimers from Stachybotrys chartarum

Bistachybotrysins D and E (1 and 2), one stereoisomeric pair of phenylspirodrimane dimers, were isolated from Stachybotrys chartarum CGMCC 3.5365. They represent novel phenylspirodrimane dimers with a central [6,5,6]-tricyclic carbon scaffold containing a cyclopentanone core. The structures of 1 and 2 were elucidated through extensive spectroscopic data analysis, and their absolute configurations were characterized by calculated electronic circular dichroism (ECD). Compounds 1 and 2 displayed potent cytotoxic activity against the four human tumor cell lines HCT116, BGC823, Daoy and HepG2 with IC_ (50)values ranging from 6.7 μmol/L to 11.6 μmol/L. Furthermore, a plausible biogenetic pathway for 1 and 2 is proposed.

A quadruple helicene with a rubicene core: synthesis, structural analyses and properties

We report the synthesis of a quadruple helicene with a rubicene core R1 by a Scholl reaction.Among the 10 stereoisomers including 4 pairs of enantiomers and 2 meso isomers,only 2 pairs of enantiomers and 1 meso isomer have been isolated.The sample structures were unambiguously determined by X-ray crystallography to be(P,P)_(6)-(P,P)_(5)/(M,M)_(6)-(M,M)_(5)-R1-A,which has a propeller-shaped structure,and(M,M)_(6)-(P,P)_(5)/(P,P)_(6)-(M,M)_(5)-R1-B and(M,P)_(6)-(P,M)_(5)-R1-C,which have saddle-shaped structures.The chiral resolutions of R1 were carried out by chiral HPLC,revealing two pairs of chiral stereoisomers(P,P)_(6)-(P,P)_(5)/(P,P)_(6)-(M,M)_(5),(M,M)_(6)-(P,P)_(5)/(M,M)_(6)-(M,M)_(5) as well as a meso isomer(M,P)_(6)-(P,M)_(5),which were further characterized by CD spectroscopy and time-dependent density functional theory(TD-DFT)calculations.Surprisingly,the UV-vis absorption and emission spectra of these resolved stereoisomers and unresolved R1 were almost identical.In addition,the chemical oxidation of R1 led to the formation of radical cations and dications at room temperature.

Synthesis of proline fullerene derivative

THE unique spherical nature and potential application of fullerene have attracted great attention. Their functionalization is in particular an active research field. Many methods are now available for the preparation of fullerene derivatives. The 1, 3-dipole cycloaddition of ylide to fullerene is one of the best known methods. We have recently reported that aminoacid esters can be added to C60 to form fulleropyrrolidine derivatives under photolysis. Our in-