Inhibitory Effect of Alcohols on Esterolytic Activity of Proteinase from Aspergillus sulphureus

(+)-Cyanofenphos was at least more than 25-fold as toxic to rice stem borer larvae as the (?)-isomer. In addition, (+)-cyanofenphos-oxon was 36-fold more potent inhibitor than the (?)-oxon toward rice stem borer larva acetylcholinesterase. The (+)-, (?)- and racemic forms of cyanofenphos were metabolized in rice stem borer larvae at almost equal rates. However, (+)-cyanofenphos produced 4- to 9-fold larger amounts of cyanofenphos-oxon in the insect body than the (?)-isomer. On the other hand, (?)-cyanofenphos-oxon was metabolized to 4-cyanophenol and its conjugate at a faster rate compared to the (+)-oxon. The difference in toxicity to rice stem borer larvae exhibited by the optical isomers of cyanofenphos is attributable to the difference in the amount and persistence of cyanofenphos-oxon isomers formed in the insect body as well as in anti-acetylcholinesterase activity of the oxon isomers.     

Relative enantiomer binding and reaction rates with propanediol dehydrase

In the dioldehydrase reaction, L(+) propanediol reacts at a faster rate than the D(?)-isomer in competitive reactions, but when the diols are run independently the rate of the D(?)-isomer is 2.3 times greater than that of the L(+)-isomer. It is assumed that this reversal is due to a difference in the Michaelis-Menten constants. A ratio of K_mD(?)/K_mL(+) = 3.2 ± 0.3 at 25° is calculated from a series of competitive reactions. It is concluded that the binding site is such that while both isomers are accomodated readily, the D(?)-isomer is hindered to some degree in its approach to the binding site. However, once the enzyme-substrate complex is formed, the D(?)-isomer is in a more favorable configuration for further reaction.     

Facile preparation of optically active jasmonates and their biological activities in rice

A facile and efficient method has been developed for the optical resolution of racemic jasmonic acid (JA) on a relatively large scale and was successfully utilized for the preparation of optically pure (+)-JA and (?)-JA. We indicated that (+)-JA has lower growth inhibitory activity than (?)-JA in the rice seedling growth test and confirmed in line with an earlier observation that their respective biologically-active forms, (+)-JA-Ile and (?)-JA-Ile, show comparable inhibitory activities. We compared the metabolism of (+)-JA and (?)-JA into (+)-JA-Ile and (?)-JA-Ile, respectively, in the JA-deficient rice cpm2, and found that the exogenously applied (+)-JA was metabolized to the corresponding Ile conjugate less efficiently as compared with (?)-JA. Such metabolic rate difference may cause a discrepancy between biological potencies of (+)-JA and (?)-JA in rice.

Abbreviations: FW: fresh weight; Ile: isoleucine; JA: jasmonic acid; JA-Ile: jasmonoyl-l-isoleucine; LC-ESI-MS/MS: liquid chromatography and electrospray ionization tandem mass spectrometry; MeJA: methyl jasmonate; OPDA: 12-oxophytodienoic acid     

Biosynthesis of chiral α- and β-pinenes in pinus species

C-3 of (+) and (?)-α-pinene and of (?)-β-pinene biosynthesized in several Pinus species was derived from C-2 of mevalonate; and the hydrogen at C-5 in all the isomers was derived from that at C-6 in nerol. This pattern is consistent with two routes for bicyclization of the acyclic biosynthetic precursor: one leads to (?)-β-pinene and the other to (+)-α-pinene of opposite absolute configuration. (?)-α-Pinene probably results from subsequent isomerisation of the (?)-β-isomer, and (very small) amounts of (+)-β-pinene result from similar (unfavoured thermodynamically) isomerisation of the (+)-α-isomer.     

Study on the stereoselective excretion of tetrahydropalmatine enantiomers in rats and identification of in vivo metabolites by liquid chromatography‐tandem mass spectrometry

The objective of this work was to study the stereoselectivity in excretion of tetrahydropalmatine (THP) enantiomers by rats and identify the metabolites of racemic THP (rac‐THP) in rat urine. Urine and bile samples were collected at various time intervals after a single oral dose of rac‐THP. The concentrations of THP enantiomers in rat urine and bile were determined using a modification of an achiral–chiral high‐performance liquid chromatographic (HPLC) method that had been previously published. The cumulative urinary excretion over 96 h of (?)‐THP and (+)‐THP was found to be 55.49 ± 36.9 μg and 18.33 ± 9.7 μg, respectively. The cumulative biliary excretion over 24 h of (?)‐THP and (+)‐THP was 19.19 ± 14.6 μg and 12.53 ± 10.4 μg, respectively. The enantiomeric (?/+) concentration ratios of THP changed from 2.80 to 5.15 in urine, and from 1.36 to 1.80 in bile. The mean cumulative amount of (?)‐THP was significantly higher than that of (+)‐THP both in urine and bile samples. However, the enantiomeric (?/+) concentration ratios in rat urine and bile were significantly lower than those ratios in rat plasma. These findings suggested the excretion of THP enantiomers was stereoselective rather than a reflection of chiral pharmacokinetic aspects in plasma and (?)‐THP was preferentially excreted in rat urine and bile. Three O‐demethylation metabolites and the parent drug rac‐THP were detected by liquid chromatography‐tandem mass spectrometry in rat urine. One metabolite was obtained by preparative HPLC and identified as 10‐O‐demethyl‐THP. Chirality, 2010. © 2009 Wiley‐Liss, Inc.     

Stereoselective Interaction Between Tetrahydropalmatine Enantiomers and CYP Enzymes in Human Liver Microsomes

Tetrahydropalmatine (THP), with one chiral center, is an alkaloid that possesses analgesic and many other pharmacological actives. The aim of the present study is to investigate stereoselective metabolism of THP enantiomers in human liver microsomes (HLM) and elucidate which cytochrome P450 (CYP) isoforms contribute to the stereoselective metabolism in HLM. Additionally, the inhibitions of THP enantiomers on activity of CYP enzymes are also investigated. The results demonstrated that (+)‐THP was preferentially metabolized by HLM. Ketoconazole (inhibitor of CYP3A4/5) inhibited metabolism of (?)‐THP or (+)‐THP at same degree, whereas the inhibition of fluvoxamine (inhibitor of CYP1A2) on metabolism of (+)‐THP was greater than that of (?)‐THP; moreover, the metabolic rate of (+)‐THP was 5.3‐fold of (?)‐THP in recombinant human CYP1A2. Meanwhile, THP enantiomers did not show obvious inhibitory effect on the activity of various CYP isoforms (CYP1A2, 2A6, 2C8, 2C9, 2C19, 2E1, and 3A4/5), whereas (?)‐THP, but not (+)‐THP, significantly inhibited the activity of CYP2D6 with the Ki value of 6.42 ± 0.38 μM. The results suggested that THP enantiomers were predominantly metabolized by CYP3A4/5 and CYP1A2 in HLM, and (+)‐THP was preferentially metabolized by CYP1A2, whereas CYP3A4/5 contributed equally to metabolism of (?)‐THP or (+)‐THP. Besides, the inhibition of CYP2D6 by (?)‐THP may cause drug–drug interaction, which should be considered. Chirality 25:43–47, 2013. © 2012 Wiley Periodicals, Inc.     

Stereoselective Toxicity and Metabolism of Lactofen in Primary Hepatocytes From Rat

The stereoselective metabolism of lactofen in primary rat hepatocytes was studied using a chiral high‐performance liquid chromatographic (HPLC) method. Rac‐lactofen and its two enantiomers, S‐(+)‐ and R‐(?)‐lactofen, as well as two of its major metabolites, acifluorfen, S‐(+)‐ and R‐(?)‐desethyl lactofen, were used as substrates,. The single and joint cytotoxicity of parent compounds and the metabolites were assessed by coincubation with rat hepatocytes as target cells. Cytotoxicity was determined by the methyl tetrazolium (MTT) assay. In hepatocyte incubations, S‐(+)‐lactofen was degraded more rapidly than R‐(?)‐lactofen, and a stereospecific formation of S‐(+)‐desethyl lactofen was detected. Metabolism of lactofen to desethyl lactofen was processed with the retention of configuration, and the achiral compound, acifluorfen, was the shared metabolite generated from both S‐(+)‐ and R‐(?)‐lactofen. There was no chiral conversion of lactofen or desethyl lactofen enantiomers during the incubation. For the cytotoxicity research, the calculated EC₅₀ values indicated that when being applied individually, the parent compound was less toxic than its metabolites, while the combination with metabolites enhanced its cytotoxic effects. The data presented here would be helpful for a more comprehensive assessment of the ecotoxicological and environmental risks of lactofen. Chirality 25:743–750, 2013. © 2013 Wiley Periodicals, Inc.     

Biotransformation of (−)-epicatechin, (+)-epicatechin, (−)-catechin,and (+)-catechin by intestinal bacteria involved in isoflavone metabolism

Isoflavone-metabolizing bacteria, Adlercreutzia equolifaciens, Asaccharobacter celatus, Slackia equolifaciens, and Slackia isoflavoniconvertens catalyzed C-ring cleavage of (–)-epicatechin and (+)-catechin, (+)-epicatechin, and (–)-catechin in varying degrees. The cleaving abilities of (–)-epicatechin and (+)-catechin were enhanced by hydrogen, except (+)-catechin cleavage by S. equolifaciens, which was not accelerated. (?)-Catechin cleavage by Ad. equolifaciens was remarkably accelerated by hydrogen.     

Stereoselective metabolism of benalaxyl in liver microsomes from rat and rabbit

Benalaxyl (BX), methyl‐N‐phenylacetyl‐N‐2,6‐xylyl alaninate, is a potent acylanilide fungicide and consist of a pair of enantiomers. The stereoselective metabolism of BX was investigated in rat and rabbit microsomes in vitro. The degradation kinetics and the enantiomer fraction (EF) were determined using normal high‐performance liquid chromatography with diode array detection and a cellulose‐tris‐(3,5‐dimethylphenylcarbamate)‐based chiral stationary phase (CDMPC‐CSP). The t_1/2 of (?)‐R‐BX and (+)‐S‐BX in rat liver microsomes were 22.35 and 10.66 min of rac‐BX and 5.42 and 4.03 of BX enantiomers. However, the t_1/2 of (?)‐R‐BX and (+)‐S‐BX in rabbit liver microsomes were 11.75 and 15.26 min of rac‐BX and 5.66 and 9.63 of BX enantiomers. The consequence was consistent with the stereoselective toxicokinetics of BX in vitro. There was no chiral inversion from the (?)‐R‐BX to (+)‐S‐BX or inversion from (+)‐S‐BX to (?)‐R‐BX in both rabbit and rat microsomes. These results suggested metabolism of BX enantiomers was stereoselective in rat and rabbit liver microsomes. Chirality, 2011. © 2010 Wiley‐Liss, Inc.     

Beta-adrenergic receptors: stereospecificity and lack of affinity for catechols

Studies of adenylate cyclase activity in rat liver, heart and fat cell microsomal preparations and in turkey and rat erythrocyte ghosts indicate that β-adrenergic receptors exhibit very strict stereospecificity for (?)-catecholamines. (+)-Isomers of active catecholamines and inactive catechol compounds do not inhibit the β-adrenergic-mediated stimulation of adenylate cyclase and thus do not interact with specific receptors. However, very high concentrations (above 10^?4 M) of (?)- and (+)-isomers, as well as of biologically inactive non-catecholamine catechols (e.g., pyrocatechol, dihydroxymandelic acid), inhibit in a nonspecific manner the basal, hormone (catecholamine, glucagon)- and NaF-stimulated adenylate cyclase activity. Studies with propranolol suggest that the low activity (0.1 to 1%) of (+)-isomers of norepinephrine can be explained by contamination with the (?)-isomer. The activity of soterenol, a potent non-catechol β-adrenergic agonist, is uninfluenced by (+)-catecholamines or catechols. It is concluded that the binding of ³H-labeled catecholamines to a variety of cells, microsomes and membranes as described in various previous studies cannot represent specific receptor interactions. Binding to receptors must demonstrate strict stereospecificity and must not be affected by unrelated catechol substances.     

Enantioselective LC/ESI-MS/MS analysis and pharmacokinetic and tissue distribution study of (2RS)-1-(7-methoxy-1H-indol-4-yloxy)-3-(2-(2-methoxyphenoxy)ethylamino)-propan-2-ol in rats

A sensitive and stereospecific liquid chromatography‐tandem mass spectrometry method for the quantitative determination of TWo8 enantiomers ((2RS)‐1‐(7‐methoxy‐1H‐indol‐4‐yloxy)‐3‐(2‐(2‐methoxyphenoxy)ethylamino)‐propan‐2‐ol) was developed and validated in rat serum and some tissues. Racemic TWo8 is a new chemical entity, and it has been shown to possess pharmacological activity in vivo. The assay involved the diastereomeric derivatization of racemic TWo8 with 2,3,4,6‐tetra‐O‐acetyl‐beta‐glucopyranosyl isothiocyanate. The TWo8 diastereoisomers quantification was performed on a triple quadrupole mass spectrometer employing an electrospray ionization technique. The precursor to the product ion transition for TWo8 derivatives and for the internal standard (carbamazepine) was m/z 776.4 → 387.2 and 237.4 → 194.4, respectively. The assay was validated with a linear range of 10–2000 ng/ml of racemic TWo8. The inter‐day precisions for (?)‐(S)‐TWo8 and (+)‐(R)‐TWo8 were 2.1% to 14.9% and 1.3% to 14.8%, respectively. The inter‐day accuracy for (?)‐(S)‐TWo8 and (+)‐(R)‐TWo8 was within 86% to 114% and 91% to 114%, respectively. A pilot pharmacokinetic study of this new β‐adrenolytic compound has shown that (?)‐(S)‐TWo8 is eliminated faster than its antipode. The terminal half‐lives of (?)‐(S)‐TWo8 and (+)‐(R)‐TWo8 were 3.2 and 3.9 h, respectively. The compound distribution into different organs, evaluated in tissue homogenate samples following TWo8 intravenous administration, showed an enantioselective penetration of TWo8 enantiomers in the liver (p < 0.03), in the kidney (p < 0.001), and in the lungs (p < 0.05). The developed method using liquid chromatography‐tandem mass spectrometry method with electrospray ionization could be employed for quantitative determination of compounds with similar structure. Chirality 24:591–599, 2012. © 2012 Wiley Periodicals, Inc.     

On the Mechanism of Metabolism of (−)-Epicatechin

(?)-Epicatechin was administered orally to rabbits and vanillic acid, 3-hydroxybenzoic acid, protocatechuic acid, and three kinds of neutral substances were found to be excreted in the urine. The three kinds of neutral substances were identified as 1-δ-(3-methoxy-4-hydroxyphenyl)-, 1-δ-(3-hydroxyphenyl)-, and 1-δ-(3,4-dihydroxyphenyl)-γ-valerolactones, which are optical isomers of the three kinds of neutral substances excreted after administration of (+)-catechin. From the presence of these intermediate metabolites, it was verified that (?)-epicatechin is metabolized by the same mechanism as (+)-catechin described earlier.     

The assembly of (+)‐vincadifformine‐ and (−)‐tabersonine‐derived monoterpenoid indole alkaloids in Catharanthus roseus involves separate branch pathways

The biological activity of monoterpenoid indole alkaloids (MIAs) has led to their use in cancer treatment and other medical applications. Their biosynthesis has involved the formation of reactive intermediates by responsible enzymes to elaborate several different chemical scaffolds. Modification of scaffolds through different substitution reactions has produced chemically diverse MIAs and related biological activities. The present study characterizes the three‐step pathway involved in the formation of (+)‐echitovenine, the major O‐acetylated MIA of Catharanthus roseus roots, and differentiates it from a parallel pathway involved in the formation of hörhammericine. Separate hydrolases convert a common reactive MIA intermediate to aspidosperma skeletons of opposite specific rotations, that is (+)‐vincadifformine and (?)‐tabersonine, respectively. The formation of (+) minovincinine from (+) vincadifformine 19‐hydroxylase (V19H) is catalyzed by a root‐specific cytochrome P450 with high amino acid sequence similarity to the leaf‐specific tabersonine‐3‐hydroxylase involved in vindoline biosynthesis. Similarly, O‐acetylation of (+)‐minovincinine to form (+) echitovenine involves minovincinine‐O‐acetytransferase. The substrate specificity of V19H and MAT for their respective (+)‐enantiomers defines the separate enantiomer‐specific pathway involved in (+)‐echitovenine biosynthesis and differentiates it from a parallel (?)‐enantiomer‐specific pathway involved in the formation of hörhammericine from (?)‐tabersonine.     

Purification and characterization of a novel O-methyltransferase from Flammulina velutipes

An enzyme catalyzing the methylation of phenolic hydroxyl groups in polyphenols was identified from mycelial cultures of edible mushrooms to synthesize O-methylated polyphenols. Enzyme activity was measured to assess whether methyl groups were introduced into (?)-epigallocatechin-3-O-gallate (EGCG) using SAM as a methyl donor, and (?)-epigallocatechin-3-O-(3-O-methyl)-gallate (EGCG3″Me), (?)-epigallocatechin-3-O-(4-O-methyl)-gallate (EGCG4″Me), and (?)-epigallocatechin-3-O-(3,5-O-dimethyl)-gallate (EGCG3″,5″diMe) peaks were detected using crude enzyme preparations from mycelial cultures of Flammulina velutipes. The enzyme was purified using chromatographic and two-dimensional electrophoresis. The purified enzyme was subsequently analyzed on the basis of the partial amino acid sequence using LC–MS/MS. Partial amino acid sequencing identified the 17 and 12 amino acid sequences, VLEVGTLGGYSTTWLAR and TGGIIIVDNVVR. In database searches, these sequences showed high identity with O-methyltransferases from other mushroom species and completely matched 11 of 17 and 9 of 12 amino acids from five other mushroom O-methyltransferases.     

Stereoselective Degradation of alpha‐Cypermethrin and Its Enantiomers in Rat Liver Microsomes

Alpha‐cypermethrin (α‐CP), [(RS)‐a‐cyano‐3‐phenoxy benzyl (1RS)‐cis‐3‐(2, 2‐dichlorovinyl)‐2, 2‐dimethylcyclopropanecarboxylate], comprises a diastereoisomer pair of cypermethrin, which are (+)‐(1R‐cis‐αS)–CP (insecticidal) and (?)‐(1S‐cis‐αR)–CP (inactive). In this experiment, the stereoselective degradation of α‐CP was investigated in rat liver microsomes by high‐performance liquid chromatography (HPLC) with a cellulose‐tris‐ (3, 5‐dimethylphenylcarbamate)‐based chiral stationary phase. The results revealed that the degradation of (?)‐(1S‐cis‐αR)‐CP was much faster than (+)‐(1R‐cis‐αS)‐CP both in enantiomer monomers and rac‐α‐CP. As for the enzyme kinetic parameters, there were some variances between rac‐α‐CP and the enantiomer monomers. In rac‐α‐CP, the V_max and CL_int of (+)‐(1R‐cis‐αS)–CP (5105.22 ± 326.26 nM/min/mg protein and 189.64 mL/min/mg protein) were about one‐half of those of (?)‐(1S‐cis‐αR)–CP (9308.57 ± 772.24 nM/min/mg protein and 352.19 mL/min/mg protein), while the K_m of the two α‐CP enantiomers were similar. However, in the enantiomer monomers of α‐CP, the V_max and K_m of (+)‐(1R‐cis‐αS) ‐CP were 2‐fold and 5‐fold of (?)‐(1S‐cis‐αR)‐CP, respectively, which showed a significant difference with rac‐α‐CP. The CL_int of (+)‐(1R‐cis‐αS)–CP (140.97 mL/min/mg protein) was still about one‐half of (?)‐(1S‐cis‐αR)–CP (325.72 mL/min/mg protein) in enantiomer monomers. The interaction of enantiomers of α‐CP in rat liver microsomes was researched and the results showed that there were different interactions between the IC₅₀ of (?)‐ to (+)‐(1R‐cis‐αS)‐CP and (+)‐ to (?)‐(1S‐cis‐αR)‐CP(IC_50(?)/(+) / IC_50(+)/(?) = 0.61). Chirality 28:58–64, 2016. © 2015 Wiley Periodicals, Inc.     

Isomeric-Activity ratios of trimetoquinol enantiomers on β-adrenergic receptor subtypes: Functional and biochemical studies

Trimetoquinol [1-(3′,4′,5′-trimethoxybenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, TMQ] exists as two enantiomers, and the (?)-(S)-isomer is a potent β-adrenergic receptor (β-AR) agonist. Experiments were conducted to examine the functional and biochemical potencies of the (S)- and (R)-enantiomers of TMQ for interaction with β-AR subtypes in tissues, membrane fractions, and cell systems. The isomeric-activity ratios (IARs) of the TMQ isomers [(S)-isomer ? (R)-isomer] for stimulation of β₁- and β₂-AR of guinea pig right atria and trachea were 224 and 1585, respectively; these IARs were similar to those observed on atypical β-AR systems of rat distal colon (575), rat brown adipocytes (398), but differed from that of rat esophageal smooth muscle (2884) in the presence of pindolol. In the absence of pindolol, the potencies for the TMQ enantiomers were slightly increased; however, the IARs remained unchanged in rat distal colon, rat brown adipocytes, and rat esophageal smooth muscle. Similarly, radioligand binding studies demonstrated that the TMQ isomer β-AR affinities were stereoselective for the (?)-(S)-isomer in membranes of guinea pig left ventricle (β₁) and lung (β₂) giving IARs of 115 and 389, respectively; and in E. coli expressing human β₁- and β₂-AR giving IARs of 661 and 724, respectively. Corresponding IARs of receptor affinities and stimulation of cAMP accumulation in Chinese hamster ovary cells expressing human β₂-AR and rat β₃-AR were 331 and 282, and 118 and 4678, respectively. These results indicate that the (?)-(S)-isomer of TMQ exhibits high affinity, and is a potent and highly stereoselective agonist for each β-AR subtype, that the isomers generally fail to differentiate between the β-AR subtypes, and that, based upon differences in IAR within β₃-AR containing systems, subtypes of atypical β (or β₃)-AR may exist in adipose tissue and smooth muscle. © 1994 Wiley-Liss, Inc.     

In vitro inhibition of aromatase by the enantiomers of aminoglutethimide and analogs

The in vitro aromatase activity in microsomal fractions from rat ovary and its inhibition by enantiomers of aminoglutethimide (AG), rogletimide (RG), and cyclohexylaminoglutethimide (ChAG) were studied by analysing the [³H]H₂O released when [1β-³H]androstenedione was converted to estrone. Maximum velocity (V_max) and the Michaelis-Menten constant (K_m) of the microsomal aromatase enzyme were 17.40 ± 0.45 pmol/ml/mg protein/min and 1.02 ± 0.06 μM, respectively. The IC₅₀s for the enantiomers were similar for (+)-R-AG and (?)-R-ChAG (0.86 ± 0.06 and 0.89 ± 0.15 μM, respectively). (+)S-ChA'G was most potent with IC₅₀ of 0.075 ± 0.003 μM. The IC₅₀s for (?)-S-AG, (+)-R-RG, and (?)-S-RG were in the same range (23.15 ± 2.74, 24.58 ± 2.46, and 24.43 ± 2.20 μM, respectively). © 1994 Wiley-Liss, Inc.     

Photo-Induced P-Methylbenzylation of 1,3-Dimethylthymine and 1, 3-Dimethyluracil in the Presence of Trifluoroacetic Acid

Abstract

Photolysis of a solution of a pyrimidine (i. e., 1, 3-dimethylthymine and 1, 3-dimethyluracil) in p-xylene in the presence of trifluoroacetic acid afforded mainly the 5, 6-dihydropyrimidine derivative together with the 5-p-methylbenzylated product and the 6-isomer as well. It is suggested that the first two products result from the C⁶-protonated pyrimidine electron adduct (III), while the 6-isomer is derived from the O⁴-protonated isomer (II).     

Pharmacokinetics of the enantiomers of verapamil in the dog

The intravenous (0.5 mg/kg) and oral (5 mg/kg) dose kinetics of verapamil were studied in 6 dogs during steady-state oral verapamil dosing (5 mg/kg every 8 h for 3 days). Racemic verapamil and norverapamil, a metabolite of verapamil, were quantitated in plasma by HPLC-fluorescence detection. The verapamil peaks eluting off the column were collected and rechromatographed on an Ultron-OVM column, which resolved the two verapamil enantiomers. After intravenous administration, the systemic clearance and apparent volume of distribution of (?)-(S)-verapamil were nearly twice that of the (+)-(R)-isomer. There was no difference in the elimination half-lives between the two isomers. After oral administration, the oral clearance of (?)-(S)-verapamil was 20 times that of the (+)-(R)-isomer. The apparent bioavailability of (+)-(R)-verapamil was over 14 times that of (?)-(S)-verapamil. The plasma protein binding of the (+)-(R)-isomer was slightly higher by 5% than (?)-(S)-verapamil; however, this effect was not enough to account for the difference between the apparent volume of distribution of the enantiomers, indicating that the tissue binding of (?)-(S)-verapamil was greater than that of the (+)-(R)-isomer. This data on the disposition of the enantiomers of verapamil in the dog is similar to that reported for man and demonstrates that the dog may be an appropriate animal model for man in future studies on the disposition of the enantiomers of verapamil. © 1993 Wiley-Liss, Inc.     

Crystal structure,conformational analysis,and molecular dynamics of tetra-O-methyl-(+) -catechin

The structure of tetra-O-methyl- (+) -catechin has been determined in the crystalline state. Two independent molecules, denoted structure A and structure B, exist in the unit cell. Crystals are triclinic, space group P1, a = 4.8125(2) Å, b = 12.9148(8) Å, c = 13.8862(11) Å, α = 86.962(6) °, β = 89.120(5)°, γ = 88.044(5)°, Z = 2, D_c = 1.336 g cm^?3, R = 0.033 for 6830 observations. The heterocyclic rings of the crystal structures are compared to previous results for 8-bromotetra-O-methyl-(+)-catechin, penta-O-acetyl-(+)-catechin, and (?) -epicatechin. One of the two molecules has a heterocyclic ring conformation similar to that observed previously for (?)-epicatechin, and the other has a heterocyclic ring conformation similar to one predicted earlier in a theoretical analysis of dimers of (+)-catechin and (?) -epicatechin. Both structure A and structure B in the crystal have heterocyclic ring conformations that place the dimethoxyphenyl substituent at C(2) in the equatorial position. However, this heterocyclic ring conformation does not explain the proton nmr coupling constant measured in solution. Molecular dynamics simulations show an equatorial ? axial interconversion of the heterocyclic ring, which can explain the nmr results. © 1993 John Wiley & Sons, Inc.