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A convenient and simple protocol has been developed for the synthesis of a series of new tetracyclic tetrahydroisoquinoline derivatives, 7,12-dihydro-6,12-methanodibenzo[c,f]-azocine-5-carboxylic acids by three component Petasis reaction with the use of aminoacetaldehyde acetals bearing substituted benzyl groups as the amine components followed by Pomeranz–Fritsch double cyclization reaction. By applying this method, several acids have been prepared in satisfactory yields. An unprecedented chemical behavior of a Petasis reaction product in diluted HCl solution leading to the formation of a phenylglycine derivative has been observed and the mechanism explaining such reactivity has been proposed.

The enantiospecific synthesis of ( S )-(−)-8-oxoxylopinine 1 was performed using a lateral metallation strategy, in which ( S )-alaninol or ( S )-phenylalaninol was applied as chiral auxiliary and building block. (4 S )-3-(4,5-Dimethoxy-2-methylbenzoyl)-2,2,4-trimethyl-1,3-oxazolidine 12 was synthesized starting from veratraldehyde 13 . The addition reaction of benzylic anion generated in situ from chiral amide 12 into 6,7,-dimethoxy-3,4-dihydroisoquinoline 7a proceeded with simultaneous cyclization leading to the protoberberine alkaloid with high enantioselectivity.

We assessed the relations between MPA, free MPA (fMPA) and MPA glucuronide (MPAG) pharmacokinetics and the clinical condition of renal transplant recipients treated with EC-MPS and tacrolimus (Tac) in the first post-transplant year. In 18 adult patients blood samples were collected up to 12 h after EC-MPS oral administration. EC-MPS metabolites’ plasma concentrations were determined using validated HPLC methods. All patients reached MPA area under the time–concentration curve (AUC0–12) above 30 µg h/mL. Most of the MPA, fMPA and all MPAG concentrations correlated significantly with respective AUC0–12 values. Some fMPA and all MPAG pharmacokinetic parameters correlated negatively with creatinine clearance and positively with creatinine concentration, whereas no such correlation was observed for MPA. Lower hemoglobin concentrations were observed in patients with higher MPA or fMPA C 0. The significant correlations between MPA C 3 as well as MPA C 4 and MPA AUC0–4 and MPA AUC0–12 may be of importance in further studies including larger number of patients in regard to establishing LSS. In patients treated with EC-MPS and Tac, monitoring MPA C 0 may be important, as too high MPA C 0 may contribute to anemia onset. In EC-MPS treated patients, MPAG concentration is related to renal function as MPAG pharmacokinetics were higher in patients with renal impairment.

The diastereoselective synthesis of (+)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (90 % ee) was accomplished by employing a combination of two synthetic methods, that is, the Petasis synthesis of amino acids and the Pomeranz–Fritsch–Bobbitt synthesis of tetrahydroisoquinoline derivatives. The stereochemical outcome of the synthesis was controlled by chiral aminoacetaldehyde acetals, which were used as the amine component of the Petasis step to yield the Pomeranz–Fritsch–Bobbitt substrate for the tetrahydroisoquinoline ring formation in one simple operation.

In the past decade, the asymmetric synthesis of chiral nonracemic isoquinoline alkaloids, a family of natural products showing a wide range of structural diversity and biological and pharmaceutical activity, has been based either on continuation or improvement of known traditional methods or on new, recently developed, strategies. Both diastereoselective and enantioselective catalytic methods have been applied. This review describes the stereochemically modified traditional syntheses (the Pictet–Spengler, the Bischler–Napieralski, and the Pomeranz–Fritsch–Bobbitt) along with strategies based on closing of the nitrogen-containing ring B of the isoquinoline core by the formation of bonds between C1–N2, N2–C3, C1–N2/N2–C3, and C1–N2/C4–C4a atoms. Methods involving introduction of substituents at the C1 carbon of isoquinoline core along with syntheses applying various biocatalytic techniques have also been reviewed.

In the past decade, the asymmetric synthesis of chiral nonracemic isoquinoline alkaloids, a family of natural products showing a wide range of structural diversity and biological and pharmaceutical activity, has been based either on continuation or improvement of known traditional methods or on new, recently developed, strategies. Both diastereoselective and enantioselective catalytic methods have been applied. This review describes the stereochemically modified traditional syntheses (the Pictet–Spengler, the Bischler–Napieralski, and the Pomeranz–Fritsch–Bobbitt) along with strategies based on closing of the nitrogen-containing ring B of the isoquinoline core by the formation of bonds between C1–N2, N2–C3, C1–N2/N2–C3, and C1–N2/C4–C4a atoms. Methods involving introduction of substituents at the C1 carbon of isoquinoline core along with syntheses applying various biocatalytic techniques have also been reviewed.

A sequence of two reactions: the Petasis reaction, in which an aminoacetaldehyde acetal was used as the amine component, followed by Pomeranz–Fritsch–Bobbitt cyclization, has been shown to be a convenient and simple method for the synthesis of tetrahydroisoquinoline-1-carboxylic acids. Using this method several acids have been prepared in good to excellent yields and characterized as hydrochloride salts.

Introduction Plasma antioxidant vitamins (retinol, α-tocopherol, β-carotene) were measured to establish the influence of clinical condition and mycophenolate mofetil (MMF) treatment on the nutritional status of renal transplant recipients. Material and methods In 106 adult patients plasma vitamins were measured and 24-h diet history questionnaires were conducted. The MMF influence on plasma vitamins was verified in 61 patients. Results The current dietary intakes of vitamins in daily food rations were lower than recommended. Plasma retinol was lower in patients suffering from gastrointestinal disorders (1.25 ±0.48 mg/l vs. 1.55 ±0.70 mg/l) and inversely associated with aminotransferases activity (p = 0.019) and creatinine clearance (p = 0.021). Retinol concentrations were positively associated with plasma creatinine (p = 0.027) and pharmacokinetic parameters of MMF phenyl glucuronide. β-Carotene concentrations were higher in women (0.39 ±0.46 mg/l vs. 0.28 ±0.23 mg/l; p = 0.041) and when MMF was co-administered with cyclosporine vs. tacrolimus (0.45 ±0.62 mg/l vs. 0.25 ±0.19 mg/l). Plasma α-tocopherol correlated negatively with the mycophenolic acid pre-dose concentration (p = 0.027) and was significantly lower in patients treated with calcineurin inhibitors (8.90 ±5.23 mg/l vs. 12.25 ±5.62 mg/l). A positive correlation was observed between α-tocopherol levels and aspartate aminotransferase (p = 0.006). In multivariate regression aspartate aminotransferase and MMF treatment significantly influenced retinol (p < 0.001). Conclusions The MMF treatment was associated with significantly lower retinol concentrations. The gastrointestinal disorders occurrence in MMF-treated patients may cause a decrease in retinol absorption. Diet adjustment and/or vitamin A supplementation should be considered.

The proper concentrations of plasma bioelements may favorably reduce the incidence of metabolic disorders, which often occur during immunosuppressive therapy. Mycophenolate mofetil (MMF) is currently one of the most frequently administered immunosuppressive agents; however, MMF treatment is often related to gastrointestinal side effects. The aim of this study was thus to verify whether the MMF treatment itself, or its metabolite pharmacokinetics, has an effect on the concentrations of plasma bioelements. To determine this, the effect of MMF on the levels of both major (sodium [Na], potassium [K], calcium [Ca], magnesium [Mg]), and trace (iron [Fe], zinc [Zn], copper [Cu]) plasma bioelements in 61 renal transplant recipients was assessed in comparison to a control group (n = 45). The pharmacokinetic parameters of mycophenolic acid were determined by the high-performance liquid chromatography method. All patients filled out a 24-h diet history questionnaire. The results showed high plasma concentrations of Fe and low plasma concentrations of Mg and Zn as compared with diagnostic norms. The patients treated with MMF had significantly lower plasma Na (P

Laterally lithiated ( S )-(−)- and ( R )-(+)- o -toluamides 6 with a chiral auxiliary derived from ( S )- and ( R )-phenylalaninol, respectively, were used as the building blocks and chirality inductors in the asymmetric modification of the Pomeranz–Fritsch–Bobbitt synthesis of isoquinoline alkaloids. Their addition to imine 2 proceeded with partial cyclization, giving isoquinolones (+)- 7 and (−)- 7 along with acyclic products, (−)- 8 and (+)- 8 , respectively. LAH-reduction of (+)- 7 and (−)- 7 , followed by cyclization, afforded both enantiomers of the alkaloid, ( S )-(−)- and ( R )-(+)- O -methylbharatamine 5 , in 32% and 40% overall yield and with 88% and 73% ees, respectively.

The reaction of 6,7-methylenedioxy-3,4-dihydroisoquinoline with laterally lithiated o -toluamides in which the amine part derived from (1 S ,2 S )-thiomicamine or (1 R ,2 S )-2-amino-1-phenylpropanol, affording ( R )-(+)- and ( S )-(−)-2,3-methylenedioxy-8-oxoberbine in 77% and 64% yield, respectively, and with enantiomeric excess >99% is described. Physical and spectral data of the synthetic product differ from those reported for the natural alkaloid, gusanlung D.

The (R)- and (S)-enantiomers of salsolidine, 2, were prepared in good yield and moderate enantioselectivity (33 and 27% e.e., respectively) by the addition of methyllithium to 6,7-dimethoxy-3,4-dihydroisoqiunoline 1 in the presence of the chiral oxazoline ligands 4 and 10.

Three isoquinoline alkaloids, (−)-salsolidine 2 , (+)-carnegine 6 and (−)-1-phenyl-2-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline 7 , were obtained in high yield and with 17–46% e.e. by the enantioselective additions of organolithium reagents to dihydroisoquinolines 1 and 5 , in the presence of (−)-sparteine as a chiral ligand.

A new ligand 2 was prepared from (+)-thiomicamine 1 and o-methoxyphenol, and its activity as an external controller of stereochemistry in enantioselective additions of methyllithium to prochiral imines 8–10 tested. The non-racemic secondary amines 11–13 were prepared in 60–90% chemical yield with the enantioselectivity ranging from 2 to 41%. 6,7-Dimethoxy-3,4-dihydroisoquinoline 8 was transformed into (+)-salsolidine 11 with an e.e. of 41%.

The metabolism of azathioprine (AZA) was studied by monitoring the concentrations of red blood cell (RBC) 6-thioguanine nucleotides (6-TGN) and of 6-methylmercaptopurine metabolites (6-mMP) in 27 renal transplantation recipients and in 10 patient subjects with glomerulonephritis (GN). Concentrations of 6-TGNs and 6-mMP metabolites were measured using high-performance liquid chromatography (HPLC). Six patients from the group of renal transplantation recipients were also administered allopurinol. Median values of RBC 6-TGN and of 6-mMP metabolites concentrations in 21 renal transplantation recipients (without allopurinol) were 122 pmol/8x10(8) RBCs (range

The absolute configuration of the title compound, C24H23NO2, has been confirmed as 3R,4R. The hydroxymethyl group and phenyl ring at the asymmetric C atoms exhibit α and β orientations, respectively, and the non-planar heterocyclic ring of the tetrahydroisoquinoline system adopts an envelope conformation. The crystal structure is stabilized through hydrogen bonds.

In the title optically active protoberberine derivative [systematic name: (S)-(−)-2,3-dimeth­oxy-5,6,13,13a-tetra­hydro-8H-dibenzo[a,g]quinolizin-8-one], C19H19NO3, the key inter­mediate in the synthesis of enanti­omerically pure (S)-(−)-O-methyl­bharatamine, the absolute configuration of the asymmetric centre at the 13a position has been confirmed as S by crystal structure refinement. The H atom at the asymmetric centre assumes an α-orientation and occupies a pseudo-axial position relative to the central non-planar rings of the tetra­cyclic skeleton.

In the title optically active protoberberine derivative, C18H15NO3, the absolute configuration has been confirmed as 13aS. The H atom at the asymmetric centre assumes an α orientation and occupies a bis­ectional position relative to the tetra­hydro­pyridine ring, and is axial to the tetra­hydro­pyridinone ring.

A sequence of two reactions: the Petasis reaction, in which an aminoacetaldehyde acetal was used as the amine component, followed by Pomeranz–Fritsch–Bobbitt cyclization, has been shown to be a convenient and simple method for the synthesis of tetrahydroisoquinoline-1-carboxylic acids. Using this method several acids have been prepared in good to excellent yields and characterized as hydrochloride salts.

INTRODUCTION The aim of the study was to analyse the influence of renal impairment on the pharmacokinetic parameters (PK) of mycophenolic acid (MPA) and its glucuronide metabolite (MPAG) in renal transplant recipients. MATERIAL AND METHODS The study included 43 adult patients during the maintenance period (> 6 months) following renal transplantation, treated with mycophenolate mofetil (MMF), calcineurin inhibitors (CNI) (tacrolimus or cyclosporine) and steroids. The study compared patients with normal renal function (n = 17; creatinine clearance (C(cr)) > 60 ml/min) and with renal impairment (n = 26; C(cr) < 60 ml/min). Areas under the 4-h curve (AUC(0-4 h)) of MPA and MPAG were determined using a validated HPLC method. RESULTS The renal impairment group showed significantly increased AUC(0-4 h) and pre-dose (C(0)) for MPAG compared to patients with normal renal function and increased MPA C(0). However, there was no significant difference in MPA AUC(0-4 h) between patients with renal impairment and patients with normal renal function. In multivariate analysis some MPA and MPAG PK parameters were correlated with sex, CNI co-administered and body weight. CONCLUSIONS Although MPAG is an inactive metabolite, its accumulation in patients with renal impairment can be unfavourable. The results of our study indicate that solely MPA C(0) determination in patients receiving MMF may be insufficient in clinical practice because of great inter-patient variability of this PK parameter caused mainly by enterohepatic recirculation.

A new ligand 2 was prepared from (+)-thiomicamine 1 and o-methoxyphenol, and its activity as an external controller of stereochemistry in enantioselective additions of methyllithium to prochiral imines 8–10 tested. The non-racemic secondary amines 11–13 were prepared in 60–90% chemical yield with the enantioselectivity ranging from 2 to 41%. 6,7-Dimethoxy-3,4-dihydroisoquinoline 8 was transformed into (+)-salsolidine 11 with an e.e. of 41%.

Stereoselectivity of the addition reaction of o-toluamides, incorporating 2-amino-l,3-propanediols as chiral auxiliary to imines has been studied. Addition products, diastereomerically enriched, after column chromatography separation were obtained and further transformed to (S)-(-)-or (R)-(+)-8-oxoberbines with ee up to 97%.

Mercaptopurine (6-MP), thioguanine (6-TG), and azathioprine (AZA) are purine antimetabolites introduced as anticancer or immunosuppressive drugs decades ago. Methylated AZA, called MAZA, is among the investigational drugs. The present study compares MAZA to the widely recognized drugs AZA, 6-MP, and 6-TG with respect to the ability of being transported across cell membranes. The obtained octanol/water phases partition coefficients and results of quantum chemical calculations predict the following sequence of hydrophobicity: MAZA > AZA > 6-TG > 6-MP.

Azathioprine is an important drug used in the therapy of autoimmune disorders and in preventing graft rejection. Its molecule is composed of two main moieties: mercaptopurine and imidazole derivative. It is an immunosuppressive agent whose biological activity results from its in vivo mercaptolysis mediated by a nucleophilic attack on the C(5i) atom of imidazole ring of the azathioprine molecule. Solvation model SM5.4 with the PM3 Hamiltonian have been applied to model the reaction of azathioprine with cysteine. The employed quantum mechanical method shed new light on the mechanism of the reaction of azathioprine with cysteine in aqueous solution. The obtained results indicated that the first step in the reaction most likely involves the nucleophilic attack of the COO(-) of cysteine on the C(5i) atom of the imidazole ring of azathioprine, followed by a subsequent intramolecular attack of the SH group of the cysteine residue. It was shown that biogenic thiols such as glutathione or cysteine facilitate the first and crucial step of azathioprine metabolism, due to the presence of COO(-), SH, and NH(3)(+) groups in their molecules.

Intracellular concentrations of 6-mercaptopurine metabolites, i.e. of 6-thioguanine nucleotides (6-TGN) and of 6-methylmercaptopurine metabolites (6-mMP) were analysed in red blood cells (RBC) of 19 children with acute lymphoblastic leukemia (ALL), the subjects of a maintenance chemotherapy of their first remission. Interpatient variations in concentrations of both metabolites were high; concentrations of 6-TGN varied from

The absolute configuration of the title compound, C(20)H(23)NO(2), has been confirmed as 4S. The benzyl residue and H atom at the asymmetric C-atom centre occupy pseudo-axial and bis-ectional positions, respectively. The oxazolidine ring adopts an envelope conformation. In the crystal structure, the mol-ecular packing is stabilized by non-classical C-H⋯O hydrogen bonds.

In the total synthesis of (±)-peshawarine (1) hydrastinine derivative 6 was acylated with 1,3-dithian 7 applied as an acyl anion equivalent. The dithian masking group in addition product 8 was reductively removed using Raney nickel.

O-Methylation of optically active 3′,4′-dideoxynorlaudanosoline-l-carboxylic acids 1 with O-methyltransferase in vitro afforded almost exclusively the 7-O-methylated acids 3. A similar result was obtained with the yellow quinonemethide 4A obtained from 1 at neutral or slightly alkaline pH by oxidative decarboxylation and affording the 3,4-dihydroisoquinoline 15 on methylation with catechol O-methyltransferase (COMT). The structure of quinonemethide 4A was determined on the basis of spectral data, by its conversion into isoquinolines of established structure, and by synthesis. Quinonemethide 4A was found to be a weak inhibitor of monoamine oxidase A (MAO A) but not a substrate. Nonenzymatic oxidative decarboxylation of dopamine-derived tetrahydroisoquinoline-l-carboxylic acids to quinonemethides may be a major factor in biochemical experimentation and should be considered in the interpretation of data.

Synthesis of the optical isomers of (±)-methyl 6,7-dimethyl-3′,4′-dideoxynorlaudanosoline-1-carboxylate ((±)-2) was accomplished by reaction of (±)-2 with (+)-(R)-1-phenylethyl isocyanate, separation of the urea diastereoisomers (−)-4A and (+)-4B, and alcoholysis of the ureas in refluxing BuOH. Optically active isoquinoline-carboxylates 2A,B and hydantoins 8A,B isolated were characterized. The absolute configuration of the reaction products was established by X-ray analysis of the optically active hydantoin (+)-8A. Hydrolysis of the methyl isoquinolinecarboxylates 2A,B with 48% HBr soln. at reflux afforded the desired optically active 3′,4′-dideoxynorlaudanosoline-1-carboxylic acids 1A,B required for enzyme-inhibition studies. Details of the X-ray diffraction analysis of (+)-methyl salsoline-1-carboxylate hydrobromide ((+)-11A·HBr) prepared earlier are included. CD spectra of (+)-(S)-methyl 6,7-dimethyl-3′,4′-dideoxynorlaudanosoline-1-carboxylate hydrobromide ((+)-2A. HBr) and (−)-(R)-methyl salsoline-1-carboxylate hydrochloride ((−)-11B·HCl) confirmed the assignment of their (S)- and (R)-configurations, respectively.

Cryptopleurospermine ( 1 ), a 1,2-secobenzylisoquinoline alkaloid was synthesized from hydrastinine derivative 2 and isovanillin 1,3-propylene dithioacetal 3 . The formation of C-C bond between these two synthons involved addition of dilithio salt of dithian 3 to aldehyde group in 2 . Reduction and hydrolysis of the masking group in addition product 4 furnished the synthesis.

O-Methylation of optically active 3′,4′-dideoxynorlaudanosoline-l-carboxylic acids 1 with O-methyltransferase in vitro afforded almost exclusively the 7-O-methylated acids 3. A similar result was obtained with the yellow quinonemethide 4A obtained from 1 at neutral or slightly alkaline pH by oxidative decarboxylation and affording the 3,4-dihydroisoquinoline 15 on methylation with catechol O-methyltransferase (COMT). The structure of quinonemethide 4A was determined on the basis of spectral data, by its conversion into isoquinolines of established structure, and by synthesis. Quinonemethide 4A was found to be a weak inhibitor of monoamine oxidase A (MAO A) but not a substrate. Nonenzymatic oxidative decarboxylation of dopamine-derived tetrahydroisoquinoline-l-carboxylic acids to quinonemethides may be a major factor in biochemical experimentation and should be considered in the interpretation of data.

Cryptopleurospermine ( 1 ), a 1,2-secobenzylisoquinoline alkaloid was synthesized from hydrastinine derivative 2 and isovanillin 1,3-propylene dithioacetal 3 . The formation of C-C bond between these two synthons involved addition of dilithio salt of dithian 3 to aldehyde group in 2 . Reduction and hydrolysis of the masking group in addition product 4 furnished the synthesis.

In the total synthesis of (±)-peshawarine (1) hydrastinine derivative 6 was acylated with 1,3-dithian 7 applied as an acyl anion equivalent. The dithian masking group in addition product 8 was reductively removed using Raney nickel.