Investigation of the coupling reaction of tetraacetylsecologanin with oxotryptamine and its derivative.

The coupling reaction of tetraacetylsecologanin with 2,3-dihydro-2-oxotryptamine and its N(b)-benzyl derivative was investigated. With the benzylated amine, the reaction was stopped at the tetracyclic ester level, and with the unsubstituted amine it was immediately followed by lactamization. In both cases, the products were formed with high stereoselectivity at C-3, but as an epimeric pair of 7R and 7S in a ratio of 1:3. The bulky benzyl substituent at N-4 directed the stereoselectivity at C-3 in favor of the S configuration. In the nonbenzylated compounds, the reversible coupling reaction is probably nonstereoselective, but in lactamization the 3R epimer is sterically favored and faster and gives the final lactam in this configuration. The formation of the spiro compounds may serve as a model reaction in the interpretation of the stereoselectivity of the coupling reaction of secologanin with tryptamine in the presence of strictosidine synthase.

Why are the terpenoid indole alkaloids of type I homochiral?

In the presence of the enzyme strictosidine synthase, the coupling reaction of secologanin and tryptamine is completely stereoselective and affords strictosidine with 3S configuration, exclusively. The stereoselectivity is transferred and retained in most indole alkaloids of type I in which C-3 is not involved in subsequent reactions. By using results of model reactions, the stereoselectivity was interpreted by the bulkiness of the enzyme temporarily attached to the N-4 atom in the formation of the indolenine intermediate. 3S configuration is kept in the subsequent 1,2-rearrangement into the beta-carboline structure. In the formation of the oxindole derivatives, the 3S configuration is preferred, but not necessarily complete.

Regio- and stereoselectivity in the coupling reaction of secologanin with dopamine derivatives.

The coupling reaction of tetraacetylsecologanin with dopamine and its N-benzyl derivative was investigated. In both series, stereoisomers at C-1, as well as regioisomer normal and neo compounds, were formed. Moreover, the N-unsubstituted products were partially lactamized, and the N-benzyl derivatives epimerized at C-1. In the products, the R configuration of C-1 over the S and the formation of the normal structure over the neo one predominated. The epimerization of both epimers gave an equilibrium of R and S in a ratio of 7:3 and was interpreted by cleavage of the C-1-N-2 bond. The fact that lactamization was much faster in the R than in the S series was explained on the basis of the supposed transition states. The structure, the configuration of C-1, and in several cases the conformations were established by detailed NMR studies and supported by chemical correlations.

[Contact dermatitis after topical use of ketoprofen gel]. / Ketoprofen tartalmú gél használatát követóen kialakult kontakt ekzema.

Authors present 5 cases of generalized contact and photocontact dermatitis due to topically applied ketoprofen, a non-steroidal anti-inflammatory drug. They investigated the sensitisation and photosensitisation to the drug and also the possible cross-reactivity.

[Synthesis of carboline alkaloid analogues]. / Karbolinvázas alkaloid analógok szintézise.

Hybrid compounds were synthesized combining the structural features of two isomer natural indolalkaloids rutaecarpine (1) and nauclefine (2). These aza-bioisosteric analogues are the first representatives of a new heterocyclic ring system. Two alternative reaction routes were developed for the synthesis of pentacyclic compounds (4, 5) in which the key step is the Fischer indolization of the 6-phenylhydrazono-dipyrido[1,2-a;4,3-d]pirimidine-11-ones. In the case of E-ring substituted derivatives the synthesis was carried out via preparation and chemical transformation of pyrido[1,2-a]pirimidine-4-ones (14, 15) to 2-substituted-3-aza-rutaecarpines (17-20). Finally, the nucleophilic displacement of the chlorine atom of 2-chloro-3-aza-rutaecarpine (18) by dialkylaminoethylamine provided the 2-amino-substituted derivative (20) having improved physico-chemical properties and increased antitumour activity. The new compounds are characterized by UV, IR, 1H, 13C NMR spectroscopy.

Configurative correlation and conformational analysis of strictosidine and vincoside derivatives

On the basis of the configuration of C-15 of the secologanin unit, using detailed NMR analysis, the configuration of C-3, the solution conformation around C-14, and the glucosidic bridge, as well as those of the dihydropyran and tetrahydropyridine rings, were determined in the vincosamide and strictosamide derivatives 4b and 5b. The stereochemical analysis was extended by chemical correlation to the 4-benzylated strictosidine and vincoside derivatives 3c and 3d. Experimental proof was presented for the interpretation of the "anomalous" chemical shift of acetylated strictosamide derivatives.

[Molecular modeling studies of prolyl endopeptidase inhibitors]. / Prolil endopeptidáz inhibitorok molekulaszerkezeti vizsgálata.

Prolyl endopeptidase, a serine protease is considered to play an important role in the degradation of neuropeptides capable of changing the performance in learning and memory tasks in both animal and human. The inhibitors seem to be promising drug candidates to treat and prevent diseases with associated memory loss such as senile dementia. In the last decade advanced and improved new technologies have appeared to stimulate ideas in the design and synthesis of new drug molecules. The goal of this short communication is to review our results and observations, exemplified by our research on the inhibitors of prolyl endopeptidase. Among them qualitative and quantitative structure-activity relationship studies using conformational analyses, NMR measurements, pharmacophoric plots and CoMFA models are summarised.

[Skin diseases associated with chronic hepatitis C]. / Krónikus C hepatitishez társult börbetegségek.

The authors are discussing hepatic and extrahepatic pathologic processes caused by hepatitis C virus (HCV) infection and they focus their interest to the skin disorders appearing in the presence of chronic, active HCV infections. The trigger of the immunologic processes leading to dermatologic manifestations are the activated T cells (CD8 + cytotoxic T lymphocytes), cytokins, and also the expansion of certain B cells. Pathologic immunologic phenomena may initiate various dermatologic manifestations. Immunoglobulins, immuncomplexes generated by the disease itself are manifested as various forms of cutan vasculitis. In the present series of patients (pts), HCV related skin disorders known from the literature were diagnosed in eleven cases and they were representing 7 different disease entities. These were palpable purpura (3 pts), urticaria, prurigo and alopecia areata (2-2 pts), lichen ruber planus, pruritus and vitiligo (1-1 patient respectively). The case reports of 2 pts, one with palpable purpura (vasculitis purpurica), one with prurigo and vitiligo are presented in details.

[Pulmonary tuberculosis revealed by lupus vulgaris]. / Lupus vulgaris kapcsán felfedezett pulmonalis tuberculosis.

The incidence of pulmonary tuberculosis in Hungary had been significantly decreased until the 1980s and its common cutaneous manifestation was found to be extremely rare. During the past years an increasing number of reports were dealing the novel increasing incidence of tuberculosis, mostly on homeless and immunocompromized persons. The present report dealt with a pulmonary tuberculotic patient on whom severe cutaneous TBC manifestations (lupus vulgaris) that was heralded the underlying systemic tuberculotic disease.

[Neurofibromatosis with abdominal and severe central nervous system complications]. / Neurofibromatosis hasi és súlyos központi idegrendszeri szövódményekkel.

A young male patient suffered in cutaneous neurofibromatosis was followed during four years. He developed tissue proliferations of various histological structures manifested in the skin, central nervous system and different splanchnic organs. The classification criteria of neurofibromatosis as well as the diagnostic and therapeutic recommendations are discussed.

Metabolism of [3-13C]pyruvate and [3-13C]propionate in normal and ischaemic rat heart in vivo: 1H- and 13C-NMR studies.

The oxidation of [3-13C]pyruvate and [3-13C]propionate was studied in vivo in infused rats. The infused [3-13C]pyruvate was quickly converted to [3-13C]lactate in the blood, and the [3-13C]lactate formed was well metabolized in both normoxic and ischaemic hearts. Large differences (200-600%) in the 13C enrichment of alanine (C-3) and acetyl-CoA (C-2) compared with lactate (C-3) were found in both normoxic and ischaemic hearts, suggesting that the extracellular [3-13C]lactate preferentially entered a region of the cytoplasm which specifically transfers the labelled pyruvate (formed from [3-13C]lactate) to the mitochondria. The highly enriched mitochondrial pyruvate gave high enrichment in alanine and acetyl-CoA, which was detected by 1H- and 13C-NMR spectroscopy. Ischaemia increased 13C incorporation into the main cytoplasmic lactate pool and decreased 13C incorporation into citric acid cycle intermediates, mainly decreasing the pyruvate anaplerosis. Isoprenaline-induced ischaemia of the heart caused only a slight decrease in pyruvate oxidation. In contrast to the decreased anaplerosis of pyruvate, the anaplerosis of propionate (and propionyl-carnitine) increased significantly in ischaemic hearts, which may contribute to the protective effect of propionyl-carnitine seen in ischaemia. In addition, we found that [3-13C]propionate preferentially labelled aspartate C-3 in rat heart, suggesting incomplete randomization of label in the succinyl-CoA-malate span of the citric acid cycle. These data show that proton observed 13C edited spectroscopic methods, i.e. heteronuclear spin-echo and the one-dimensional heteronuclear multiple quantum coherence sequence, can be successfully used to study heart metabolism in vivo.

Determination of protonation macro- and microconstants and octanol/water partition coefficient of the antiinflammatory drug niflumic acid.

The drug niflumic acid is an amphoteric substance with overlapping pKa values. The acid-base chemistry of the molecule has been characterized in terms of protonation macroconstants (with reference to stoichiometric ionizations) and microconstants (with reference to ionizations of individual species). The proton-binding sites were assigned using 1H and 13C NMR spectroscopy. Due to the very poor water solubility of niflumic acid, the aqueous pKa values were determined from the apparent ionization constants in methanol-water solutions of various proportions by extrapolation to zero co-solvent using the Yasuda-Shedlovsky procedure. The kz tautomerization microconstant of the equilibrium unionized form<-->zwitterionic form was determined from mixtures of organic solvent (dioxane or methanol) with aqueous buffer (at the pH of isoelectric point) by UV spectroscopy, and used for calculation of the other protonation microconstants. The zwitterionic form of the molecule predominates over the uncharged form, the concentration being maximal at the isoelectric pH. The apparent partition coefficients (Papp) of niflumic acid were measured in octanol/water solution by the shake-flask method over a wide pH range. The lipophilicity profile (logPapp vs pH) shows a parabolic shape near its maximum at the isoelectric point. A relationship derived between Papp, PXH0(micropartition coefficient of the uncharged microspecies) and PX-(partition coefficient of the anion) is valid for amphoteric drugs, in cases where the partition of the unionized form and the ion-pair partition of anion can be confirmed. The logP values of microspecies indicate the high lipophilicity of niflumic acid, which is consistent with its good skin penetration and absorption.

[NMR spectroscopy of selegiline and related compounds]. / Selegilin és rokon vegyületeinek vizsgálata NMR spektroszkópiával.

In the course of the 1H NMR investigation of Selegiline and compounds related to it, the 3J coupling constants of the protons of the alpha and the beta carbon of the beta-phenyl-ethylamine moiety were determined. The rotameric population around the single bond of the alpha and beta carbons were calculated from these values. It is discussed how substituents at the alpha-carbon atom, at the nitrogen atom and on the phenyl ring as well as the solvent influence the conformational equilibria. The optical purity of the samples were determined using chiral europium shift reagents, however different reagents have to be used for primary, secondary and tertiary amine derivatives. The coordination process between p-F-amphetamine and Eu(tcf)3 was studied in detail, the formation constant of the complex and the bound shifts were determined.

Isolation and structure elucidation of new antibiotics related to angolamycin.

Angolamycin (1) and two novel analogues (2 and 3) were isolated from the culture broth of a Streptomyces strain. NMR and MS analysis proved that 2 is the 18-dihydro-, while 3 is the 18-deoxo-18-dihydro derivative of angolamycin. Full experimental assignment of the 1H and the 13C NMR spectra of these compounds was obtained from 1D and 2D chemical shift correlation measurements. Compounds 2 and 3 are less potent antibiotics than angolamycin.

Rearrangement of unsaturated 2,4-O-benzylidenehexitol derivatives into C-glycosylbenzene derivatives.

Acetolysis of (Z)-1,3-di-O-acetyl-2,4-O-benzylidene-6-C-(2,4-dichlorophenyl)-D-xylo-he x- 5-enitol (3) afforded (E)-1,2,3,4-tetra-O-acetyl-6-C-(2,4-dichlorophenyl)-D-xylo-hex-5-enit ol and 2-C-[(R)-acetoxy(2,4-dichlorophenyl)methyl]-3,4,6-tri-O-acetyl-2-deoxy- beta-L-galacto- and -beta-L-gulo-hexopyranosylbenzene. The mechanism of this new rearrangement was studied by exchanging the substituents at C-1 and C-3 in 3 and those of the aromatic ring attached to C-6.

Synthesis of 2,6,7-trideoxy-7-C-(2,4-dichlorophenyl)-D-xylo-heptonic acid and 6-(2,4-dichlorophenyl)-D-xylo-2,3,4-tri-hydroxyhexanesulfonic acid.

2,4-O-Benzylidene-L-xylose was converted via a Wittig reaction into Z-2,4-O-benzylidene-5,6-dideoxy-6-C-(2,4-dichlorophenyl)-D-xylo-hex-5-++ +enitol (17), which, on hydrogenation, gave 5,6-dideoxy-6-C-(2,4-dichlorophenyl)-D-xylo- hexitol (33). tert-Butyldimethylsililation of the primary hydroxyl group of 33, followed by 4-methoxybenzylation, and desilylation afforded 5,6-dideoxy-6-C-(2,4-dichlorophenyl)-2,3,4-tri-O-(4-methoxybenzyl)-D-xyl o- hexitol (54). A Mitsunobu-type reaction of 54 replaced HO-1 by cyanide to give, after hydrolysis and hydrogenolysis, 2,6,7-trideoxy-7-C-(2,4- dichlorophenyl)-D-xylo-heptono-1,4-lactone (55). Mesylation of 33 and then acetylation gave 2,3,4-tri-O-acetyl-5,6-dideoxy- 6-C-(2,4-dichlorophenyl)-1-O-methanesulfonyl-D-xylo-hexitol (63), which was converted via its 1-thiobenzoate into bis[1,5,6-trideoxy-6-C-(2,4-dichlorophenyl)-D-xylo-hexitol] 1,1'-disulfide (65). Acetylation of 65, followed by permanganate oxidation and deacetylation, afforded sodium 6-(2,4-dichlorophenyl)-D-xylo- 2,3,4-trihydroxy-hexanesulfonate (67). Both 57 (obtained from 55 by hydrolysis with NaOH) and 67 are weak inhibitors of HMG-CoA reductase.

Synthesis of 7-(2,4-dichlorophenyl)-D-erythro-3-hydroxy-5-heptanolide, 6-(2,4-dichlorophenyl)-D-erythro-2,4-dihydroxyhexane-1-sulfonic acid, and 6-(2,4-dichlorophenyl)-D-erythro-2,4-dihydroxyhexylphosphonic acid.

6-(2,4-Dichlorophenyl)-D-erythro-1,2,4-hexanetriol, synthesised from D-glucose, was partially silylated, then reacted with 2-methoxypropene to afford 1-O-tert-butyldimethylsilyl-6-(2,4- dichlorophenyl)-2,4-O-isopropylidene-D-erythro-1,2,4-hexanetriol (17). Desilylation of 17 gave 6-(2,4-dichlorophenyl)-2,4-O-isopropylidene-D- erythro-1,2,4-hexanetriol, which was converted into the 1-tosylate 18 and the 1-bromo derivative 19. Reaction of 18 with potassium thiolbenzoate gave, after debenzoylation, oxidation, and deprotection, 6-(2,4-dichlorophenyl)-D-erythro-2,4-dihydroxyhexane-1-sulfonic acid (4). Reaction of 18 or 19 with triethyl phosphite gave, after deprotection, 6-(2,4-dichlorophenyl)-D-erythro-2,4-dihydroxyhexyl-phosphonic acid (5), and reaction of 19 with potassium cyanide gave, after subsequent hydrolysis and deprotection, 7-(2,4-dichlorophenyl)-D-erythro-3-hydroxy-5-heptanolide (3).

Protonation equilibria of quinolone antibacterials.

The acid-base properties of seven antibacterial 7-piperazinyl fluoroquinolone derivatives were studied by potentiometry and UV and NMR spectroscopy. These molecules contain two proton-binding sites of similar basicity, namely, the piperazine amino and the carboxylate groups, as proven by 1H NMR spectroscopy. The basicities are quantitated at the molecular level in terms of macroconstants, and also at the submolecular level in terms of microconstants. The microconstants are then used to calculate the concentration of the positive, zwitterionic, neutral, and negatively charged species (microspeciation). The zwitterionic forms always predominate over their neutral protonation isomers, but the zwitterionic:neutral concentration ratio is considerably different for the examined fluoroquinolone derivatives.