Biomedical subjects

Jerzy W Jaroszewski

Publications and source records attributed to Jerzy W Jaroszewski.

At least 19 recordsLinked to original sources

PubMed2004

Solid-phase synthesis of rigid acylpolyamines using temporary N-4,4'-dimethoxytrityl protection in the presence of trityl linkers.

An N-protection protocol employing the 4,4'-dimethoxytrityl (Dmt) group in combination with borane reduction of resin-bound polyamides was shown to be an efficient methodology that enables synthesis of novel analogues of natural acylpolyamine toxins. Thus, three philanthotoxins containing polyamine chains with piperidyl and cyclohexyl structural elements, which introduce conformational rigidity, increased lipophilicity, and altered proteolytic properties, were obtained in 39-44% overall yield.

Boranes↗

PubMed2004

Carbamoylcholine homologs: synthesis and pharmacology at nicotinic acetylcholine receptors.

In a recent study, racemic 3-(N,N-dimethylamino)butyl-N,N-dimethylcarbamate (1) was shown to be a potent agonist at neuronal nicotinic acetylcholine receptors with a high selectivity for nicotinic over muscarinic acetylcholine receptors [Mol. Pharmacol. 64 (2003) 865-875]. Here we present the synthesis and pharmacological characterization of a series of analogs of, where the methyl group at C-3 has been replaced by different alkyl substituents. Ring systems have been incorporated into the carbon backbone of some of the molecules, or the amino group has been build into ring systems. Furthermore, the (+)- and (-)-enantiomers of have been separated, and X-ray crystallography has revealed that (-)-1 possesses (S)-configuration. The compounds have been characterized pharmacologically at recombinant nicotinic receptor subtypes. The structure-activity relationship study has provided valuable insight into the mode of interactions of and its analogs with neuronal nicotinic acetylcholine receptors.

Animals↗

PubMed2004

Expedient protocol for solid-phase synthesis of secondary and tertiary amines.

[reaction: see text] An expedient solid-phase synthetic approach to secondary and tertiary amines was developed. The protocol employs conversion of resin-bound amino alcohols to the corresponding iodides, followed by iodide displacement with primary or secondary amines or with unprotected amino alcohols. This two-step procedure, affording products in good to excellent yields, is suitable for solid-phase synthesis of polyamines.

Journal Article↗

PubMed2004

Erythrocyte membrane modifying agents and the inhibition of Plasmodium falciparum growth: structure-activity relationships for betulinic acid analogues.

The natural triterpene betulinic acid and its analogues (betulinic aldehyde, lupeol, betulin, methyl betulinate and betulinic acid amide) caused concentration-dependent alterations of erythrocyte membrane shape towards stomatocytes or echinocytes according to their hydrogen bonding properties. Thus, the analogues with a functional group having a capacity of donating a hydrogen bond (COOH, CH(2)OH, CONH(2)) caused formation of echinocytes, whereas those lacking this ability (CH(3), CHO, COOCH(3)) induced formation of stomatocytes. Both kinds of erythrocyte alterations were prohibitive with respect to Plasmodium falciparum invasion and growth; all compounds were inhibitory with IC(50) values in the range 7-28 microM, and the growth inhibition correlated well with the extent of membrane curvature changes assessed by transmission electron microscopy. Erythrocytes pre-loaded with betulinic acid or its analogues and extensively washed in order to remove excess of the chemicals could not serve as hosts for P. falciparum parasites. Betulinic acid and congeners can be responsible for in vitro antiplasmodial activity of plant extracts, as shown for Zataria multiflora Boiss. (Labiatae) and Zizyphus vulgaris Lam. (Rhamnaceae). The activity is evidently due to the incorporation of the compounds into the lipid bilayer of erythrocytes, and may be caused by modifications of cholesterol-rich membrane rafts, recently shown to play an important role in parasite vacuolization. The established link between erythrocyte membrane modifications and antiplasmodial activity may provide a novel target for potential antimalarial drugs.

Animals↗

PubMed2004

Antiplasmodial constituents of Cajanus cajan.

Bioactivity-guided fractionation of extracts of roots and leaves of Cajanus cajan afforded 8 compounds: betulinic acid, biochanin A, cajanol, genistein and 2'-hydroxygenistein, longistylin A and C, and pinostrobin. The two stilbenes, longistylin A and C, and betulinic acid showed a moderately high in vitro activity against the chloroquine-sensitive Plasmodium falciparum strain 3D7.

Animals↗

PubMed2004

Antifungal constituents of Melicope borbonica.

Fractionation of extracts of the leaves of Melicope borbonica (syn. Euodia borbonica var. borbonica), a medicinal plant from the Réunion Island that is traditionally used for wound healing and other ailments, afforded an acetophenone (xanthoxylin) and two coumarins, scoparone and limettin, as the major constituents. All three compounds exhibited moderate antifungal activity against Candida albicans and Penicillium expansum, in accordance with the traditional use of the plant. Moreover, 2,4,6-trimethoxyacetophenone (methylxanthoxylin), three other coumarins [7-(3-methyl-2-butenyloxy)-6-methoxycoumarin, cedrelopsin and psoralen], two sesquiterpenes (alpha-curcumene and 3,6-epidioxy-1,10-bisaboladiene), eugenol, methyleugenol and a lignan (sesamin) were isolated. None of the isolated constituents exhibited antiin fl ammatory activity in vitro. No alkaloids were detected.

Antifungal Agents↗

PubMed2004

Labdanes and isopimaranes from Platycladus orientalis and their effects on erythrocyte membrane and on Plasmodium falciparum growth in the erythrocyte host cells.

Six labdanes (1-6) and four isopimaranes (7-10), including three new natural products (7, 9, and 10), were isolated from Platycladus orientalis, and their structures determined using 1D and 2D NMR methods, ion-cyclotron resonance HRMS, and optical rotation data. Relative configurations of all chiral centers in the isopimaranes were determined using NOESY experiments at 600 and 800 MHz. Specific optical rotation data were used to correlate absolute configurations. Compounds 1-9 and aframodial (11) were tested for their in vitro antiplasmodial activity and for their ability to induce changes of erythrocyte shape in order to obtain data about possible correlation between the two effects. All compounds tested exhibited weak (IC(50) > 25 microM) in vitro antiplasmodial effects against Plasmodium falciparum strain 3D7. At the same time, the compounds caused echinocytic or stomatocytic changes of the erythrocyte membrane curvature, indicative of their incorporation into the lipid bilayer, in the concentration region where the antiplasmodial activity was observed. The antiplasmodial effect of these compounds thus appears to be an indirect effect on the erythrocyte host cell. Weak or moderate antiplasmodial activity observed with many other apolar natural products, in particular those with amphiphilic structures, is also likely to be an indirect effect.

Animals↗

PubMed2004

Isolation of a library of aromadendranes from Landolphia dulcis and its characterization using the VolSurf approach.

A library of nine aromadendrane-type sesquiterpenes (1-9), including eight new natural products (1-5 and 7-9), was isolated from Landolphia dulcis var. barteri along with a previously described cadinane derivative (10) and a new muurolane derivative (11). The structures of all compounds were established by means of NMR methods including COSY, NOESY, HSQC, and HMBC experiments, supported by HRMS and optical rotation data. Virtual characterization of the aromadendrane library (1-9) was performed using chemoinformatics tools. 3D molecular fields were calculated with the GRID program using low-energy structures obtained with the MMFF force field. VolSurf descriptors were calculated from the GRID maps and subsequently analyzed by multivariate statistics. The analysis disclosed the presence of a common motif for possible interactions of the aromadendranes with a putative target receptor. At the same time, a considerable chemical diversity within the library was disclosed, despite a close biosynthetic relationship of its members. The results can be interpreted in terms of evolutionary optimization of structures of secondary metabolites for interaction with macromolecular targets and are of interest in terms of assessment of potential "drug-likeness" of natural products.

Apocynaceae↗

PubMed2004

Ancistrotanzanine C and related 5,1'- and 7,3'-coupled naphthylisoquinoline alkaloids from Ancistrocladus tanzaniensis.

Three new naphthylisoquinoline alkaloids, the 7,3'-coupled ancistrotanzanine C (6), the 5,1'-coupled O-methylancistrocladinine (7), and the likewise 5,1'-coupled O,N-dimethylancistrocladine (8, previously known only as a partial-synthetic compound), have been isolated from the highland liana Ancistrocladus tanzaniensis, along with the two known 7,3'-coupled naphthylisoquinoline alkaloids ancistrocladidine (4) and ancistrotectorine (5). All of the compounds are S-configured at C-3 and bear an oxygen at C-6, and thus belong to the so-called Ancistrocladaceae type, similar to 1-3 previously isolated from this newly discovered plant species. The structural elucidation was achieved by chemical, spectroscopic, and chiroptical methods. The biological activities of the alkaloids against the pathogens causing malaria tropica, leishmaniasis, Chagas' disease, and African sleeping sickness were evaluated.

Alkaloids↗

PubMed2004

Cyclopentanoid cyanohydrin glucosides and amides of Lindackeria dentata.

A mixture of cyanogenic glucosides epivolkenin and taraktophyllin, 1,4-dihydroxy-2-cyclopentenecarboxamide, and uridine were isolated from leaves of Lindackeria dentata (Flacourtiaceae). Another cyclopentanoid amide, (1 R,4 S,5 R)-1,4,5-trihydroxy-2-cyclopentenecarboxamide, was synthesized in two steps from gynocardin, and shown to have the same relative configuration as a partially identified amide previously isolated from L. dentata bark.

Amides↗

PubMed2004

Selagoline, a new alkaloid from Huperzia selago.

A new natural product, named selagoline, and two known alkaloids, huperzine A and serratidine, were isolated from Huperzia selago (Lycopodiaceae) collected in Iceland. Their structures were determined using 600 and 800MHz one- and two-dimensional NMR methods supported by Fourier-transform mass spectrometry. Possible role of selagoline as a precursor of 5,15-oxidolycopodane, a component of the classical alkaloids L28 and L31, is discussed.

Alkaloids↗

PubMed2004

The antiparasitic compound licochalcone a is a potent echinocytogenic agent that modifies the erythrocyte membrane in the concentration range where antiplasmodial activity is observed.

The well-known antiparasitic compound licochalcone A is a potent membrane-active agent that transforms normal erythrocytes into echinocytes in parallel with the inhibition of growth of Plasmodium falciparum cultures, the in vitro antiplasmodial effect apparently being an indirect effect on the host cell. In vitro experiments with synchronous cultures demonstrate that inhibition of invasion is the principal mechanism of growth inhibition. The erythrocyte membrane-modifying effect was also transiently observed in vivo in mice after intravenous administration.

Animals↗

PubMed2003

Solid-phase polyamine synthesis using piperazine and piperidine building blocks.

[reaction: see text]. Polyamines containing piperidine and piperazine moieties have been synthesized on solid support using SN2 alkylation of resin-bound secondary amines with 2-nitrobenzenesulfonates (nosylates). The effect of solvent on this alkylation was investigated. The methodology was employed for the total synthesis of novel analogues of wasp polyamine toxins (philanthotoxins).

Journal Article↗

PubMed2003

A new class of spermidine-derived alkaloids.

[structure: see text] Four new alkaloids, dovyalicins A-D, were isolated from Dovyalis macrocalyx. Their structures were established by two-dimensional COSY, NOESY, HSQC, and HMBC NMR experiments as well as chiroptical methods. The compounds, possessing spermidine as part of a perhydro-1,5-diazocine or a perhydro-1,4-diazepine moiety, constitute a new group of polyamine-derived alkaloids.

Journal Article↗

PubMed2003

A sequential high-yielding large-scale solution-method for synthesis of philanthotoxin analogues.

A general, improved procedure for rapid synthesis of philanthotoxin analogues, a pharmacologically important class of polyamine conjugates, is described. The solution-phase procedure is illustrated by gram-scale synthesis of philanthotoxins PhTX-343 and PhTX-12. Selectively protected polyamines are coupled to N(alpha)-Fmoc-protected amino acid pentafluorophenyl esters. After removal of the N(alpha)-Fmoc group, the amine is coupled with carboxylic acid pentafluorophenyl esters. Deprotection followed by a rapid and efficient purification by vacuum liquid chromatography on octadecylsilyl silica (RP-18 phase) gave the philanthotoxin analogues in 74-78% overall yield.

Chromatography, Liquid↗

PubMed2003

Ancistrotanzanine A, the first 5,3'-coupled naphthylisoquinoline alkaloid, and two further, 5,8'-linked related compounds from the newly described species Ancistrocladus tanzaniensis.

The first phytochemical investigation of the recently discovered East African liana Ancistrocladus tanzaniensis is described, resulting in the isolation and structural elucidation of two new naphthylisoquinoline alkaloids, ancistrotanzanines A (5) and B (6), and the known compound ancistrotectoriline A (7). Ancistrotazanine A (5) represents a hitherto unprecedented 5,3'-coupling type between the naphthalene and isoquinoline portions, while 6 and 7 are 5,8'-coupled. The structures of the compounds were determined by spectroscopic, chemical, and chiroptical methods. Compounds 5 and 6 showed good activities against the pathogens of leishmaniasis and Chagas' disease, Leishmania donovani and Trypanosoma cruzi, while 5-7 displayed moderately potent antiplasmodial activities against Plasmodium falciparum parasites.

Alkaloids↗

PubMed2003

Terpenoids of Salvia hydrangea: two new, rearranged 20-norabietanes and the effect of oleanolic acid on erythrocyte membranes.

Four abietane-type terpenoids, including two known royleanones and two new, rearranged 20-norabietanes, were isolated from the roots of the Iranian medicinal plant Salvia hydrangea DC. ex Bentham (Lamiaceae), which is used as an anthelmintic and antileishmanial remedy. Their structures were established using COSY, NOESY, HSQC, and HMBC spectral data. The possible identity of one of the 20-norabietanes with demethylmulticauline, previously reported from a different Salvia species, is discussed. A moderate in vitro antiplasmodial effect of the extract of S. hydrangea flowers was found to be associated with the presence of large amounts of pentacyclic triterpenes, mainly oleanolic acid. The observed antiplasmodial activity of oleanolic acid is apparently due to its incorporation into the erythrocyte membrane, which adversely affects the growth of Plasmodium falciparum parasites. Thus, oleanolic acid caused transformation of erythrocytes into stomatocytes in the concentration range where the in vitro antiplasmodial activity was observed.

Abietanes↗

PubMed2003

Contrasting actions of philanthotoxin-343 and philanthotoxin-(12) on human muscle nicotinic acetylcholine receptors.

Whole-cell recordings and outside-out patch recordings from TE671 cells were made to investigate antagonism of human muscle nicotinic acetylcholine receptors (nAChR) by the philanthotoxins, PhTX-343 and PhTX-(12). When coapplied with acetylcholine (ACh), PhTX-343 caused activation-dependent, noncompetitive inhibition (IC50 = 17 microM at -100 mV) of whole-cell currents that was strongly voltage-dependent. However, preapplication of PhTX-343 unveiled a voltage-independent antagonism that also required receptor activation, which is suggestive of desensitization enhancement. In single-channel studies, 10 microM PhTX-343 significantly reduced the mean open time of channel openings evoked by 1 microM ACh from 4.42 +/- 0.44 to 1.58 +/- 0.10 ms with a minor increase (1.26-fold) in mean closed time. These data indicate that PhTX-343 predominantly blocks the open channel gated by ACh. In contrast, PhTX-(12) caused potent (IC50 = 0.77 microM at-100 mV), activation-dependent, noncompetitive inhibition of ACh-induced whole-cell currents that was only weakly voltage-dependent and suggestive of desensitization enhancement. It caused only a small decrease (7.5%) in the mean open time of channel openings induced by 1 microM ACh, whereas the mean closed time was significantly increased from 200 +/- 45 ms to 586 +/- 145 ms. The different voltage-dependencies of the two modes of action of these philanthotoxins suggest two binding sites, one deep in the nAChR pore, the other near the extracellular entrance to the pore.

Cells, Cultured↗