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At least 667 records · Page 37Linked to original sources

PubMed1996

Novel L-lyxo and 5'-deoxy-5'-modified TSAO-T analogs: synthesis and anti-HIV-1 activity.

Novel L-lyxo-TSAO-T analogs with an inverted configuration at the C-4'-position of the sugar moiety and 5'-deoxy-5'-modified TSAO-T derivatives have been prepared and evaluated for their inhibitory effect on human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) replication in cell culture. None of the compounds showed marked antiviral efficacy. The inactivity of the TSAO-T derivatives may most likely be explained by either their different 4'-configuration or their different chemical structure that may not allow an optimal interaction of the molecules with the lipophilic binding pocket of the HIV-1 reverse transcriptase.

Anti-HIV Agents↗

PubMed2001

Cytotoxic and novel compounds from Solanum indicum.

Solavetivone (1), cytotoxic to OVCAR-3 cells with an IC(50) value of 0.1 mM, has been isolated from Solanum indicum. In addition, a novel solafuranone (2) and three known compounds, scopoletin, N-(p-trans-coumaroyl)tyramine, and N-trans-feruloyltyramine, were isolated for the first time from this plant. The structures of the above compounds were established by means of spectroscopic and X-ray analyses.

Antineoplastic Agents, Phytogenic↗

PubMed1993

Synthesis and pharmacological evaluation of a new class of 2-oxo-8-azaspiro (4,5)decan-1-ones as analogues of the muscarinic agonist RS-86.

A new series of 8-substituted-2-oxo-8-azaspiro (4,5)decan-1-ones has been synthesized and compounds tested for their cholinergic properties in comparison with the muscarinic agonist RS-86. Preliminary in vitro and in vivo pharmacological data indicate that none of them is provided with significant cholinergic effects either at central or peripheral level. A possible explanation for the lack of activity is given on the basis of conformational studies.

Animals↗

PubMed1995

New spiropiperidines as potent and selective non-peptide tachykinin NK2 receptor antagonists.

The synthesis of a series of 2-(5-fluoro-1H-indol-3-yl)ethyl spiropiperidines is described together with their tachykinin NK2 receptor affinities measured in a rat colon binding assay. Equivalent NK2 receptor binding affinity was observed for the spirooxazolidinone 3-benzyl-8-[2-(5-fluoro-1H-indol-3-yl)ethyl]-1-oxa-3,8-diazaspiro[4.5] decan-2-one (3a), the imidazolidinone 3-benzyl-8-[2-(5-fluoro-1H-indol-3-yl)ethyl]-1,3,8-triazaspiro[4.5 ] decan-2-one (3s), and the pyrrolidinone 2-benzyl-8-[2-(5-fluoro-1H-indol-3-yl)ethyl]-2,8-diazaspiro[4.5]decan -3 - one (3t). Substitution in the phenyl ring of compound 3a produced no significant enhancement in NK2 binding affinity. Replacement of the phenyl ring in 3a with other aromatic rings resulted in a significant loss in binding affinity. Compound 3a was shown to be a potent NK2 receptor antagonist in guinea pig trachea where it also demonstrated 1000-fold selectivity for NK2 receptors over NK1. In the anesthetized guinea pig, compound 3a administered by the intravenous or oral route displayed potent and long-lasting antagonist activity against NK2 receptor agonist induced bronchoconstriction.

Animals↗

PubMed1986

Synthesis and biological evaluation of 1-(1,2-benzisothiazol-3-yl)- and (1,2-benzisoxazol-3-yl)piperazine derivatives as potential antipsychotic agents.

Members of the series of title compounds were tested for potential antipsychotic activity in relevant receptor binding assays and behavioral screens. Structure-activity relationships within the series are discussed. Compound 24 (BMY 13859-1), a (1,2-benzisothiazol-3-yl)piperazine derivative, was selected for further study because of its potent and selective profile in primary CNS tests. It was active in the Sidman avoidance paradigm and blocked amphetamine-induced stereotyped behavior in dogs for up to 7 h. The compound's lack of typical neuroleptic-like effects in the rat catalepsy test and its failure to produce dopamine receptor supersensitivity following chronic administration indicate that it should not cause the movement disorders commonly associated with antipsychotic therapy. Although 24 has potent affinity for dopaminergic binding sites, its even greater affinity for serotonin receptors suggests that a serotonergic component may be relevant to its atypical profile. Compound 24 is currently undergoing clinical evaluation in schizophrenic patients.

Animals↗

PubMed2006

Antimalarial activity of crambescidin 800 and synthetic analogues against liver and blood stage of Plasmodium sp.

Structural features associated with the antimalarial activity of the marine natural product crambescidin 800 were studied using synthetic analogues of the related compound ptilomycalin A. The study suggests that the guanidine moiety is cytotoxic, whereas the spermidine-containing aliphatic chain increases activity. The most active analogue, compound 11, had in vitro activity against Plasmodium falciparum strain 3D7 (IC50=490 nM) that was stronger than the in vitro activity against murine L5178Y cells (IC50 = 8.5-59 microM). In vitro growth inhibition of liver stages of P. yoelii yoelii in mouse hepatocytes was observed (IC50 = 9.2 microM). The compound did not significantly prolong median survival time after a single subcutaneous administration of 80 mg/kg in P. berghei-infected mice. Compound 11 did not cause DNA fragmentation in an in vitro micronucleus assay.

Animals↗

PubMed1994

Characterization of natural toxins with inhibitory activity against serine/threonine protein phosphatases.

Recent studies suggest that the ability to inhibit the activity of certain serine/threonine protein phosphatases underlies the toxicity of several natural compounds including: okadaic acid, microcystin-LR, nodularin, calyculin A and tautomycin. To characterize further the actions of these toxins, this study compares the inhibitory effects of okadaic acid, chemical derivatives of okadaic acid, microcystin-LR, microcystin-LA, nodularin, calyculin A and tautomycin on the activity of serine/threonine protein phosphatases types 1 (PP1), 2A (PP2A) and a recently identified protein phosphatase purified from bovine brain (PP3). This study shows that, like PP1 and PP2A, the activity of PP3 is potently inhibited by okadaic acid, both microcystins, nodularin, calyculin A and tautomycin. Further characterization of the toxins employing the purified catalytic subunits of PP1, PP2A and PP3 under identical experimental conditions indicates that: (a) okadaic acid, microcystin-LR, and microcystin-LA inhibit PP2A and PP3 more potently than PP1 (order of potency PP2A > PP3 > PP1); (b) nodularin inhibits PP1 and PP3 at a similar concentration that is slightly higher than that which affects PP2A, and (c) both calyculin A and tautomycin show little selectivity among the phosphatases tested. This study also shows that the chemical modification of the (C1) carboxyl group of okadaic acid can have a profound influence on the inhibitory activity of this toxin. Esterification of okadaic acid, producing methyl okadaate, or reduction, producing okadaol, greatly decreases the inhibitory effects against all three enzymes tested. Further reduction, producing 1-nor-okadaone, or acetylation, producing okadaic acid tetraacetate, results in compounds with no inhibitory activity. In contrast, the substitution of alanine (-LA) for arginine (-LR) in microcystin has no apparent effect on the inhibitory activity against PP1, PP2A or PP3.

Animals↗

PubMed1992

Applications of the improved computerized analysis of 2D INADEQUATE spectra.

This paper illustrates the use of the program CCBond to determine the carbon skeletons of bioorganic molecules in low concentration samples. Discussed is the structure elucidation of bistramide A, a compound extracted from a Fijian Lissoclinum sp. and cholesterol in 71- and 20-mumol samples, respectively. The detection limit of the automated bond extraction is shown to be dramatically improved compared to the manual interpretation of 2D INADEQUATE spectra.

Acetamides↗

PubMed1981

Fredericamycin A, a new antitumor antibiotic. I. Production, isolation and physicochemical properties.

A new antitumor antibiotic, fredericamycin A (FCRC-A48, NSC-305263), has been isolated from a strain of Streptomyces griseus (FCRC-48). Based on its unique ultraviolet-visible spectrum, infrared spectrum, proton and carbon-13 nuclear magnetic resonance spectra and mass spectra, it is judged to be a novel acid-base indicator type of compound. Its production, isolation and physicochemical properties are discussed. The isolation, ultraviolet-visible spectrum and some biological properties of two minor components, fredericamycin B and fredericamycin C, are also described.

Antibiotics, Antineoplastic↗

PubMed1994

Synthesis and aldose reductase inhibitory activity of 2-substituted-6-fluoro-2,3-dihydrospiro [4H-1-benzopyran-4, 4'-imidazolidine]-2',5'-diones.

Optically active and racemic 2-substituted-6-fluoro-2,3-dihydrospiro[4H-1-benzopyran-4, 4'-imidazolidine]-2',5'-diones were synthesized from (+)-, (-)-, and (+-)-6-fluoro-3,4-dihydro-4-oxo-2H-1-benzopyran-2-carboxylic acid. These compounds were then evaluated for in vitro and in vivo aldose reductase inhibitory activity. The 2S,4S isomers were found to be more potent aldose reductase inhibitors than the other corresponding stereoisomers. Among these compounds, (2S,4S)-6-fluoro-2,3-dihydro-2',5'-dioxospiro[4H-1-benzopyran-4, 4'-imidazolidine]-2-carboxamide ((+)-1b, SNK-860, CAS 105300-43-4) showed the most potent in vitro and in vivo activity.

Aldehyde Reductase↗

PubMed1997

Down-regulation of G-protein-mediated Ca2+ sensitization in smooth muscle.

Prolonged treatment with guanosine 5'-[gamma-thio]triphosphate (GTP gamma S; 5-16 h, 50 microM) of smooth muscle permeabilized with Staphylococcus aureus alpha-toxin down-regulated (abolished) the acute Ca2+ sensitization of force by GTP gamma S, AIF-4, phenylephrine, and endothelin, but not the response to phorbol dibutyrate or a phosphatase inhibitor, tautomycin. Down-regulation also abolished the GTP gamma S-induced increase in myosin light chain phosphorylation at constant [Ca2+] and was associated with extensive translocation of p21rhoA to the particulate fraction, prevented its immunoprecipitation, and inhibited its ADP ribosylation without affecting the immunodetectable content of G-proteins (p21rhoA, p21ras, G alpha q/11, G alpha i3, and G beta) or protein kinase C (types alpha, beta 1, beta 2, delta, epsilon, eta, theta, and zeta). We conclude that the loss of GTP gamma S- and agonist-induced Ca2+ sensitization through prolonged treatment with GTP gamma S is not due to a decrease in the total content of either trimeric (G alpha q/11, G alpha i3, and G beta) or monomeric (p21rhoA and p21ras) G-protein or protein kinase C but may be related to a structural change of p21rhoA and/or to down-regulation of its (yet to be identified) effector.

Aluminum Compounds↗

PubMed2003

In vivo comparison of two 5-HT1A receptors agonists alnespirone (S-20499) and buspirone on locus coeruleus neuronal activity.

The aim of the present study was to compare, in chloral-hydrate anaesthetized rats, the alpha(2)-adrenergic properties of the selective 5-HT(1A) receptor agonist, alnespirone (S-20499), with those of buspirone, a 5-HT(1A) receptor agonist exhibiting potent alpha(2)-adrenoceptor antagonist properties via its principal metabolite, 1-(2-pyrimidinyl)-piperazine. Both locus coeruleus spontaneous firing activity and noradrenaline release in the medial prefrontal cortex were potently inhibited by the alpha(2)-adrenoceptor agonist clonidine, at a dose of 40 microg/kg (i.p.). Such an inhibition was neither prevented nor reversed by alnespirone (10 mg/kg, i.p.), while buspirone, at the same dose, potently antagonized the locus coeruleus inhibitory effects of clonidine. These data demonstrate that, in contrast with some aryl-piperazine compounds (such as buspirone), alnespirone, either on its own or via a possible metabolite such as buspirone, is devoid in vivo of significant alpha(2)-adrenoceptor antagonist properties.

Animals↗

PubMed1993

Nanomolar-affinity, non-peptide oxytocin receptor antagonists.

Non-peptide antagonists of the peptide hormone oxytocin (OT) with nanomolar OT receptor affinities are described. These compounds incorporate novel amido- and amidoalkylcamphor variations to the lead structure L-366,509 (1) to achieve receptor affinity enhancements of 2-3 orders of magnitude over that compound. The new OT antagonist L-367,773 (35) is shown to be an orally bioavailable agent with good duration in vivo and to inhibit OT-stimulated uterine contractions effectively in several in vitro and in vivo models.

Animals↗

PubMed2001

[GC-MS analysis of essential oils from rhizomes of Atractylodes lancea (Thunb.) DC. and A. chinensis (DC.) Koidz].

OBJECTIVE: To analyze the constituents from the rhizomes of Atractylodes lancea and A. chinensis in essential oils. METHOD: GC-MS method was used. RESULT: 32 and 29 compounds were identified respectively. CONCLUSION: The main constituents in the essential oils from the rhizome of A. chinensis are beta-eudesmol or a mixture of beta-eudesmol and atractylone, whereas from that of A. lancea are hinesol, a mixture of beta-eudesmol and atractylone, and atractylone.

Atractylodes↗

PubMed1990

[Plasma kinetics of a spiroarsorane trypanocidal agent in sheep trypanosomiasis].

In a previous study, spiroarsoranes were very effective against both the two pathogenic phases of the experimental sheep trypanosomiasis. In this paper, the authors had studied the plasmatic pharmacokinetics of these compounds. Data had shown one peak 10 min after injection of a 3 months inoculated sheep, and 90 min for the control sheep. Spiroarsorane had a good diffusion into the central nervous system, but the trypanocidal activity, during the second phase of the disease, was effective only after repeated treatment. The spiroarsorane low toxicity could allow its direction against nervous trypanosomiasis.

Animals↗

PubMed2005

Norpiperidine imidazoazepines as a new class of potent, selective, and nonsedative H1 antihistamines.

Clinical doses of available H(1) antihistamines are limited mainly by sedative side effects. However, higher doses are often required to obtain optimal therapeutic activity, especially in dermatology. We report the synthesis of three norpiperidine imidazoazepines representative of a new class of selective and nonsedating H(1) antihistamines. The compounds were at least as potent as cetirizine and loratadine as measured by H(1) receptor binding affinity, by protection against compound 48/80- and histamine-induced lethality in rats and guinea pigs, respectively, and by skin reaction tests in rats, guinea pigs, and dogs. The compounds, in particular 3a, were less prone than the reference compounds to penetrate the brain and to occupy central H(1) receptors, suggesting absence of sedative side effects. In vitro and in vivo cardiovascular safety tests showed that 3a had no intrinsic potential to prolong ventricular repolarization or induce cardiac arrhythmias. Compound 3a has been selected for further clinical development, mainly for application in dermatology.

Anaphylaxis↗

PubMed1995

A paradigm for drug discovery employing encoded combinatorial libraries.

Very large combinatorial libraries of small molecules on solid supports can now be synthesized and each library element can be identified after synthesis by using chemical tags. These tag-encoded libraries are potentially useful in drug discovery, and, to test this utility directly, we have targeted carbonic anhydrase (carbonate dehydratase; carbonate hydro-lyase, EC 4.2.1.1) as a model. Two libraries consisting of a total of 7870 members were synthesized, and structure-activity relationships based on the structures predicted by the tags were derived. Subsequently, an active representative of each library was resynthesized (2-[N-(4-sulfamoylbenzoyl)-4'-aminocyclohexanespiro]-4-oxo-7 -hydroxy- 2,3-dihydrobenzopyran and [N-(4-sulfamoylbenzoyl)-L-leucyl]piperidine-3-carboxylic acid) and these compounds were shown to have nanomolar dissociation constants (15 and 4 nM, respectively). In addition, a focused sublibrary of 217 sulfamoylbenzamides was synthesized and revealed a clear, testable structure-activity relationship describing isozyme-selective carbonic anhydrase inhibitors.

Benzopyrans↗

PubMed1993

Design, synthesis and biological study of new antiparasitic spiroarsoranes.

Thirty-eight new spiroarsoranes were synthesized after structure-activity relationship studies from the first series. These compounds were predicted to cross more easily the membrane of protozoae or the cuticle of Nematodes and to reach their biological target with efficiency. The spiroarsoranes were evaluated for their antiparasitic properties, on helminths and protozoa models in regard of their parent arsonic acids. The following parasite models were used: Entamoeba histolytica and Trichomonas vaginalis in vitro; Molinema dessetae infective larvae in vitro, adults and microfilariae in vivo; Nippostrongylus brasiliensis infective larvae in vitro. The results obtained on these models indicated that the "spiranization" of arsonic acids produced new compounds with a biological activity 10-fold superior to those of arsonic acids. Nevertheless, each parasite had its own sensitivity to spiroarsoranes. Moreover, in vivo results showed that the lipophilicity of the molecules should be optimal to avoid high toxicity in host such as arsenical encephalopathy.

Animals↗