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PubMed1994

(Fluorocyclopropyl)quinolones. 2. Synthesis and Stereochemical structure-activity relationships of chiral 7-(7-amino-5-azaspiro[2.4]heptan-5-yl)-1-(2-fluorocyclopropyl)quinolone antibacterial agents.

A series of novel chiral 7-(7-amino-5-azaspiro[2.4]heptan-4-yl)-8-chloro-1-(2-fluo rocyclopropyl)- quinolones were synthesized as a continuation of a research project of 1-(2-fluorocyclopropyl)-quinolones by considering stereochemical and physicochemical properties of the molecule. Absolute configurations of the 1-(cis-2-fluorocyclopropyl) moiety and the 7-(7-amino-5-azaspiro-[2.4]heptan-5-yl) moiety were determined by X-ray crystallographic analysis. Stereochemical structure-activity relationship studies indicated that 1-[(1R,2S)-2-fluorocyclopropyl] and 7-[(7S)-amino-5-azaspiro[2.4]heptan-5-yl] derivatives are more potent against Gram-positive and Gram-negative bacteria than the other stereoisomers and 7-[(7S)-7-amino-5-azaspiro[2.4]-heptan-5-yl]-8-chloro-1-[(1R ,2S)-2- fluorocyclopropyl]quinolone (33) is the most potent of all stereoisomers. Pharmacokinetic profiles and physicochemical properties of the selected compounds were also examined, and it was found that 33 (DU-6859a) possesses moderate lipophilicity and good pharmacokinetic profiles.

Animals↗
PubMed2001

New sesquiterpene derivatives from the red alga Laurencia scoparia. Isolation, structure determination, and anthelmintic activity.

Eleven sesquiterpenes (1-11) and one long chain aldehyde (12) have been isolated from the dichloromethane extract of the red alga Laurencia scoparia. Four of them are new natural products. Scopariol (1) is a new natural product with an unusual rearranged chamigrane-type structure. The other three are beta-chamigrenes: isorigidol (2), (+)-3-(Z)-bromomethylidene-10 beta-bromo-beta-chamigrene (3), and (-)-3-(E)-bromomethylidene-10 beta-bromo-beta-chamigrene (4). The in vitro activity of compounds 1-12 against the parasitant stage of Nippostrongylus brasiliensis (L4) has been studied.

Animals↗
PubMed1994

Production of cladospirone bisepoxide, a new fungal metabolite.

Cladospirone bisepoxide (1), a novel metabolite, was isolated from cultures of a fungus which was characterized as a coelomycete by the formation of pycnidia. By optimization of media and fermentation conditions, a titer of up to 1.5 g/liter on shake level and 1.16 g/liter on bioreactor scale could be achieved. The isolation of the compound was performed by solvent extraction of the culture broth and subsequent crystallization. Cladospirone bisepoxide displays selective antibiotic activity against several bacteria and fungi and inhibits germinations of Lepidium sativum at low concentrations.

Anti-Bacterial Agents↗
PubMed2001

Spiroiminodihydantoin is the major product of the 8-oxo-7,8-dihydroguanosine reaction with peroxynitrite in the presence of thiols and guanosine photooxidation by methylene blue.

[reaction: see text]. The potent oxidant, peroxynitrite, will oxidize 8-oxo-7,8-dihydroguanosine to give several products. In the presence of a thiol agent, the major final product has been determined to be a spiroiminodihydantoin compound. Additionally, we have found that the spiroiminodihydantoin, and not the previously reported 4-hydroxy-8-oxo-4,8-dihydroguanosine, is the major final product formed during the methylene blue-mediated photooxidation of guanosine.

Chromatography, High Pressure Liquid↗
PubMed1994

Synthesis of new 16-spirosteroids.

Reaction of estrone methyl ether 1 with sodium hydride and 1,3-dibromopropane, 1,4-dibromobutane, and 1,5-dibromopentane, respectively, gives the 16-spirosteroid derivatives 2-4, which were reduced to the 17 beta-alcohols 7-9. Acetylation afforded the acetates 10-12. In the reaction of 1 and 1,3-dibromopropane a bis-allyl compound 5 and an annulated dihydropyran 6 were also formed. Cleavage of the ether moiety in 2 and 3 was accomplished with diisobutylaluminum hydride to give 3,17 beta-diols 13 and 14, respectively.

Acetylation↗
PubMed2004

Hybrids of [TSAO-T]-[foscarnet]: The first conjugate of foscarnet with a non-nucleoside reverse transcriptase inhibitor through a labile covalent ester bond.

This paper describes the first example of combination of non-nucleoside reverse transcriptase inhibitors such as TSAO derivatives and foscarnet (PFA) in a single molecule through a labile covalent ester bond. The essential criteria in the design of these hybrids [TSAO-T]-[PFA] was to explore if the conjugation of foscarnet with the highly lipophilic TSAO derivative may facilitate the penetration of the conjugates through the cell membrane and if the hybrids escape extracellular hydrolysis and regenerate the parent inhibitors intracellulary. Several [TSAO-T]-[PFA] conjugates proved markedly inhibitory to HIV-1. Some of them also showed potent activity against PFA-resistant HIV-1 strains but fewer had detectable inhibitory activity against TSAO-resistant HIV-1 strains. These results indicated a pivotal role of the TSAO component of the hybrid but not the PFA component in the activity of the conjugates. Moreover, stability studies of the [TSAO-T]-[PFA] conjugates demonstrated that the compounds were stable in PBS whereas some of the conjugates regenerated the parent inhibitors in extracts from CEM cells.

Cell Extracts↗
PubMed1987

The effects of cannabinoids and cannabispiro compounds on Escherichia coli adhesion to tissue culture cells and on leukocyte functions in vitro.

delta 9-Tetrahydrocannabinol, cannabidiol, cannabidiolic acid, tetrahydrocannabidiolic acid, cannabispirol, acetylcannabispirol, cannabispirone, and cannabispirenone in a low concentration did not affect the adhesion of Escherichia coli on cultured HEp-2 cells. Cannabinoids at 10(-6) M increased the chemiluminescence of human polymorphonuclear leukocytes, while the cannabispiro compounds failed to enhance the oxidative burst of leukocytes. In lymphocyte and granulocyte function tests (E- and EA-rosette formation, blast transformation of T-lymphocytes in the presence of phytohaemagglutinin and concanavalin-A, ADCC and phagocytosis) all compounds displayed immunosuppressive effect at 1.5 X 10(-5) M. Tetrahydrocannabidiolic acid exerted the weakest immunosuppression on human leukocyte functions.

Antibody-Dependent Cell Cytotoxicity↗
PubMed2005

Bioactive deoxypreussomerins and dimeric naphthoquinones from Diospyros ehretioides fruits: deoxypreussomerins may not be plant metabolites but may be from fungal epiphytes or endophytes.

Deoxypreussomerin derivatives, palmarumycins JC1 (1) and JC2 (2), and two dimeric naphthoquinones, isodiospyrin (3) and its new derivative isodiospyrol A (4), were isolated from dried fruits of Diospyros ehretioides. Structures of the isolated compounds were elucidated by spectroscopic analyses. Palmarumycins were not found in the extract of freshly collected fruits; however, they were present in dried fruit extract. The absence of palmarumycins in fresh fruits of D. ehretioides, together with the chemotaxonomic point of view, we proposed that palmarumycins JC1 (1) and JC2 (2) are more likely to be fungal metabolites, i.e., endophytes or epiphytes. The isolation of palmarumycins 1 and 2 from dried D. ehretioides fruits could be reproducible; both plant samples collected in the years 2002 and 2004 provided the same result, and, therefore, symbiont fungal strains should be specific to the plant host, D. ehretioides, and they can grow on the fruits during drying the sample. Palmarumycin JC1 (1) did not exhibit antimalarial, antifungal, antimycobacterial, and cytotoxic activities. Palmarumycin JC2 (2) exhibited antimalarial (IC50 4.5 microg/ml), antifungal (IC50 12.5 microg/ml), antimycobacterial (MIC 6.25 microg/ml), and cytotoxic (IC50 11.0 microg/ml for NCI-H187 cell line) activities. In our bioassay systems, isodiospyrin (3) did not exhibit antimycobacterial, antifungal, antimalarial, and cytotoxic activities. Isodiospyrol A (4) exhibited antimalarial (IC50 2.7 microg/ml) and antimycobacterial (MIC 50 microg/ml) activities, but was inactive towards Candida albicans. Compound 4 also exhibited cytotoxicity against BC cells (IC50 12.3 microg/ml), but not towards KB and Vero cell lines.

Animals↗
PubMed2006

A 2-iminohydantoin from the oxidation of guanine.

The nucleobase guanine was oxidized with dimethyldioxirane (DMDO) to explore the role of epoxidizing agents in oxidative DNA damage. Treatment of guanine with 10% molar excess DMDO in aqueous solution at 0 degrees C and pH 7.5 followed by workup under mild conditions gave 5-carboxamido-5-formamido-2-iminohydantoin (1) as the sole isolable product in 71% yield. The structure of 1 was established on the basis of mass spectrometry and NMR studies on 1 and its isotopomers generated by the oxidation of [4-(13)C] and [7-(15)N]guanine, which yield [5-(13)C]1 and [7-(15)N]1. The distribution of 13C and 15N labels in the isotopomeric products supports initial epoxidation of the C4-C5 bond of guanine followed by a 1,2-acyl migration of guanine C6. Compound 1 is suggested as a possible primary DNA lesion from putative epoxidizing agents, including hydroperoxides present during biological processes such as lipid peroxidation.

Guanine↗
PubMed1998

Investigation on the effect of experimental phospholipase A2 inhibitors on the formyl-methionyl-leucyl-phenylalanine-stimulated chemotaxis of human leukocytes in vitro.

We investigated the effects of phospholipase A2 (PLA2) activation and inhibition on the chemotaxis of mixed human leukocytes (MHL) in a 48-well microchemotaxis chamber and on the production of leukotriene B4 (LTB4) by an enzyme immuno assay. LTB4 is the eicosanoid which is most likely responsible for induction of chemotaxis and its production can be used as an indicator of PLA2 stimulation. Formyl-methionyl-leucyl-phenylalanine (F-met-leu-phe, f-MLP), a well known inducer of PLA2 in our experiments stimulated dose-dependently the chemotaxis of MHL with a maximum at 10 nmol/l. In accordance with the chemotaxis assay the maximum LTB4-production was found at 10 nmol/l f-MLP. The preincubation of MHL with the PLA2 inhibitors mepacrine (1-100 mumol/l), manoalide (1-100 mumol/l) and BM 16.2115 (1,6-dioxadispiro[4.1.5.1]trideca-8,11-diene-2,10-dione, 0.5-50 mumol/l) dose-dependently reduced the chemotaxis of MHL induced by 10 nmol/l f-MLP. The inhibitory effect of the experimental compound BM 16.2115 was about 2 times stronger than those of the reference compounds mepacrine and manoalide. Thus inhibitors of PLA2 reduce chemotaxis of leukocytes probably by reducing production of LTB4. This mechanism could be of considerable interest for the development of anti-inflammatory drugs.

Cell Survival↗
PubMed2006

A combined marble burying-locomotor activity test in mice: a practical screening test with sensitivity to different classes of anxiolytics and antidepressants.

Over the last decades, the inhibition of spontaneous burying of glass marbles by mice has been used as an index of anxiolytic drug action in the so-called marble burying test. Indeed, acute administration of rapid-onset (e.g. diazepam) and slow-onset (e.g. fluoxetine) anxiolytics inhibit marble burying. However, non-anxiolytic compounds such as classical antipsychotics also reduce marble burying thus suggesting that the predictive validity of this procedure for anxiety may be limited. In the present study, after having selected a strain of mice (C57BL/6J) that showed spontaneous avoidance of glass marbles, we tried to improve the predictive validity of the marble burying test for anxiety by measuring locomotor activity during the marble burying test and--if needed--in control experiments by using a videotracking system. Twenty-four reference compounds were tested including anxiolytics, anxiogenics, antidepressants, antipsychotics and other classes. By comparing marble burying scores with locomotor measures, we found that, based on our criteria, most of the anxiolytics and antidepressants selectively inhibited marble burying in contrast to most of the other compounds (e.g. haloperidol, morphine). Two putative anxiolytics, i.e. the nociceptin orphanin FQ peptide receptor agonist Ro 64-6198 and the metabotropic glutamate 5 receptor antagonist 2-methyl-6-(phenylethynyl)pyridine, also showed a selective profile. We propose this modified procedure, requiring only a limited number of animals, as a valuable screening test for the detection of compounds having anxiolytic effects.

Animals↗
PubMed1999

Atiprimod (SK&F 106615), a novel macrophage targeting agent, enhances alveolar macrophage candidacidal activity and is not immunosuppressive in Candida-infected mice.

Azaspiranes are novel macrophage-targeting agents with activity in preclinical animal models of autoimmune disease and transplantation. The purpose of this work was to determine the effects of atiprimod (SK&F 106615), an azaspirane being developed for the treatment of rheumatoid arthritis, on rat pulmonary alveolar macrophage (AM) function and immunocompetance in Candida-infected mice. AM from rats treated with 20 mg/kg/day of atiprimod for 15 days demonstrated enhanced killing of Candida albicans ex vivo. Concentration-dependent increases in candidacidal activity were also observed as early as one hour after exposure in vitro in AM from untreated normal rats. Treatment of AM with atiprimod in vitro did not increase particulate-stimulated superoxide production or phagocytosis of Candida but decreased their ability to concentrate acridine orange, indicating an increase in lysosomal pH. Increased candidacidal activity was inhibited by superoxide dismutase and catalase, suggesting a role for reactive oxygen intermediates (ROI). Atiprimod also increased free radical-mediated killing of Candida in the presence of H2O2, iron and iodide in a cell-free system. These findings indicated that treatment with atiprimod increased the candidacidal activity of rat AM in a free radical-dependent manner. The data also suggested that atiprimod did not increase ROI production by AM, but rather increased the efficiency of radical-mediated killing. This increase may be caused by cyclization of atiprimod, facilitating electron transfer and peroxidation of lipid membranes. In vivo studies in Candida-infected CBA mice showed that atiprimod (10 mg/kg/day), did not compromise immune function in the infected mice and could be differentiated from prototypical immunosuppressive compounds used for treatment of autoimmune diseases.

Acridine Orange↗
PubMed2001

Synthesis of derivatives of the novel cyclophilin-binding immunosuppressant sanglifehrin A with reduced numbers of polar functions.

The syntheses and the biological activities of 53-deoxo sanglifehrin A (2) and 61-deoxy octahydrosanglifehrin A (3) are described. Compound 2 shows intracellular cyclophilin (CyP)-binding and immunosuppressive activity in the mixed-lymphocyte reaction (MLR) similar to that of sanglifehrin A (1). Compound 3 is much less active in the MLR despite unchanged intracellular CyP-binding. This indicates that the 53-keto group is not necessary for immunosuppressive activity, while the 61 hydroxy group is required.

Animals↗
PubMed1983

Antihypertensive 9-substituted 1-oxa-4,9-diazaspiro[5.5]undecan-3-ones.

Forty-one 9-substituted 1-oxa-4,9-diazaspiro[5.5]undecan-3-ones were prepared for antihypertensive screening in the spontaneously hypertensive rat (SHR). For the 9-(2-indol-3-ylethyl) series, the parent compound, 9-(2-indol-3-ylethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one (21), was the most potent antihypertensive agent. Substitution of lower alkyl groups on the spirolactam ring gave compounds close in activity to 21, while substitution with large alkyl or aryl groups led to a significant decrease in activity. Ring-opened analogues of 21 that contained the same functionality were markedly less active. Several 1-oxa-4,9-diazaspiro[5.5]undecan-3-ones substituted at the 9 position with 1,4-benzodioxan-2-ylmethyl, 1,4-benzodioxan-2-ylhydroxyethyl, and 2-phenylethyl groups also demonstrated significant activity. Compound 21 was chosen for a detailed pharmacological evaluation. Its antihypertensive activity appears to be predominantly due to peripheral alpha 1-adrenoceptor blockade.

Adrenergic alpha-Antagonists↗
PubMed2002

Spirotetrahydronaphthalene analogues of sympathomimetic catecholamines. Synthesis and adrenergic activity of 5,6- and 6,7-dihydroxy-3,4-dihydrospiro[naphthalen-1 (2H)-3'-piperidines].

The 5,6- (5a) and 6,7-dihydroxy-3,4-dihydrospiro[naphthalen-1 (2H)-3'-piperidine] (6a) and their N-isopropyl derivatives (5b and 6b), DDSNPs, were synthesized. These compounds can be viewed as the result of the combination of the structure of the 3-(3,4-dihydroxyphenyl)-piperidine 2a or 2b, with the structure of the corresponding 1-(aminomethyl)-5,6-dihydroxy-(3a or 3b) or 1-(aminomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (4a or 4b), 1-AMDTNs. The new compounds (5a, b and 6a, b) were assayed for their alpha and beta adrenergic properties by means of binding experiments and functional tests and the results were compared with those obtained for catecholamines 1a, b and the previously described 3-(3,4-dihydroxyphenyl)piperidine (3-DPP; 2) and 1-AMDTNs (3, 4). Comparison of the affinity and activity data of novel derivatives with those of reference compounds 2, 3 and 4 shows a general low ability of DDSNPs 5 and 6 to interact with both alpha and beta- adrenoceptors.

Animals↗
PubMed1996

Disease-modifying activity of SK&F 106615 in rat adjuvant-induced arthritis. Multiparameter analysis of disease magnetic resonance imaging and bone mineral density measurements.

OBJECTIVE: To evaluate the effect of SK&F 106615 on joint integrity in rats with adjuvant-induced arthritis (AIA). METHODS: AIA was induced in Lewis rats on day 0, and the animals were treated either prophylactically (days 0-16 or days 0-23) or therapeutically (days 10-23) with SK&F 106615. Efficacy was determined by measurements of paw inflammation, bone mineral density (BMD) using dual x-ray absorptiometry, and magnetic resonance imaging (MRI). Joint integrity was also determined histologically, and serum interleukin-6 (IL-6) levels were measured as a marker of the antiinflammatory effects of the compound. RESULTS: Prophylactic treatment (days 0-16) of AIA rats with SK&F 106615 significantly inhibited paw volume at doses of 545 mg/kg/day given orally on 5 days each week. Extensive evaluation of joint integrity in rats treated with SK&F 106615 20 mg/kg/day orally for 23 days showed inhibition of paw volume, normalization of BMD, and significant improvement in disease by MRI and histologic assessment compared with the AIA controls. Elevated levels of serum IL-6 in AIA rats were reduced dramatically by SK&F 106615. Therapeutic treatment (days 10-23) resulted in similar protective effects measured by paw inflammation, BMD, and MRI. In the therapeutic protocol, serum IL-6 appeared to be a more sensitive marker of antiinflammatory activity than paw edema. CONCLUSION: Symptoms of AIA in rats are significantly reduced by prophylactic and therapeutic treatment with SK&F 106615. Of particular note, this compound appears to exert a protective effect on joint integrity and to have disease-modifying properties.

Absorptiometry, Photon↗