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At least 19 recordsLinked to original sources
PubMed2000

A potent inhibitor of inducible nitric oxide synthase, ONO-1714, a cyclic amidine derivative.

(1S,5S,6R,7R)-7-Chloro-3-imino-5-methyl-2-azabicyclo[4.1.0]heptane hydrochloride (ONO-1714), a novel cyclic amidine analogue, inhibits human inducible nitric oxide (iNOS) with a K(i) of 1.88 nM and rodent iNOS with similar potency in vitro. ONO-1714 was found to be 10-fold selective for human iNOS over human endothelial NOS (ecNOS). When the inhibitory activity of ONO-1714 was compared for iNOS, it was found to be 451-fold and >20,000-fold more potent than L-NMMA and aminoguanidine (AG), respectively. In terms of human iNOS selectivity, ONO-1714 was approximately 34- and 2-fold more selective for iNOS than L-NMMA and AG, respectively. ONO-1714 inhibited the LPS-induced elevation of plasma nitrate/nitrite in mice with an ID(50) value of 0.010 mg/kg, s.c. The maximum tolerated dose of ONO-1714 was 30 mg/kg, i.v. Thus, ONO-1714 represents one of the most potent iNOS inhibitors in vitro and in vivo to date and has great potentials for use as an inhibitor for clarifying the pathophysiological roles of iNOS and for use as a therapeutic agent.

Amidines↗
PubMed1997

Binding of biotin to streptavidin stabilizes intersubunit salt bridges between Asp61 and His87 at low pH.

The remarkable stability of the streptavidin tetramer towards subunit dissociation becomes even greater upon binding of biotin. At two equivalent extensive monomer-monomer interfaces, monomers tightly associate into dimers that in turn associate into the tetramer at a less extensive dimer-dimer interface. To probe the structural basis for the enhancement of the stability of streptavidin by biotin, the crystal structures of apostreptavidin and its complexes with biotin and other small molecule and cyclic peptide ligands were determined and compared at resolutions as high as 1.36 A over a range of pH values from as low as 1.39. At low pH dramatic changes occur in the conformation and intersubunit hydrogen bonds involving the loop comprising Asp61 to Ser69. The hydrogen-bonded salt bridge between Asp61 Odelta2 and His87 Ndelta1, observed at higher pH, is replaced with a strong hydrogen bond between Asp61 Odelta1 and Asn85 Odelta1. Through crystallography at multiple pH values, the pH where this conformational change occurs, and thus the pKa of Asp61, was determined in crystals of space group I222 and/or I4122 of apostreptavidin and complexes. A range in pKa values for Asp61 was observed in these structures, the lowest being 1.78+/-0.19 for I222 streptavidin-biotin in 2.9 M (NH4)2SO4. At low pH the decrease in pKa of Asp61 and preservation of the intersubunit Asp61 Odelta2-Ndelta1 His87 hydrogen-bonded salt bridge in streptavidin-biotin versus apostreptavidin or streptavidin-peptide complexes is associated with an ordering of the flexible flap comprising residues Ala46 to Glu51, that in turn orders the Arg84 side-chain of a neighboring loop through resulting hydrogen bonds. Ordering of Arg84 in close proximity to the strong intersubunit interface appears to stabilize the conformation associated with the Asp61 Odelta2-Ndelta1 His87 hydrogen-bonded salt bridge. Thus, in addition to the established role of biotin in tetramer stabilization by direct mediation of intersubunit interactions at the weak interface through contact with Trp120, biotin may enhance tetramer stability at the strong interface more indirectly by ordering loop residues.

Alkynes↗
PubMed1995

EPR/spin-label technique as an analytical tool for determining the resistance of reactive topical skin protectants (rTSPs) to the breakthrough of vesicant agents.

Ointment formulations of reactive topical skin protectants (rTSPs) or topical skin protectants (TSPs) based on perfluorinated polyether material (PFPE, i.e., fomblin RT-15) were prepared and spin labeled. Four N-oxyl-4-4'-dimethyloxazolidine derivatives of stearic acid, 5-NS, 7-NS, 12-NS, and 16-NS, were used as spin probes. The spin-labeled vehicle, fomblin-RT-15, and vehicle containing chloroamide (S-330, an antivesicant) were exposed to various concentrations of half-mustard gas. The order parameter (S) was dependent on the depth of penetration of the paramagnetic group into the vehicle (fomblin) and on the chemical composition of the reactive antivesicant under investigation. The net change of the viscosity of the vehicle and the chemical composition were seen to affect the penetration profile. This will provide a useful in vitro screening technique to develop antivesicant TSPs.

Alkynes↗
PubMed2026

Efficacy and safety of deucravacitinib, an oral, selective tyrosine kinase 2 inhibitor, in patients with active psoriatic arthritis: 52-week results from the randomised, double-blind, placebo-controlled phase 3 POETYK PsA-1 trial.

OBJECTIVES: The randomised, double-blind, placebo-controlled, phase 3 Program fOr Evaluation of TYK2 inhibitor Psoriatic Arthritis-1 (POETYK PsA-1) trial evaluated the efficacy, safety, and tolerability of deucravacitinib, an oral, selective tyrosine kinase 2 inhibitor, in patients with PsA na&#xef;ve to biologic disease-modifying antirheumatic drugs. METHODS: Adults with active PsA, high-sensitivity C-reactive protein concentration &#x2265; 3 mg/L, and &#x2265; 1 PsA-related hand and/or foot erosion detectable via radiograph were randomised 1:1 to oral deucravacitinib 6 mg once daily or placebo through week (W) 16. At W16, patients continued receiving deucravacitinib or switched from placebo to deucravacitinib through W52. The primary endpoint was American College of Rheumatology 20% improvement in response (ACR20) at W16. Nonresponder imputation was used for missing data. Efficacy and safety were evaluated through W52. Post hoc rank analysis of covariance was used to evaluate structural damage with no missing data imputation. RESULTS: In 670 patients, a significantly greater proportion of those receiving deucravacitinib vs placebo achieved ACR20 at W16 (54.2% vs 34.1%, P < .001). Responses with deucravacitinib were increased at W52. Patients who switched from placebo to deucravacitinib achieved improvements similar to those in patients who received continuous deucravacitinib. Inhibition of structural damage was observed at W16 and W52. At W16, incidences of serious adverse events (AEs) (deucravacitinib, 1.8%; placebo, 2.4%) and discontinuations due to AEs (2.4%; 1.8%) were low and remained low through W52, without imbalances in cardiovascular events, malignancies, or opportunistic infections. No new safety signals were detected; no deaths occurred. CONCLUSIONS: Deucravacitinib demonstrated superiority vs placebo for clinical responses, patient-reported outcomes, and structural damage inhibition in patients with PsA, with favourable tolerability and safety.

Humans↗
PubMed2000

Anxiolytic-like properties of melatonin receptor agonists in mice: involvement of mt1 and/or MT2 receptors in the regulation of emotional responsiveness.

The anxiolytic-like properties of melatonin have been established in rodents. The present study investigated the possible involvement of melatonin receptors/binding sites in the regulation of emotional responsiveness in mice, using an mt1/MT2 receptor specific agonist (S 23478) and two specific ligands of MT3 binding sites with agonistic properties (N-acetylserotonin (NAS) and 5-methoxycarbonylamino N-acetyltryptamine (5-MCA-NAT)). We examined the behavioural effects of these compounds in C3H/He mice confronted with two anxiety models: the free-exploratory test, in which C3H/He mice present neophobic reactions ("trait" anxiety), and the light/dark choice test, which is an unconditioned conflict test (inducing "state" anxiety). Melatonin and S 23478 decreased anxious reactions in both the free-exploratory test (5-25 mg/kg) and the light/dark choice test (melatonin: 20 mg/kg; S 23478: 10-20-40 mg/kg). NAS exerted anxiolytic-like effects only at a dose of 35 mg/kg in the free-exploratory test and at a dose of 40 mg/kg in the light/dark choice test. Finally, 5-MCA-NAT was devoid of anxiolytic-like effects in both tests. These results suggest that the anxiolytic properties of melatonin could involve the activation of mt1 and/or MT2 receptors rather than of the MT3 binding site.

Analysis of Variance↗
PubMed2000

Potato micro-tuber inducing hydroxylasiodiplodins from Lasiodiplodia theobromae.

Three hydroxylasiodiplodins were isolated from the mycelium extracts of Lasiodiplodia theobromae IFO 31059; and their structures were identified as (3R),(4S)-4-hydroxylasiodiplodin, (3R),(6R)-6-hydroxy-de-O-methyllasiodiplodin and (3R),(5R)-5-hydroxy-de-O-methyllasiodiplodin. All showed potato micro-tuber inducing activity.

Heterocyclic Compounds, 2-Ring↗
PubMed2000

Synthesis and diuretic activity of bicyclic fused heterocycles containing oxime-O-sulfonic acid moiety.

In order to investigate the origin of the loop-type diuretic activity of M17055 (1), several variants (3-9) were designed and synthesized by modifying the quinolinone skeleton, and their diuretic activities were compared with the lead 1 and furosemide in dogs. It was found that the negative charge distribution pattern afforded by the dispositional arrangement of the 4-oxime-O-sulfonic acid and 1-N-acyl carbonyl moiety attached to the tetrahydropyridine ring system is inevitable for the development of the activity, which strongly supports the previously proposed model for the active site of the Na(+)-K(+)-2Cl(-) cotransporter. Also reported is the first synthesis of the dihydrothieno[3,2-b]pyridine-7(4H)-one ring system required in the synthesis of compound 9.

Animals↗
PubMed2000

The effects of nitroxide radicals on oxidative DNA damage.

The indolinonic and quinolinic aromatic nitroxides synthesized by us are a novel class of biological antioxidants, which afford a good degree of protection against free radical-induced oxidation in different lipid and protein systems. To further our understanding of their antioxidant behavior, we thought it essential to have more information on their effects on DNA exposed to free radicals. Here, we report on the results obtained after exposure of plasmid DNA and calf thymus DNA to peroxyl radicals generated by the water-soluble radical initiator, 2,2'-azobis(2-amidinopropane)dihydrochloride (AAPH), and the protective effects of the aromatic nitroxides and their hydroxylamines, using a simple in vitro assay for DNA damage. In addition, we also tested for the potential of these nitroxides to inhibit hydroxyl radical-mediated DNA damage inflicted by Fenton-type reactions using copper and iron ions. The commercial aliphatic nitroxides 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL), and bis(2,2, 6,6-tetramethyl-1-oxyl-piperidin-4-yl)sebacate (TINUVIN 770) were included for comparison. The results show that the majority of compounds tested protect: (i) both plasmid DNA and calf thymus DNA against AAPH-mediated oxidative damage in a concentration-dependent fashion (1-0.1 mM), (ii) both Fe(II) and Cu(I) induced DNA oxidative damage. However, all compounds failed to protect DNA against damage inflicted by the presence of the transition metals in combination with H(2)O(2). The differences in protection between the compounds are discussed in relation to their molecular structure and chemical reactivity.

Amidines↗
PubMed1999

Protein kinase C modulators bearing dicarba-CLOSO-dodecaborane as a hydrophobic pharmacophore.

The size and position of a hydrophobic moiety on a benzolactam skeleton, which reproduces the active conformation and biological activity of teleocidins, play an important role in the appearance of the activity. We have designed and synthesized benzolactams bearing dicarba-closo-dodecaborane. These compounds showed potent binding affinity to protein kinase C, providing a further example of the application of carborane as the hydrophobic pharmacophore of biologically active molecules.

Boron Compounds↗
PubMed1999

Synthesis and structure-activity relationships of phenylenebis(methylene)-linked bis-azamacrocycles that inhibit HIV-1 and HIV-2 replication by antagonism of the chemokine receptor CXCR4.

Bis-tetraazamacrocycles such as the bicyclam AMD3100 are a class of potent and selective anti-HIV-1 and HIV-2 agents that inhibit virus replication by binding to the chemokine receptor CXCR4, the co-receptor for entry of X4 viruses. With the aim of optimizing the anti-HIV-1 and HIV-2 activity of bis-azamacrocycles, a series of analogues were synthesized which contain neutral heteroatom (oxygen, sulfur) or heteroaromatic (of lower pK(a) than a secondary amine) replacements for the amino groups of AMD3100. The introduction of one or more heteroatoms such as oxygen or sulfur into the macrocyclic ring of p-phenylenebis(methylene)-linked dimers (to give N(3)X or N(2)X(2) bis-macrocycles) gave analogues with substantially reduced anti-HIV-1 (III(B)) and anti-HIV-2 (ROD) potency. In addition, the bis-sulfur analogue was also markedly more cytotoxic to MT-4 cells. However, bis-tetraazamacrocycles featuring a single pyridine group incorporated within the macrocyclic framework exhibited anti-HIV-1 and HIV-2 potency comparable to that of their saturated, aliphatic counterparts. The p-phenylenebis(methylene)-linked dimer of the py[14]aneN(4) macrocycle inhibited HIV-1 replication at a 50% effective concentration (EC(50)) of 0.5 microM while remaining nontoxic to MT-4 cells at concentrations approaching 200 microM. A series of analogues containing macrocyclic heteroaromatic groups of varying pK(a) were also synthesized, and their ability to inhibit HIV replication was evaluated. Replacing the pyridine moiety of the py[14]aneN(4) macrocyclic ring with pyrazine or pyridine groups substituted in the 4-position (with electron-withdrawing or -donating groups) either reduced antiviral potency or increased cytotoxicity to MT-4 cells. Finally, we synthesized a series of analogues in which the ring size of the bis-pyridyl macrocycles was varied between 12 and 16 members per ring including the py[iso-14]aneN(4) ring system, an isomer of the py[14]aneN(4) macrocycle. The p-phenylenebis(methylene)-linked dimer of the py[iso-14]aneN(4) (AMD3329) displayed the highest antiviral activity of the bis-azamacrocyclic analogues reported to date, exhibiting EC(50)'s against the cytopathic effects of HIV-1 and HIV-2 replication of 0.8 and 1.6 nM, respectively, that is, about 3-5-fold lower than the EC(50) of AMD3100. AMD3329 also inhibited the binding of a specific CXCR4 mAb and the Ca(2+) flux induced by SDF-1alpha, the natural ligand for CXCR4, more potently than AMD3100. Furthermore, AMD3329 also interfered with virus-induced syncytium formation at an EC(50) of 12 nM.

Anti-HIV Agents↗
PubMed1999

Cytotoxic terpenoids from the Formosan soft coral Nephthea brassica.

Two new cytotoxic cembranoid diterpenes, brassicolide (1) and brassicolide acetate (2); a new cytotoxic sesquiterpene, (-)-4alpha-O-acetyl-selin-11-en (3); and six cytotoxic terpenoids, (-)-selin-11-en-4alpha-ol (4), 2-hydroxynephthenol (5), nephthenol (6), cembrene A (7), epoxycembrene A (8), and (-)-beta-elemene (9), have been isolated from the Formosan soft coral Nephthea brassica. The structures of compounds 1-9 were determined by spectral, chemical, and X-ray crystallographic analysis.

Animals↗
PubMed2000

Synthesis of cyclic sulfonamides via intramolecular copper-catalyzed reaction of unsaturated iminoiodinanes.

Olefinic primary sulfonamides were treated with iodobenzene diacetate and potassium hydroxide in methanol to give intermediate iminoiodinanes. Catalytic copper(I) or (II) triflate then provided intramolecular nitrene delivery leading to aziridine formation except in one case where a rare copper-catalyzed C-H insertion was observed. The aziridines could be opened by various nucleophiles (methanol, thiophenol, allylmagnesium bromide, benzylamine) to give the corresponding substituted cyclic sulfonamides.

Aziridines↗
PubMed2000

Total synthesis of the marine alkaloid (-)-lepadin B.

An enantioselective total synthesis of (-)-lepadin B has been developed starting from (2S,4S)-2,4-O-benzylidene-2, 4-dihydroxybutanal. The key steps in the synthesis include the use of an aqueous intramolecular acylnitroso Diels-Alder reaction to afford the trans-1,2-oxazinolactam and Suzuki cross-coupling reaction to elaborate the (E,E)-octadienyl unit.

Alkaloids↗
PubMed1999

Desymmetrization by ring-closing metathesis leading to 6,8-dioxabicyclo[3.2.1]octanes: a new route for the synthesis of (+)-exo- and endo-brevicomin.

[formula: see text] The 6,8-dioxabicyclo[3.2.1]octane skeleton is a common structural subunit in natural products. A conceptionally new strategy affording these structures is described for the syntheses of (+)-exo-brevicomin and rac-endo- and enantiomerically enriched (+)-endo-brevicomin, employing desymmetrization of trienes derived from diols with C2 and meso symmetry via ring-closing metathesis.

Animals↗
PubMed2000

Synthesis of (-)-dysiherbaine.

[reaction: see text] The first synthesis of (-)-dysiherbaine has been accomplished using intramolecular SN2 substitutions of a carbamate anion on an epoxide and an alkoxide on a secondary mesylate to efficiently construct the bicyclic skeleton stereospecifically from xylose. A general sequence has been developed to introduce an allyl group and convert it to the alanine side chain that should be useful for the construction of dysiherbaine analogues.

Alanine↗