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PubMed1991

Acyclic analogues of pyrazofurin: syntheses and antiviral evaluation.

Acyclic analogues of pyrazofurin, including 4-hydroxy-3(5)-[( 2-hydroxy-1-(hydroxymethyl)-ethoxy]methyl)-1H-pyrazole-5 (3)-carboxamide (36) and 4-hydroxy-3(5)-[(2-hydroxyethoxy)methyl]-1H-pyrazole-5(3)-carboxamide (27), that possess the side chains of ganciclovir and acyclovir, respectively, were prepared by heating methyl 4-acetoxy-1-acetyl-3-bromomethyl-1H-pyrazole-5-carboxylate (15) and sodium acetate in the requisite alcohols or, for 36, with the sodium alkoxide in dry tetrahydrofuran. These analogues have no antiviral activity, except 4-hydroxy-3(5)-[(3-hydroxypropoxy)methyl]-1H-pyrazole-5(3)-carboxamide (28), which exhibited slight activity against human cytomegalovirus.

Amides↗
PubMedDate not supplied

Comparison of ballooned hepatocytes in alcoholic and non-alcoholic liver injury in rats.

Ballooned hepatocytes are commonly observed in alcoholic and sometimes in non-alcoholic liver diseases. To clarify whether pathogenesis of this change is different in alcoholic and non-alcoholic liver diseases, changes of the livers in rats fed alcohol with pyrazole for 12 weeks were compared with those of CCl4 treated rats. Both groups of rats showed marked ballooning of the hepatocytes in the centrolobular area. Immunohistochemically, the ballooned hepatocytes in alcohol-pyrazole treated rats reacted strongly with transferrin and albumin staining. However, staining reaction of the ballooned hepatocytes in the CCl4 treated rats was slight. In alcohol-pyrazole treated rats, hepatic microtubules were significantly decreased. Retention of transferrin and albumin were found only in the ballooned hepatocytes of alcohol-pyrazole treated rats. However, in the CCl4 treated rats, neither microtubular alteration nor retention of the exportable proteins was observed. These findings indicate that the pathogenesis of ballooning of hepatocytes is different in alcoholic and non-alcoholic liver injuries. In alcoholic liver injury, microtubular alteration may lead to retention of protein and ballooning of hepatocytes by interfering with the hepatic secretion of proteins.

Animals↗
PubMed2004

GABA receptor antagonists and insecticides: common structural features of 4-alkyl-1-phenylpyrazoles and 4-alkyl-1-phenyltrioxabicyclooctanes.

Fipronil [5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylsulfinylpyrazole] is one of the most important insecticides. Structure-activity studies described here reveal that fipronil retains its very high binding potency at the human beta3 and house fly gamma-aminobutyric acid (GABA) receptors and toxicity to house flies on replacing the pyrazole trifluoromethylsulfinyl moiety with tert-butyl or isopropyl and the phenyl trifluoromethyl substituent with ethynyl, trifluoromethoxy, bromo or chloro. Among the compounds studied, those with other alkyl groups at the 4-position of the pyrazole, as well as phenyl substitution without one or both of the 2,6-dichloro groups, are less effective. 5-Amino-4-tert-butyl-3-cyano-1-(2,6-dichloro-4-ethynylphenyl)pyrazole is highly effective and almost isosteric with 4-tert-butyl-3-cyano-1-(4-ethynylphenyl)-2,6,7-trioxabicyclo[2.2.2]octane (the most potent 4-alkyl-1-phenyltrioxabicyclooctane) as a noncompetitive GABA antagonist and insecticide. These findings are interpreted as three binding subsites in the GABA receptor: a hydrophobic site undergoing steric interaction with the tert-butyl or equivalent group; a hydrogen bonding site to pyrazole N-2; a pi bonding site to the face of the phenyl moiety; with supplemental enhancement by the 3-cyano and 4-ethynyl substituents.

Alkylation↗
PubMed2006

Both estrogen receptor alpha and estrogen receptor beta agonists enhance cell proliferation in the dentate gyrus of adult female rats.

This study investigated the involvement of estrogen receptors alpha and beta in estradiol-induced enhancement of hippocampal neurogenesis in the adult female rat. Subtype selective estrogen receptor agonists, propyl-pyrazole triol (estrogen receptor alpha agonist) and diarylpropionitrile (estrogen receptor beta agonist) were examined for each receptor's contribution, individual and cooperative, for estradiol-enhanced hippocampal cell proliferation. Estradiol increases hippocampal cell proliferation within 4 h [Ormerod BK, Lee TT, Galea LA (2003) Estradiol initially enhances but subsequently suppresses (via adrenal steroids) granule cell proliferation in the dentate gyrus of adult female rats. J Neurobiol 55:247-260]. Therefore, animals received s.c. injections of estradiol (10 microg), propyl-pyrazole triol and diarylpropionitrile alone (1.25, 2.5, 5.0 mg/0.1 ml dimethylsulfoxide) or in combination (2.5 mg propyl-pyrazole triol+2.5 mg diarylpropionitrile/0.1 ml dimethylsulfoxide) and 4 h later received an i.p. injection of the cell synthesis marker, bromodeoxyuridine (200 mg/kg). Diarylpropionitrile enhanced cell proliferation at all three administered doses (1.25 mg, P<0.008; 2.5 mg, P<0.003; 5 mg, P<0.005), whereas propyl-pyrazole triol significantly increased cell proliferation (P<0.0002) only at the dose of 2.5 mg. Our results demonstrate both estrogen receptor alpha and estrogen receptor beta are individually involved in estradiol-enhanced cell proliferation. Furthermore both estrogen receptor alpha and estrogen receptor beta mRNA was found co-localized with Ki-67 expression in the hippocampus albeit at low levels, indicating a potential direct influence of each receptor subtype on progenitor cells and their progeny. Dual receptor activation resulted in reduced levels of cell proliferation, supporting previous studies suggesting that estrogen receptor alpha and estrogen receptor beta may modulate each other's activity. Our results also suggest that a component of estrogen receptor-regulated cell proliferation may take place through alternative ligand and/or cell-signaling mechanisms.

Analysis of Variance↗
PubMed1989

Immunochemical characterization of cytochrome P-450 isozymes responsible for benzene oxidation in the rat liver.

The contribution of cytochrome P-450 isozymes to benzene metabolism in liver microsomes from fed, fasted, pyrazole-, phenobarbital (PB)- and ethanol-treated rats and in respective isocaloric controls was investigated using monoclonal antibodies (mAbs). Clone 1-7-1 mAb did not inhibit benzene metabolism, whereas clone 2-66-3 inhibited only in PB-induced microsomes at a high concentration of benzene (6.26 mM), and clone 1-91-3 mAb inhibited benzene metabolism in all cases. The degree of inhibition was as follows: fed congruent to isocaloric control congruent to PB less than fasted less than pyrazole congruent to ethanol. The pattern of inhibition was similar with clone 1-91-3 for low (0.23 mM) and high concentrations of benzene, except in PB-induced microsomes. Western blot analysis showed that clone 1-7-1 mAb did not bind any liver microsomal protein in the region of cytochrome P-450s, whereas with clone 2-66-3 a clear-cut band was seen only in liver microsomes from PB-treated rats, with clone 1-98-1, a band was detected in microsomes from all treated groups, in the following order: PB = isocaloric control less than fed less than fasted less than pyrazole less than ethanol. These results indicate that (i) cytochromes P-450b,e and P-450j contribute to benzene metabolism in rat liver; (ii) the former has a low affinity to benzene and is induced by PB; and (iii) P-450j has a high affinity to benzene and is induced by 1-day fasting, pyrazole and ethanol, but decreased by PB treatment.

Animals↗
PubMed2003

Endoplasmic reticulum stress due to altered cellular redox status positively regulates murine hepatic CYP2A5 expression.

Murine hepatic cytochrome P450 2A5 (CYP2A5) is uniquely induced by a variety of agents that cause liver injury and inflammation, conditions that are typically associated with downregulation of P450s. We hypothesized that induction of CYP2A5 occurs in response to hepatocellular damage resulting in endoplasmic reticulum (ER) stress. Treatment of mice in vivo and mouse hepatocytes in primary culture with the CYP2A5 inducer pyrazole resulted in overexpression of the ER stress biomarker glucose-regulated protein (GRP) 78. Treatment of primary hepatocytes with ER stress activators thapsigargin, tunicamycin, and trans-4,5-dihydroxy-1,2-dithiane (DTT(ox)) and the calcium ionophore A23187 (calcimycin) resulted in elevated GRP78 mRNA levels; however, only the reducing agent DTT(ox) induced levels of CYP2A5 mRNA, protein, and coumarin 7-hydroxylase activity. To test the hypothesis that CYP2A5 induction is due to liver injury resulting from altered cellular redox status, we demonstrated that CYP2A5 induction, elevated serum alanine aminotransferase, and oxidative protein damage occur concurrently in pyrazole-treated mice. Pyrazole also induced the expression of cytosolic alpha and mu class glutathione S-transferase expression both in vivo and in primary mouse hepatocytes. Moreover, treatment of hepatocytes with the redox cycling quinone menadione resulted in overexpression of CYP2A5 and GSTM1 mRNA. Finally, pretreatment of hepatocytes with the antioxidants N-acetylcysteine and vitamin E attenuated pyrazole-mediated increases in CYP2A5 mRNA levels. These findings clearly indicate that induction of mouse hepatic CYP2A5 during liver injury occurs via a novel mechanism involving ER stress due to altered cellular redox status.

Animals↗
PubMed2005

S-adenosyl-L-methionine attenuates hepatotoxicity induced by agonistic Jo2 Fas antibody following CYP2E1 induction in mice.

S-Adenosyl-l-methionine (SAM) has been shown to be hepatoprotective against many toxic agents. Its possible effectiveness in protecting against CYP2E1-dependent toxicity is not known. We recently reported that treatment of mice with pyrazole to induce CYP2E1 increased hepatotoxicity produced by Fas agonistic Jo2 antibody. The current study was designed to investigate the effect of exogenous administration of SAM on the synergistic hepatotoxicity produced by Fas agonistic Jo2 antibody plus CYP2E1 following pyrazole pretreatment in C57BL/6 mice. Suboptimal administration of Jo2 Fas antibody combined with pyrazole pretreatment caused severe hepatotoxicity as determined by elevations in serum transaminase levels and histopathology. Exogenous administration of SAM (50 mg i.p./kg body weight every 12 h for 3 days) significantly decreased serum transaminases and ameliorated morphological changes of the liver. Addition of SAM elevated hepatic SAM and total reduced glutathione levels and inhibited CYP2E1 activity. SAM also lowered the elevated oxidative stress (lipid peroxidation, protein carbonyls, and superoxide production) and nitrosative stress (induction of inducible nitric-oxide synthase and 3-nitrotyrosine adducts) and increases in caspase-8 and -3 activation produced by the pyrazole plus Jo2 treatment. SAM did not prevent the increase in serum TNF-alpha levels or the decrease in catalase activity in this model. These results indicate that SAM can have an important hepatoprotective role as an effective reagent against Fas plus CYP2E1-induced hepatotoxicity by lowering oxidative and nitrosative stress.

Animals↗
PubMed1994

Temperature regulation in mice during withdrawal from ethanol dependence.

Temperature regulation during withdrawal from ethanol dependence was studied in mice. Dependence was induced utilizing ethanol vapor inhalation combined with injections of pyrazole, an alcohol dehydrogenase inhibitor. One control group received vehicle (0.9% NaCl); another received pyrazole (68.1 mg/kg) in vehicle. During withdrawal, mice were placed in a thermal gradient, with core temperature (Tc) and preferred temperature (Tpref) continuously recorded for 26 h. During the period of maximal withdrawal severity (4-10 h after removal from ethanol vapor), the withdrawal group was more active than controls. Withdrawal group Tc [36.4 +/- 0.1 (SE) degrees C] was similar to that of NaCl (36.2 +/- 0.1 degrees C) and pyrazole (36.3 +/- 0.2 degrees C) controls. Withdrawal group Tpref (30.5 +/- 0.5 degrees C) was significantly lower than either NaCl (33.5 +/- 0.3 degrees C) or pyrazole (32.9 +/- 0.5 degrees C) controls. Analysis of covariance with activity as covariate indicated that the difference between Tc and Tpref was greater for the withdrawal group and was due to more than increased activity. Mice withdrawing at constant temperature (29.5 degrees C) did not show Tc different from that of controls. These results support the conclusion that regulated body temperature is not altered during withdrawal. We propose that the lower Tpref of withdrawing mice represents a means of dissipating excess heat that is partly generated by the hypermetabolic state accompanying withdrawal from ethanol dependence.

Alcoholism↗
PubMed1992

Synthesis and evaluation of antimicrobial activity of new 4-nitroso and 4-diazopyrazole derivatives.

Some N-(pyrazol-5-yl)-2-nitrobenzamides, variably substituted in the pyrazole nucleus as well as in the amidic group, were reacted in acetic acid media with potassium nitrite and hydrochloric acid. The different chemical behaviour of the reacted pyrazole derivatives in relation to the substitution pattern in both the pyrazole nucleus and the amidic group, was observed. All compounds isolated from the reaction mixtures (4-nitroso, 4-nitro, 4-diazo and 4-chloro derivatives) were evaluated by the agar diffusion method for their "in vitro" growth inhibitory activity against Candida albicans (our collection), Candida tropicalis ATCC 13803, Saccharomyces cerevisiae ATCC 36375, Escherichia coli ATCC 25922, Staphylococcus aureus ATCC 25923 and Pseudomonas aeruginosa ATCC 27853. The 1-methylpyrazole derivatives showed larger inhibition zones than the 1-phenyl ones in the antimicrobial tests.

Anti-Bacterial Agents↗
PubMed1987

Metabolic basis of ethylene glycol monobutyl ether (2-butoxyethanol) toxicity: role of alcohol and aldehyde dehydrogenases.

2-Butoxyethanol (BE) is a massively produced glycol ether of which more than 230 million pounds was produced in the United States in 1983. It is extensively used in aerosols and cleaning agents intended for household use. This creates a high potential for human exposure during its manufacturing and use. A single exposure of rats to BE causes severe hemolytic anemia accompanied by secondary hemoglobinuria as well as liver and kidney damage. Butoxyacetic acid (BAA) was earlier identified as a urinary metabolite of BE. In addition, we have recently identified two additional urinary metabolites of BE, namely, BE-glucuronide and BE-sulfate conjugates. The current studies were undertaken to investigate the metabolic basis of BE-induced hematotoxicity in male F344 rats. Treatment of rats with pyrazole (alcohol dehydrogenase inhibitor) protected rats against BE-induced hematotoxicity and inhibited BE metabolism to BAA. Pyrazole inhibition of BE metabolism to BAA was accompanied by increased BE metabolism to BE-glucuronide and BE-sulfate as determined by quantitative high-performance liquid chromatography analysis of BE metabolites in urine. There was approximately a 10-fold decrease in the ratio of BAA to BE-glucuronide + BE-sulfate in the urine of rats treated with pyrazole + BE compared to rats treated with BE alone. Pretreatment of rats with cyanamide (aldehyde dehydrogenase inhibitor) also significantly protected rats against BE-induced hematotoxicity and modified BE metabolism in a manner similar to that caused by pyrazole. Administration of equimolar doses of BE, the metabolic intermediate butoxyacetaldehyde, or the ultimate metabolite BAA caused similar hematotoxic effects. Cyanamide also protected rats against butoxyacetaldehyde-induced hematotoxicity. Further evidence of the involvement of metabolism in hematotoxicity was demonstrated by the administration of deuterium-labeled BE (1,1-dideuterio-2-BE) which resulted in a significant delay in the development of hematotoxicity. It is therefore concluded that: a) there is a strong correlation between the amount of BAA in the urine and BE-induced hematotoxicity; b) metabolic activation of BE via alcohol and aldehyde dehydrogenases is a prerequisite for the development of BE-induced hematotoxicity; and c) hematotoxicity induced by BE can be attributed to its metabolite BAA. Finally, the current studies may prove beneficial in the treatment of acute glycol ethers poisoning with alcohol dehydrogenase inhibitors.

Acetaldehyde↗
PubMed2000

Mutagenicity of N-nitrosodiethylamine in the Ames test with S. typhimurium TA1535 is due to volatile metabolites and is not dependent on cytochrome P4502E1 induction.

N-Nitrosodiethylamine (NDEA) is carcinogenic in all investigated animal species at relatively low dosages. No threshold has been detected for these carcinogenic effects. The substance has been extensively investigated in various in vitro systems, revealing only weak mutagenicity at relatively high dosages. We reinvestigated NDEA in the Ames test with Salmonella typhimurium TA1535 to establish appropriate modifications of the standard Ames test protocol, to achieve a dose-dependent mutagenic response at a reasonably low dose range. Two main modifications were evaluated. Since the metabolism of dialkylnitrosamines is postulated to be mainly dependent on cytochrome P4502E1, a pyrazole-induced rat liver S9 was applied. The second modification involved a gastight preincubation, since metabolites of NDEA might evaporate from the incubation mixture. Cytochrome P4502E1 induction in Wistar rats was achieved by pyrazole treatment. For comparison, a rat liver S9-fraction produced by beta-naphtoflavone/phenobarbital induction was used. N-Nitrosopyrrolidine served as positive control for pyrazole-induced S9-mix with TA1535. NDEA showed no mutagenic response under all test conditions in the presence of pyrazole-induced S9-mix. A strong mutagenic response, exceeding the base rate up to 15-fold at a dose range of 25-1000 microg/plate, was observed using beta-naphtoflavone/phenobarbital-induced S9-mix, gastight preincubation and TA1535. In conclusion the Ames test with gastight preincubation can be useful for the testing of volatile compounds or substances leading to gaseous metabolites. The weak response of NDEA in the Ames test observed previously seems mainly to be due to the volatile character of its mutagenic metabolites. Our results do not support the hypothesis that cytochrome P4502E1 is a major toxifying enzyme for the formation of Ames-test-positive metabolites from NDEA.

Animals↗
PubMed2004

Synthesis and antibacterial activity of novel and potent DNA gyrase inhibitors with azole ring.

The 4-piperidyl moiety and the pyrazole ring in 1-(3-chlorophenyl)-5-(4-phenoxyphenyl)-3-(4-piperidyl)pyrazole 2, which has previously shown improved DNA gyrase inhibition and target-related antibacterial activity, were transformed to other groups and the in vitro antibacterial activity of the synthesized compounds was evaluated. The selected pyrazole, oxazole and imidazole derivatives showed moderate inhibition against DNA gyrase and topoisomerase IV with similar IC(50) values (IC(50)=9.4-25 microg/mL). In addition, many of the pyrazole, oxazole and imidazole derivatives synthesized in this study exhibited potent antibacterial activity against quinolone-resistant clinical isolates and coumarin-resistant laboratory isolates of Gram-positive bacteria with minimal inhibitory concentration values equivalent to those against susceptible strains.

Anti-Bacterial Agents↗
PubMed1989

Characterization of Coturnix quail liver alcohol dehydrogenase enzymes.

Livers from male or female Coturnix quail possess up to four electrophoretically distinct bands of alcohol dehydrogenase (ADH) activity. Three pyrazole-sensitive bands of enzymatic activity, designated ADH-1, ADH-2, and ADH-3, are cathodic at pH 8.2, and the fourth, ADH-An, is neutral to slightly anodic and insensitive to pyrazole. ADH-2 and ADH-3, and occasionally ADH-1, are present in livers from immature females. The predominant enzyme in immature male livers is ADH-3. At sexual maturity all three pyrazole-sensitive enzymes are present in livers from male birds, and livers from females possess predominantly ADH-3. ADH-2 and ADH-3, purified from female livers, are dimers of 80,000 daltons possessing 4 mol of Zn2+/mol of native protein. Both ADH-2 and ADH-3 were inhibited by 4-methylpyrazole with KI values of 430 and 335 nM, respectively. These values are similar to those of human class I isoenzymes. Neither enzyme oxidized methanol or ethylene glycol, which distinguished them from mammalian pyrazole-sensitive ADH isoenzymes. Both ADH-2 and ADH-3 showed specificity toward hydrophobic primary alcohols and were most active toward benzyl alcohol and n-octanol.

Alcohol Dehydrogenase↗
PubMed1981

Simian liver alcohol dehydrogenase: isolation and characterization of isoenzymes from Saimiri sciureus.

The alcohol dehydrogenase (ADH) of squirrel monkey liver can be purified and separated into pyrazole-insensitive and pyrazole-sensitive isoenzymes by affinity chromatography. This is the first demonstration of two functionally distinct classes of ADH in a species other than man. The inhibition of the two enzyme fractions by 4-methylpyrazole is analogous to that observed for the corresponding isoenzymes of human liver. Similarly, the substrate specificity of the pyrazole-insensitive form is more limited and its Km for ethanol (4 mM at pH 7.5) and acetaldehyde (11 mM at pH 7.0) is larger than that of the pyrazole-sensitive isoenzymes. However, their physicochemical and compositional characteristics, i.e., molecular weight, zinc content, and dimeric structure, are all virtually identical with those of other mammalian alcohol dehydrogenases studied thus far. Zinc is essential for the enzymatic function of both molecular forms as demonstrated by inhibition with chelating agents.

Alcohol Oxidoreductases↗
PubMed2005

Synthetic control of Pt...Pt separation and photophysics of binuclear platinum complexes.

A new series of luminescent mu-pyrazolate-bridged cyclometalated platinum binuclear complexes having the formula CwedgeNPt(mu-pz')2PtCwedgeN (CwedgeN = 2-(2,4-difluorophenyl)pyridyl, pz' = pyrazolate for 1, 3,5-dimethylpyrazolate for 2, 3-methyl-5-tert-butylpyrazolate for 3, and 3,5-bis(tert-butyl)pyrazolate for 4) have been synthesized and characterized. The two Pt(CwedgeN) moieties are bridged by two mu-pyrazolate ligands in an exo-bidentate fashion. A mononuclear complex with an isolated Pt center, CwedgeNPt(pz)2BEt2, 5, is also described. The X-ray crystal structures of 1-4 show the following Pt-Pt spacings: 1 = 3.3763(7) A, 2 = 3.1914(9) A, 3 = 3.0457(7) A, and 4 = 2.8343(6) A. At 77 K, the emission energy of the complexes varies from blue (for 1, 2, and 5) to green (for 3) to red (for 4). The changes in the photophysical properties of the binuclear complexes can be correlated with the decreasing Pt-Pt distance; the emissive state changes from a mixed ligand center triplet/metal-to-ligand charge transfer excited state (for 1 and 2) to a lower-energy, Pt-Pt metal-metal-to-ligand charge transfer state (for 3 and 4).

Journal Article↗
PubMed2004

Design, synthesis, and biological evaluation of new 8-heterocyclic xanthine derivatives as highly potent and selective human A2B adenosine receptor antagonists.

Here we report the synthesis of 8-heterocycle-substituted xanthines as potent and selective A(2B) adenosine receptor antagonists. The structure-activity relationships (SAR) of the xanthines synthesized in binding to recombinant human A(2B) adenosine receptors (ARs) in HEK-293 cells (HEK-A(2B)) and at other AR subtypes were explored. The synthesized compounds showed A(2B) adenosine receptor affinity in the nanomolar range and good levels of selectivity evaluated in radioligand binding assays at human (h) A(1), A(2A), A(2B), and A(3) ARs. We introduced several heterocycles, such as pyrazole, isoxazole, pyridine, and pyridazine, at the 8-position of the xanthine nucleus and we have also investigated different spacers (substituted acetamide, oxyacetamide, and urea moieties) on the heterocycle introduced. Various groups at the 3- and 4-positions of phenylacetamide moiety were studied. This study allowed us to identify the derivatives 2-(3,4-dimethoxyphenyl)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide (29b, MRE2028F20) [K(i)(hA(2B)) = 38 nM, K(i)(hA(1),hA(2A),hA(3)) >1000 nM], N-benzo[1,3]dioxol-5-yl-2-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yloxy]acetamide (62b, MRE2029F20) [K(i)(hA(2B)) = 5.5 nM, K(i)(hA(1),hA(2A),hA(3)) > 1000 nM], and N-(3,4-dimethoxyphenyl)-2-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yloxy]acetamide (72b, MRE2030F20) [K(i)(hA(2B) = 12 nM, K(i)(hA(1),hA(2A), hA(3)) > 1000 nM], which showed high affinity at the A(2B) receptor subtype and very good selectivity vs the other ARs. Substitution of the acetamide with an urea moiety afforded bioisosteric xanthines with good affinity and selectivity comparable to the acetamide derivatives. Substitution at the para-position of a 4-benzyloxy group of the phenylacetamido chain enhanced affinity at the A(2B) receptor [compound 30b (K(i)(hA(2B)) = 13 nM) vs compound 21b (K(i)(hA(2B) = 56 nM)] but did not favor selectivity. The derivatives with higher affinity at human A(2B) AR proved to be antagonists, in the cyclic AMP assay, capable of inhibiting the stimulatory effect of NECA (100 nM) with IC(50) values in the nanomolar range, a trend similar to that observed in the binding assay (62b, IC(50) = 38 nM; 72b, IC(50) = 46 nM). In conclusion, the 8-pyrazolo-1,3-dipropyl-1H-purine-2,6-dione derivatives described herein represent a new family of selective antagonists for the adenosine A(2B) receptor.

Adenosine A1 Receptor Antagonists↗
PubMed2005

Amino acid promoted CuI-catalyzed C-N bond formation between aryl halides and amines or N-containing heterocycles.

CuI-catalyzed coupling reaction of electron-deficient aryl iodides with aliphatic primary amines occurs at 40 degrees C under the promotion of N-methylglycine. Using l-proline as the promoter, coupling reaction of aryl iodides or aryl bromides with aliphatic primary amines, aliphatic cyclic secondary amines, or electron-rich primary arylamines proceeds at 60-90 degrees C; an intramolecular coupling reaction between aryl chloride and primary amine moieties gives indoline at 70 degrees C; coupling reaction of aryl iodides with indole, pyrrole, carbazole, imidazole, or pyrazole can be carried out at 75-90 degrees C; and coupling reaction of electron-deficient aryl bromides with imidazole or pyrazole occurs at 60-90 degrees C to provide the corresponding N-aryl products in good to excellent yields. In addition, N,N-dimethylglycine promotes the coupling reaction of electron-rich aryl bromides with imidazole or pyrazole to afford the corresponding N-aryl imidazoles or pyrazoles at 110 degrees C. The possible action of amino acids in these coupling reactions is discussed.

Amines↗
PubMed2006

Tris(pyrazolyl)borate carbosilane dendrimers and metallodendrimers.

A modified tris(pyrazolylborate) ligand has been prepared in two steps. First, reaction of triisopropylborate with allylmagnesium bromide and further treatment with benzoyl chloride gave CH(2) = CHCH(2)B(O(i)Pr), which was then reacted with potassium pyrazolate and pyrazole to give the compound K[CH(2) = CHCH(2)Bpz(3)]. The new allyl-containing scorpionate anion of acts as a bi- or tri-dentate ligand, as shown by the mononuclear complexes [CH(2) = CHCH(2)Bpz(3)M(LL)] (M = Rh, LL = nbd, ; LL = tfb, ; LL = (CO)(PPh(3)), ; M = Ir, LL = cod, ), obtained from reactions of the chlorido-bridged dinuclear complexes [{M(mu-Cl)(LL)}(2)] with 2. Furthermore, the borate represents a key material to achieve the attachment of tris(pyrazolyl)borate groups to the peripheries of carbosilane dendrimers. Thus, the platinum-catalyzed hydrosilylation reactions of compound with the dendritic cores Si[(CH(2))(3)SiMe(2)H](4) (G(0)-(SiH)(4)), (G(1)-(SiH)(8)), and (G(2)-(SiH)(16)) gave the corresponding borate-containing dendrimers Si[(CH(2))(3)SiMe(2)(CH(2))(3)B(O(i)Pr)(2)](4) (G(0)-B(4)), Si[(CH(2))(3)SiMe{(CH(2))(3)SiMe(2)(CH(2))(3)B(O(i)Pr)(2)}(2)](4) (G(1)-B(8)), and Si[(CH(2))(3)SiMe{(CH(2))(3)SiMe[(CH(2))(3)SiMe(2)(CH(2))(3)B(O(i)Pr)(2)](2)}(2)](4) (G(2)-B(16)) selectively in the anti-Markovnikov direction. Further reactions of G(0)-B(4), G(1)-B(8) and G(2)-B(16) with potassium pyrazolate and pyrazole rendered the corresponding polyanionic dendrimers K(4)[Si{(CH(2))(3)SiMe(2)(CH(2))(3)Bpz(3)}(4)] (G(0)-(Bpz(3))(4)), G(1)-(Bpz(3))(8), and G(2)-(Bpz(3))(16), respectively, which contain 4, 8, and 16 tris(pyrazolyl)borate groups symmetrically located around the dendritic peripheries. These unusual polyanionic dendrimers are excellent scaffolds to support metal centres, as shown by the reactions of G(0)-(Bpz(3))(4), G(1)-(Bpz(3))(8), and G(2)-(Bpz(3))(16) with [{Rh(mu-Cl)(nbd)}(2)] to give the neutral rhodadendrimers [Si{(CH(2))(3)SiMe(2)(CH(2))(3)Bpz(3)Rh(nbd)}(4)] G(0)-(Bpz(3)Rh)(4), G(1)-(Bpz(3)Rh)(8) and G(2)-(Bpz(3)Rh)(16) as stable solids in excellent yields. Following this protocol, mixed rhodium/iridium metallodendrimers can be prepared.

Journal Article↗