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The 243 coupling constants of eight N-R-pyrazoles [R=H, CH3, C6H5, COCH3, NH2, NO2, SO2CF3, Si(CH3)3] have been calculated and compared with 131 experimental values. The agreement is good and can be used to estimate new couplings. The whole collection has been statistically analyzed.
Since estrogens have vital functions in the uterus but might also contribute to endometrial cancer, we sought to determine the in vitro effects of methyl-piperidino-pyrazole (MPP), raloxifene, and beta-estradiol on Ishikawa and RL-95 endometrial cancer, and ovine luminal endometrial (oLE) cell lines and the in vivo effects of these compounds in the rodent uterus. MPP and raloxifene (1 nM) induced significant apoptosis in the endometrial cancer and oLE cell lines compared to beta-estradiol treated and control cells (P <or= 0.0001-0.001). To determine the in vivo uterine effects of these compounds, ovariectomized wild-type (WT) and estrogen receptor-beta knockout (ERbetaKO) mice were treated with 25, 50, 100, or 150 microg of each compound. Although raloxifene caused no significant increase in uterine weight, the presumptive ERalpha antagonist, MPP (25-150 microg) increased uterine weight, and cell proliferation significantly relative to vehicle control in WT and ERbetaKO mice (P <or= 0.001). However, MPP did not increase uterine wet weight as effectively as beta-estradiol (P <or= 0.0001), and administration of either 50 microg of MPP or raloxifene effectively reversed the positive effects of 50 and 100 microg beta-estradiol. Unexpectedly, in view of the in vitro studies, MPP and raloxifene treatment of ovariectomized mice did not induce apoptosis of the luminal epithelial cells but rather these compounds induced apoptosis of the underlying uterine stromal cells. These results demonstrate that MPP and raloxifene can exert apparently contrasting in vitro versus in vivo effects, and that they have mixed agonist/antagonist action on murine uterine ERalpha in vivo.
We synthesized and evaluated a series of 5-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamides to identify potent inhibitors of calcium-release-activated calcium (CRAC) channels with greater selectivity than voltage-operated calcium (VOC) channels. These efforts resulted in identification of compounds 22 and 24. The former exhibits highly potent and selective CRAC channel inhibitory activity, and the latter inhibited phytohemagglutinin-induced interleukin-2 production by Jurkat T lymphocytes and concanavalin A-induced hepatitis in mice.
Synthesis of [18F]4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide ([18F]celecoxib), a selective COX-2 inhibitor, is achieved via a bromide to [18F]F- exchange reaction. Synthesis of the precursor for radiolabeling was achieved from 4'-methylacetophenone in four steps with 22% overall yield. Under non-radioactive conditions, fluorination was achieved using TBAF in DMSO at 135 degrees C in 80% yield. Synthesis of [18F]celecoxib was achieved using [18F]TBAF in DMSO at 135 degrees C in 10+/-2% yield (EOS) with >99% chemical and radiochemical purities. The specific activity was 120+/-40 mCi/micromol (EOB). [18F]celecoxib was found to be stable in ethanol, however, de[18F]fluorination (6.5%) was observed after 4 h in 10% ethanol-saline solution. Rodent PET studies show bone labeling indicating in vivo de[18F]fluorination of [18F]celecoxib. PET studies in baboon indicated a lower rate of de[18F]fluorination than rat and retention of radioactivity in brain regions consistent with the known distribution of COX-2. A radiolabeling method that can generate consistent high specific activity is needed for routine human use.
Synthesis and biological evaluation of possible prodrugs of COX-2 inhibitors involving sulfonamide and hydroxymethyl groups of 2-hydroxymethyl-4-(5-phenyl-3-trifluoromethyl-pyrazol-1-yl) benzenesulfonamides are described. Out of many options, the sodium salt of N-propionyl sulfonamide demonstrated much improved pharmacological profiles and physicochemical properties suitable for oral as well as parenteral administration.
A series of 5-((1H-pyrazol-4-yl)methylene)-2-thioxothiazolidin-4-one inhibitors of ADAMTS-5 (aggrecanase-2) is described. These compounds show microM functional inhibition of ADAMTS-5, and represent a new class of agents with the potential of inhibiting degradation of aggrecan, a major component of cartilage which is lost in osteoporosis. Compound 12 is noteworthy in that it has an ADAMTS-5 IC50: 1.1 microM and shows >40-fold functional selectivity over ADAMTS-4 (aggrecanase-1).
Some new 1H-pyrazole-3-carboxylic acid and pyridazinone derivatives were synthesized and evaluated for their antibacterial activities against Bacillus cereus ATCC 7064, Staphylococcus aureus ATCC 6538, Escherichia coli ATCC 4230 and Pseudomonas putida using tube dilution method. The minimal inhibitory concentrations (MICs) experiments revealed that all chemical compounds showed inhibitor effects on the growth of the test microorganisms. Moreover, the results of this research showed that the compound named as 5c was the best compound in the series, exhibiting antibacterial activity against both Gram-positive and Gram-negative bacteria.
Three new complexes [Cu(L)(2)(NO(3))](NO(3))(H(2)O)(1/2)(CH(3)OH)(1/2) (1), [Cd(L)(2)(NO(3))(2)](H(2)O)(3) (2) and [Cd(L)(2)(ClO(4))(CH(3)OH)](ClO(4))(H(2)O)(1/4)(CH(3)OH) (3) (L=1-[3-(2-pyridyl)pyrazol-1-ylmethyl]naphthalene) were synthesized and characterized by elemental analyses, IR and X-ray diffraction analysis. Among them, the Cu(II) and Cd(II) ions were both coordinated by four N donors from two distinct L ligands via N,N-bidentate chelating coordination mode. Additional weak interactions, such as the face-to-face pi-pi stacking and C-Hcdots, three dots, centeredO H-bonding interactions, linked the mononuclear unit into 1D chain and further into 2D network. Complexes 1-3 were subjected to biological assays in vitro against six different cancer cell lines. All of them exhibited cytotoxic specificity and notable cancer cell inhibitory rate. The interactions of 1-3 with calf thymus DNA were investigated by thermal denaturation, viscosity measurements, spectrophotometric and electrophoresis methods. The results indicate that these complexes bound to DNA by intercalation mode via the ligand L and had different nuclease activities, which were in good agreement with their DNA-binding strength. Moreover, the central metal ions of 1-3 played a vital role in DNA-binding behaviors, DNA-cleavage activities and cytotoxicities, whereas the contribution of the different counter anions to their bioactivities also should not be ignored.
Atypical antipsychotic properties of 4-(4-fluorobenzylidene)-1-[2-[5-(4-fluorophenyl)-1H-pyrazol-4-yl]ethyl] piperidine (NRA0161) were investigated by in vitro receptor affinities, in vivo receptor occupancies and findings were compared with those of risperidone and haloperidol in rodent behavioral studies. In in vitro receptor binding studies, NRA0161 has a high affinity for human cloned dopamine D(4) and 5-HT(2A) receptor with Ki values of 1.00 and 2.52 nM, respectively. NRA0161 had a relatively high affinity for the alpha(1) adrenoceptor (Ki; 10.44 nM) and a low affinity for the dopamine D(2) receptor (Ki; 95.80 nM). In in vivo receptor binding studies, NRA0161 highly occupied the 5-HT(2A) receptor in rat frontal cortex. In contrast, NRA0161 did not occupy the striatal D(2) receptor. In behavioral studies, NRA0161, risperidone and haloperidol antagonized the locomotor hyperactivity in mice, as induced by methamphetamine (MAP). At a higher dosage, NRA0161, risperidone and haloperidol dose-dependently antagonized the MAP-induced stereotyped behavior in mice and NRA0161 dose-dependently and significantly induced catalepsy in rats. The ED(50) value in inhibiting the MAP-induced locomotor hyperactivity was 30 times lower than that inhibiting the MAP-induced stereotyped behavior and 50 times lower than that which induced catalepsy. These findings suggest that NRA0161 may have atypical antipsychotic activities yet without producing extrapyramidal side effects.
Twenty-five 2-phenyl-5,6-dihydro-2H-thieno[3,2-c]pyrazol-3-ol derivatives were synthesized for evaluation as new inhibitors of bacterial cell wall biosynthesis. Many of them demonstrated good inhibitory activity against Staphylococcus aureus MurB, MurC and MurD enzymes in vitro and antimicrobial activity against gram-positive bacteria including MRSA, VRE and PRSP. However, when they were tested in the presence of 4% bovine serum albumin, the MIC values increased to greater than 128 microg/mL against PRSP. None of the compounds demonstrated activity against gram-negative bacteria at MIC <32 microg/mL.
A series of 3-(pyrazol-3-yl)-1-azabicyclo[2.2.2]octane derivatives C (Fig. 1) was synthesized and tested for muscarinic activity in receptor binding assays using [3H]-oxotremorine-M (OXO-M) and [3H]-pirenzepine (PZ) as ligands. Potential muscarinic agonistic or antagonistic properties of the compounds were determined using binding studies measuring their potencies to inhibit the binding of OXO-M and PZ. Preferential inhibition of OXO-M binding was used as an indicator for potential muscarinic agonistic properties; this potential was confirmed in functional studies on isolated organs.
Using 5-hydroxy-hex-3-yne-2-one (9) as a model substrate, the utility of the gamma-hydroxyl alkynyl ketone scaffold for the preparation of combinatorial libraries of furans, isoxazoles, and pyrazoles is described. The addition of hydrazoic acid to the acetylenic ketone 9 forms in a single step both 3-azido-2,5-dimethyl furan (10) and alpha,5-dimethyl-3-isoxazolemethanol (11). Reaction of a mixture of (E)- and (Z)-bromoenediones (5 and 6), accessible from 3-bromo-2,5-dimethyl furan (17), with 1,1-dimethylhydrazine afforded a nearly quantitative yield of 1,3-dimethyl-5-acetylpyrazole (18). When the (E)- and (Z)-vinyl bromides 5 and 6 were reacted with sodium azide, 3-acetyl-5-methylisoxazole (7) formed via the intermediate (Z)-3-azido-3-hexene-2,5-dione (4), was the only product.
An efficient method for the synthesis of multidentate molecules, with various building blocks, such as pyrazolyl, triazolyl, pyridyl, furyl, or bispinidyl derivatives, is reported. This approach is based on the condensation of easily available N-alkyl heteroarylamines with N-hydroxymethyl pyrazoles or triazoles.
Slow uptake of molecular dihydrogen by the diiridium(I) prototype [Ir(mu-pz)(PPh(3))(CO)](2) (1: pzH = pyrazole) is accompanied by formation of a 1,2-dihydrido-diiridium(II) adduct [IrH(mu-pz)(PPh(3))(CO)](2) (2), for which an X-ray crystal structure determination reveals that (unlike in 1) the PPh(3) ligands are axial, with the hydrides occupying trans coequatorial positions across the Ir-Ir bond (2.672 A). Reaction with CCl(4) effects hydride replacement in 2, affording the monohydride Ir(2)H(Cl)(mu-pz)(2)(PPh(3))(2)(CO)(2) (3) in which Ir-Ir = 2.683 A. At one metal center, H is equatorial and PPh(3) is axial, while at the other, Cl is axial as is found in the symmetrically substituted product [Ir(mu-pz)(PPh(3))(CO)Cl](2) (4) (Ir-Ir = 2.754 A) that is formed by action of CCl(4) on 1. Treatment of 1 with I(2) yields the diiodo analogue 5 of 4, which reacts with LiAlH(4) to afford the isomorph Ir(2)H(I)(mu-pz)(2)(PPh(3))(2)(CO)(2) (6) of 3 (Ir-Ir = 2.684 A). Protonation (using HBF(4)) of 1 results in formation of the binuclear cation Ir(2)H(mu-pz)(2)(PPh(3))(2)(CO)(2)(+) (7: BF(4)(-) salt), which shows definitive evidence (from NMR) for a terminally bound hydride in solution (CH(2)Cl(2) or THF), but 7 crystallizes as an axially symmetric unit in which Ir-Ir = 2.834 A. Reaction of 7 with water or wet methanol leads to isolation of the cationic diiridium(III) products [Ir(2)H(2)(mu-OX)(mu-pz)(2)(PPh(3))(2)(CO)(2)]BF(4) (8, X = H; 9, X = Me).
The reaction of ZnCl(2) with tert-butylphosphonic acid and 3,5-dimethylpyrazole in the presence of triethylamine as a hydrogen chloride scavenger affords a trinuclear molecular zinc phosphonate [Zn(3)Cl(2)(3,5-Me(2)Pz)(4)(t-BuPO(3))(2)]. The structure of this compound contains a planar trizinc assembly containing two bicapping mu(3) [t-BuPO(3)](2-) ligands and terminal pyrazole and chloride ligands. In contrast an analogous reaction of ZnCl(2) with phenylphosphonic acid and 3,5-dimethylpyrazole affords a hexanuclear zinc phosphonate [Zn(6)Cl(4)(3,5-Me(2)PzH)(8)(PhPO(3))(4)]. The six zinc centers are arranged in a chairlike conformation. The four phosphonates in this complex also act as bridging tripodal mu(3) [RPO(3)](2-) ligands.
Reaction of [(HBpz(3))RhCl(2)(PPh(3))] (Hpz = pyrazole) with silver salts AgA (A = BF(4), NO(3), SbF(6)) affords the unexpected heterotrinuclear compounds [[(HBpz(3))Rh(PPh(3))(mu-Cl)(2)](2)Ag]A (A = BF(4) (1), NO(3) (2), SbF(6) (3)). The compounds have been fully characterized by IR, (1)H, (31)P[(1)H], and (13)C[(1)H] NMR spectroscopy and FAB(+) mass spectrometry. The solid structure of compound 1 was determined by single-crystal X-ray diffraction. The cation consists of two (HBpz(3))RhCl(2)(PPh(3)) units bonded to a silver atom through two double mu-Cl bridges in an unusual distorted square-planar arrangement.
The synthesis of a number of 3d transition metal binary pyrazolates in microcrystalline form, thus suitable for a full XRPD characterization, has been pursued. The crystal and molecular structures of the Fe(pz)3, Co(pz)2, Co(pz)3, and Ni(pz)2 polymers, together with the few congeners reported in the recent literature, show that these species tend to afford highly crystalline materials where strictly collinear chains of metal atoms are present. Depending on the synthetic strategy used, Ni(pz)2 has been found to crystallize as two different alpha (orthorhombic) and beta (monoclinic) phases, possessing nearly identical intramolecular features. Data for each compound follow. Fe(pz)3: C9H9FeN6, hexagonal, P63/m, a = 9.1745(3) A, c = 7.2191(4) A, Z = 2. Co(pz)2: C6H6CoN4, orthorhombic, Ibam, a = 7.5239(5) A, b = 14.3461(9) A, c = 7.4331(5) A, Z = 4. Co(pz)3: C9H9CoN6, hexagonal, P63/m, a = 9.1966(3) A, c = 7.1051(3) A, Z = 2. Alpha-Ni(pz)2: C6H6N4Ni, orthorhombic, Cmcm, a = 16.6758(11) A, b = 6.4872(4) A, c = 6.9423(6) A, Z = 4. Beta-Ni(pz)2: C6H6N4Ni, monoclinic, P21/m, a = 9.967(2) A, b = 6.975(1) A, c = 6.016(1), A, beta = 98.50(1)degrees, Z = 2. The thermal stability and the detailed structural properties of these model compounds have been evaluated, in the light of the technologically relevant crystal phases (the well-known metal-diazolates showing reversible spin-crossover or spin-transition behavior) obtainable upon doping, magnetic dilution, and ring substitution (in the 4-position).
The supramolecular architecture of trinuclear gold(I) pyrazolato aggregates is held together by intermolecular aurophilic attractions, sterically governed by the substituents on the pyrazole rings. A two-dimensional network of [Au(mu-pz)]3 complexes, 1 (pz = pyrazolato anion, C3H3N2-), and a large intricate aggregate of 16 [Au(mu-4-Me-pz)]3 complexes in 2 have been determined crystallographically. Under UV irradiation at ambient temperature, solid samples of 1 and 2 luminesce with lambda max = 626 and 631 cm-1, respectively, attributed to intermolecular Au...Au aurophilic contacts.