- Mechanistic study of carboxylic acid and phosphate ester cleavage by oximate metal complexes surpassing the limiting reactivity of highly basic free oximate anions
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Two tridentate and one tetradentate new ligands containing the terminal oxime group separated from secondary amino and pyridine groups as additional binding sites by two or three methylene groups have been prepared. Their acid-base properties, as well as the composition and stability of their complexes with Zn(ii) and Cd(ii) ions, were determined by potentiometric and spectrophotometric titrations. The X-ray structure of a Cd(ii) complex of a related tridentate oxime ligand previously studied in solution was determined. All oximate complexes show high reactivity in the cleavage of aryl acetates, paraoxon, parathion and 4-nitrophenyl diphenyl phosphate, with rate constants significantly surpassing the limiting rate constants observed for highly basic free oximate anions. The second-order rate constants for individual oximate complexes in solution are assigned to each ligand, metal cation and substrate. The results of the cleavage of 4-substituted phenyl acetates were analyzed in terms of Br?nsted correlations with the leaving group pKa, which demonstrated a change in the rate determining step from the nucleophilic attack to the leaving group departure upon an increase in the leaving group basicity. The zero slope of the Br?nsted correlation for the nucleophilic attack indicates transition state stabilization through electrophilic assistance by the metal ion. This interpretation is supported by metal selectivity in the relative efficiency of the cleavage of paraoxon and parathion. The existence of the alpha-effect in ester cleavage by coordinated oximates is confirmed by an analysis of the Br?nsted correlations with the nucleophile basicity for metal bound oximate and alkoxo or hydroxo nucleophiles. The very high reactivity of the oximate complexes of the new ligands is attributed to transition state stabilization and to the removal of the solvational imbalance of oximate anions that impedes the expected increase in the reactivity of highly basic free anions.
- Flores-Alamo, Marcos,Gómez-Tagle, Paola,Lugo-González, José Carlos,Yatsimirsky, Anatoly K.
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p. 2452 - 2467
(2020/03/05)
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- Validation of Phosphodiesterase-10 as a Novel Target for Pulmonary Arterial Hypertension via Highly Selective and Subnanomolar Inhibitors
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Pulmonary arterial hypertension (PAH) causes pathological increase in pulmonary vascular resistance, leading to right-heart failure and eventual death. Previously, phosphodiesterase-10 (PDE10) was reported to be a promising target for PAH based on the studies with a nonselective PDE inhibitor papaverine, but little progress has been made to confirm the practical application of PDE10 inhibitors. To validate whether PAH is ameliorated by PDE10 inhibition rather than other PDE isoforms, here we report an integrated strategy to discover highly selective PDE10 inhibitors as chemical probes. Structural optimization resulted in a PDE10 inhibitor 2b with subnanomolar affinity and good selectivity of >45 000-fold against other PDEs. The cocrystal structure of the PDE10-2b complex revealed an important H-bond interaction between 2b and Tyr693. Finally, compound 2b significantly decreased the arterial pressure in PAH rats and thus validated the potential of PDE10 as a novel anti-PAH target. These findings suggest that PDE10 inhibition may be a viable treatment option for PAH.
- Huang, Yi-You,Yu, Yan-Fa,Zhang, Chen,Chen, Yiping,Zhou, Qian,Li, Zhuoming,Zhou, Sihang,Li, Zhe,Guo, Lei,Wu, Deyan,Wu, Yinuo,Luo, Hai-Bin
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p. 3707 - 3721
(2019/04/26)
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- Chemoselective hydrogenation of nitriles to primary amines catalyzed by water-soluble transition metal catalysts
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The water-soluble rhodium complex generated in situ from [Rh (COD)Cl]2 in aqueous ammonia has been revealed as a highly efficient catalyst for the hydrogenation of aromatic nitriles, to primary amines with excellent yields. The catalyst is also highly selective towards primary amines in the case of sterically hindered aliphatic nitriles. The catalytic system can also be recycled and re-used with no significant loss of activity.
- Nait Ajjou, Abdelaziz,Robichaud, André
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- HIV INTEGRASE INHIBITORS
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The present invention features compounds that are HIV integrase inhibitors and therefore are useful in the inhibition of HIV replication, the prevention and/or treatment of infection by HIV, and in the treatment of AIDS and/or ARC.
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- Modification and optimization of the bis-picolylamide-based relay protection for carboxylic acids to be cleaved by unusual complexation with Cu2+ salts
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A simple modification of our recently published protection scheme for carboxylic acids as amides resulted in a new protecting group with significantly improved properties. It requires shorter reaction times for deprotection and allows us to replace Cu(OTf)2 by CuCl2, indicating at the same time the importance of the nature of the anion of the Cu2+ source. Since the new scheme fulfills all criteria required for an ideal protection group it should find widespread application in synthetic organic chemistry.
- Mundinger, Stephan,Jakob, Uwe,Bichovski, Plamen,Bannwarth, Willi
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p. 8968 - 8979,12
(2012/12/11)
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- A strategic approach for the synthesis of new porphyrin rings, attractive for heme model purpose
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Novel complexes have been efficiently synthesized with a facile route using two different atropisomers of the same porphyrin. These compounds feature a tridentate binding site, a tyrosine molecule, and a proximal base, all bound to the porphyrin ring in different fashions, making them attractive for heme modeling purposes.
- Ladomenou, Kalliopi,Charalambidis, Georgios,Coutsolelos, Athanassios G.
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p. 2882 - 2887
(2007/10/03)
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- Mononuclear, dinuclear, and pentanuclear [{N,S(thiolate)}iron(II)] complexes: Nuclearity control, incorporation of hydroxide bridging ligands, and magnetic behavior
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The mixed N3S(thiolate) ligand 1-[bis(2-(pyridin-2-yl)ethyl} amino]-2-methylpropane-2-thiol (Py2SH) was used in the synthesis of four iron(II) complexes: [(Py2S)FeCl] (1), [(Py2S)FeBr] (2), [(Py2S)4Fe5II(μ-OH) 2]-(BF4)4 (3). and [(Py2S) 2Fe2II(μ-OH)]BF4 (4). The X-ray structures of 1 and 2 revealed monomeric iron(II)-alkylthiolate complexes with distorted trigonal-bi-pyramidal geometries. The paramagnetic 1H NMR spectra of 1 and 2 display resonances from δ = -25 ppm to + 100 ppm, consistent with a high-spin iron(II) ion (S=2). Spectral assignments were made on the basis of chemical shift information and T1 measurements and show the monomeric structures are intact in solution. To provide entry into hydroxide-containing complexes, a novel synthetic method was developed involving strict aprotic conditions and limiting amounts of H2O. Reaction of Py2SH with NaH and Fe-(BF4)2·6H 2O under aprotic conditions led to the isolation of the pentanuclear, μ-OH complex 3, which has a novel dimer-of-dimers type structure connected by a central iron atom. Conductivity data on 3 show this structure is retained in CH2Cl2. Rational modification of the ligand-to-metal ratio allows control over the nuclearity of the product, yielding the dinuclear complex 4. The X-ray structure of 4 reveals an unprecedented face-sharing, biooctahedral complex with an [S2O] bridging arrangement. The magnetic properties of 3 and 4 in the range 1.9-300 K were successfully modeled. Dinuclear 4 is antiferromagnetically coupled [J = -18.8(2) cm-1]. Pentanuclear 3 exhibits ferrimagnetic behavior, with a high-spin ground state of ST=6, and was best modeled with three different exchange parameters [J= -15.3(2), J′ = -24.7(3), and J″ = -5.36(7) cm-1]. DFT calculations provided good support for the interpretation of the magnetic properties.
- Krishnamurthy, Divya,Sarjeant, Amy N.,Goldberg, David P.,Caneschi, Andrea,Totti, Federico,Zakharov, Lev N.,Rheingold, Arnold L.
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p. 7328 - 7341
(2007/10/03)
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- Tetracyclic benzimidazole derivatives and combinatorial libraries thereof
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The present invention relates to novel tetracyclic benzimidazole derivative compounds of the following formula: wherein R1to R10have the meanings described in here. The invention further relates to combinatorial libraries containing two or more such compounds, as well as methods of preparing tetracyclic benzimidazole derivative compounds.
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- 2-aminobenzoxazole derivatives and combinatorial libraries thereof
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The present invention relates to novel 2-aminobenzoxazole derivative compounds of the following formula: wherein R1 to R4 and Z have the meanings provided herein. The invention further relates to combinatorial libraries containing two or more such compounds, as well as methods of preparing 2-aminobenzoxazole derivative compounds.
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- 4-unsubstituted dihydroisoquinolinone derivatives and combinatorial libraries thereof
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The present invention relates to novel dihydroisoquinolinone (DHQ) derivative compounds of the following formula: wherein R1to R7, X, Y, Z, b, c and d have the meanings provided herein. The invention further relates to combinatorial libraries containing two or more such compounds, as well as methods of preparing DHQ derivative compounds.
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- 2-aminopyridine derivatives and combinatorial libraries thereof
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The present invention relates to novel 2-aminopyridine derivative compounds of the following formula: wherein R1to R5have the meanings provided herein. The invention further relates to combinatorial libraries containing two or more such compounds, as well as methods of preparing 2-aminopyridine derivative compounds.
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- Benzothiazole derivatives with activity as adenosine receptor ligands
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The present invention relates to substituted benzothiazole derivitives and to their pharmaceutically acceptable salts useful for the treatment of diseases related to the adenosine receptor.
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- N-(aryl-,aryloxy-,arylthio-arylsulfinyl-and arylsulfonyl-)alkyl-N,N'-(or n'n')alkylaminoalkyl ureas and cyanoguanidines
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Novel N-(Aryl-,aryloxy-,arylthio-,arylsulfinyl-and arylsulfonyl-)alkyl-N,N'-(or N',N')alkylaminoalkyl ureas, thioureas and cyanoguanidines represented by the following formula: STR1 wherein Ar is aryl selected from the group consisting of 1- and 2-naphthyl, 2,3-dihydro-1H-inden-4(or 5)-yl,2-furanylmethyl,2-pyridinyl, phenyl and phenyl substituted by 1-3 radicals commonly used in the pharmaceutical art; (X)d is oxygen, thio, sulfinyl, sulfonyl or d is zero; Z and W are each R or-(CH2)m -NR1 R2 wtih the proviso that when Z is R, W is-(CH2)m -NR1 R2 and when Z is-(CH2)m -NR1 R2, W is R; B is carbonyl, thioxomethyl, or cyanoiminomethyl; R, R1, R2, R3 and R4 are selected from the group consisting of hydrogen, loweralkyl, cycloalkyl, phenyl or phenyl-loweralkyl wherein phenyl may be substituted by 1-3 radicals commonly used in the pharmaceutical art; R1 and R2, and R3 and R4 may together with the adjacent nitrogen form the heterocyclic ring structure 1-homopiperidinyl, 4-morpholinyl, 1-piperazinyl, 4-substituted-1-piperazinyl, 1-pyrrolidinyl or 1-piperidinyl and the pharmaceutically acceptable salts thereof are disclosed. A pharmaceutical method for administering the compounds for their cardiac antiarrhythmic effect and pharmaceutical compositions for the treatment of cardiac arrhythmia are also disclosed.
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- Mitomycin analogs
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Novel methods for treatment of neoplastic disease states in animals, which methods comprise administering a therapeutically effective amount of a compound of the formula IIIa, STR1 wherein: Y is hydrogen or lower alkyl; and Z is an hydroxy substitited 1-pyrrolidinyl radical, or a lower alkyl substituted piperidyl radical, or a 1-piperazinyl radical or an acetamino, acetyl, carbamido, cyano, carboxy lower alkylamino, di-lower alkoxy, nitro, sulfamyl, or lower alkyl substituted anilino radical, or a radical of the formula, STR2 wherein R is hydrogen or lower alkyl and R1 is a nitrogen containing heterocyclic radical selected from the group consisting of amino substituted triazolyl, lower alkyl substituted isothiazolyl, benzothiazolyl, and nitro and halo substituted derivatives of benzothiazolyl, or R1 is a substituted lower alkyl radical selected from the group consisting of amino lower alkyl, lower alkylamino lower alkyl, hydroxy lower alkylamino lower alkyl, hydroxy lower alkoxy lower alkyl, imidazolyl lower alkyl, nitro substituted imidazolyl lower alkyl, mono- and di-hydroxy phenyl lower alkyl, nitro substituted pyridylamino lower alkyl, piperazinyl lower alkyl, and pyridyl ethyl.
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- INTRAMOLECULAR GENERAL-BASE CATALYSIS OF SCHIFF-BASED HYDROLYSIS BY TERTIARY AMINO GROUPS.
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Hydrolysis of a series of Schiff bases derived from benzophenone and various amines has been studied kineticlly in aqueous solution. A linear correlation of the log of the rate constants for the water reaction with the Schiff base pK//a (slope minus 0. 70) shows large positive deviations for Schiff bases derived from (2-aminoethyl)diethylamine, N-(2-aminoethyl)morpholine, N-(2-aminoethyl)piperazine and 2-(aminomethyl)pyridine (1i) but small deviations for Schiff bases from N-(3-aminopropyl)morpholine and 2-(2-aminoethyl)pyridine. The deviations found are attributed to intramolecular general-base catalysis of the water reaction by the internal tertiary amino groups. Magnitudes of the rate enhancement are correlated well with pK//a//l of the internal catalyst ( beta equals 0. 49). Effective concentrations of the internal bases are estimated to range from 340 (1e) to 40 M.
- Okuyama,Shibuya,Fueno
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p. 730 - 736
(2007/10/02)
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- Process for the catalytic production of 2-substituted pyridines
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A process for the catalytic production of a 2-substituted pyridine which comprises reacting a corresponding cyano compound and acetylene in the presence of cobaltocene. Favorable conversion speed, conversion of at least 90 percent, good yield and high selectivity are obtained.
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- Separation of blood coagulation factors with non-activating polyelectrolytes
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Blood coagulation factors such as Factor VIII are separated from admixture with other blood proteins without producing activation of said coagulation factors by contacting with a water-insoluble, cross-linked polyelectrolyte copolymer of (a) C2-18 unsaturated monomer and (b) C4-12 unsaturated polycarboxylic acid or anhydride which is partially substituted at its free carboxyl or anhydride sites with amine-imides and in which substantially all the remaining free carboxyl or anhydride sites are blocked with alkoxyalkylamine to form alkoxyalkylimide units.
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- 9-Xanthylamin oalkylpyridine derivatives
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9-Xanthylaminoalkylpyridine derivatives are prepared. These compounds are inhibitors of gastric acid secretion.
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