- Design and Biological Evaluation of Manganese- and Ruthenium-Based Hybrid CO-RMs (HYCOs)
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Interest in the therapeutic effects of carbon monoxide (CO), a product of heme degradation catalyzed by the enzyme heme oxygenase-1 (HO-1), has led to the development of CO-releasing molecules (CO-RMs) for the controlled delivery of this gas in vivo. We recently proposed conjugating a cobalt-based CO-RM with various activators of nuclear factor erythroid 2-related factor 2 (Nrf2), the transcription factor that regulates HO-1 expression, in order to exploit the beneficial effects of exogenous and endogenous CO. In this study, we describe the preparation of hybrid molecules (termed HYCOs) conjugating a fumaric acid derivative as an Nrf2 activator to a Mn- or a Ru-based CO-RM known to be pharmacologically active. With the exception of an acyl-manganese complex, these hybrids were obtained by associating the two bioactive entities by means of a linker of variable structure. X-ray diffraction analyses and preliminary biological investigations are also presented.
- Ollivier, Anthony,Foresti, Roberta,El Ali, Zeina,Martens, Thierry,Kitagishi, Hiroaki,Motterlini, Roberto,Rivard, Michael
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Read Online
- A Bioinspired Multicomponent Catalytic System for Converting Carbon Dioxide into Methanol Autocatalytically
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Nature utilizes multicomponent catalyst systems to convert simple, abundant starting materials into complex molecules that are essential for life. In contrast, synthetic chemical transformations rarely adopt this strategy because it is difficult to replicate the sophisticated supramolecular assemblies used by biology for active-site separation and substrate trafficking. Here, we describe a method for multicomponent catalyst separation that involves encapsulating transition-metal complexes in nanoporous materials called metal-organic frameworks. The multicomponent catalyst system was highly active for converting hydrogen and carbon dioxide to methanol, and it could be formulated to be readily recyclable. Moreover, we uncovered an autocatalytic feature that was possible only when we utilized the multicomponent catalyst strategy. These results open avenues for obtaining fuel from abundant and renewable resources. Methanol is a promising renewable fuel that can be adapted to the current liquid fuel infrastructure. It can be produced from hydrogen and carbon dioxide, mitigating greenhouse gas emissions and storing hydrogen in the process. However, the industrial production of methanol through this hydrogenation reaction currently requires elevated temperatures and pressures and can produce significant amounts of unwanted byproducts. Here, we employ a bioinspired tandem catalytic system to efficiently hydrogenate carbon dioxide to methanol selectively at low temperatures. We achieved superior performance by eliminating catalyst incompatibility through encapsulating at least one of the catalysts involved in the tandem process in nanoporous materials called metal-organic frameworks. In the long term, this method could be applied to other tandem catalytic processes, allowing more efficient access to alternative fuels, commodity chemicals, and valuable pharmaceutical products. Tsung and co-workers describe a three-component tandem catalytic process for the hydrogenation of carbon dioxide to methanol. The bioinspired process is enabled by encapsulation of at least one of the two ruthenium-based catalysts required in the metal-organic framework (MOF) UiO-66. The reaction was found to have an autocatalytic feature that enables the reaction to be carried out without superstoichiometric additives. Encapsulating both ruthenium-based catalysts in the MOF allowed the catalyst to be recycled.
- Rayder, Thomas M.,Adillon, Enric H.,Byers, Jeffery A.,Tsung, Chia-Kuang
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supporting information
p. 1742 - 1754
(2020/05/25)
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- Pd(II) Complexes with Chelating Phosphinoferrocene Diaminocarbene Ligands: Synthesis, Characterization, and Catalytic Use in Pd-Catalyzed Borylation of Aryl Bromides
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We developed a novel, straightforward route toward Pd(II)-aminocarbene complexes bearing a P-chelating phosphinoferrocenyl substituent based on a three-component reaction of 1′-(diphenylphosphino)-1-isocyanoferrocene (1) with [PdCl2(cod)] (cod = cycloocta-1,5-diene) and nucleophilic amines. Depending on the type of the amine, the reaction produced acyclic diaminocarbenes and their saturated (imidazolin-2-ylidene) and unsaturated (imidazol-2-ylidene) cyclic counterparts (NHCs). Using (S)-2-(chloromethyl)pyrrolidine as the nucleophile, this method afforded a separable pair of stable diastereomeric bicyclic imidazolin-2-ylidene carbenes with different configurations of the planar-chiral ferrocene unit. The prepared P-chelating carbenes were characterized using spectroscopic methods, X-ray crystallography, and DFT methods. The last were used to explain the formation of isomeric open diaminocarbenes featuring NHR groups at the wing-tip position, trends in Pd-Cl bond lengths reflecting similar trans influences of the particular carbene and phosphine donors, and the results from cyclic voltammetric measurements. Furthermore, the carbenes were used as defined (pre)catalysts in Miyaura borylation of aryl bromides with bis(pinacolato)diboron. When applying the optimized catalytic system (1 mol % Pd catalyst, KOAc as the base, 2-propanol, 85 °C), this reaction produced a range of simple and substituted arylboronate pinacol esters in high yield and without biaryl side products.
- ?koch, Karel,Schulz, Ji?í,Císa?ová, Ivana,?těpni?ka, Petr
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supporting information
p. 3060 - 3073
(2019/08/20)
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- A strategy combining quantitative reactions and reversible-covalent chemistry for sequential synthesis of sequence-controlled polymers with different sequences
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A new strategy combing quantitative reactions and reversible-covalent chemistry is proposed for sequential synthesis of a series of sequence-controlled polymers with different sequences. Using a Michael addition reaction between acrylate and thiol, an aminolysis reaction of five-membered cyclic dithiocarbonate and a thiol substitution reaction of bromomaleimide and thiol, AB-, AB'C- and AB'CD-sequenced molecules are synthesized via AB, AB'C and AB'CD sequential monomer additions, respectively. These three molecules all have furan-protected maleimido group at one end, and the other end of AB-, AB'C- and AB'CD-sequenced molecules is amine, thiol and anthracene groups, respectively. Due to the fact that the furan-protected maleimido group can be efficiently transformed to maleimide group at high temperature via retro Diels-Alder reaction, AB-, AB'C- and AB'CD-sequenced molecules polymerize into sequence-controlled polymers with corresponding sequences at 120 °C. Through this strategy, the synthesis of molecular modules does not require separation and purification, and sequence-controlled polymers with specific sequence can be synthesized in a one-pot process via adding different monomers and adjusting reaction condition.
- Xu, Chao-Ran,Zhang, Ze,Pan, Cai-Yuan,Hong, Chun-Yan
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p. 294 - 304
(2019/04/25)
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- FUMARATE-CO-RELEASING MOLECULE HYBRIDS, THEIR USE IN THE TREATMENT OF INFLAMMATORY OR CARDIOVASCULAR DISEASES AND THEIR PROCESS OF PREPARATION
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The present invention relates to hybrid fumarate-CO-releasing molecules capable of increasing heme oxygenase-1 (HO-1) activity and HO-1 protein expression and simultaneously releasing CO, their synthesis and their use in therapeutic applications, in particular their use in the treatment of inflammatory or cardiovascular diseases.
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Page/Page column 33
(2015/11/10)
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- Side chain impacts on pH- and thermo-responsiveness of tertiary amine functionalized polypeptides
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The systemic investigation of the structural impacts of side chains on the pH- and thermo-responsiveness of tertiary amine functionalized poly(l-glutamate)s (TA-PGs) was carried out. The TA-PGs polymers were effectively synthesized by Cu(I)-catalyzed azide-alkyne cycloaddition click reaction of azido tertiary amines with poly(γ-propargyl-l-glutamate) (PPLG). Turbimetric measurements were performed to characterize the pH- and temperature-induced phase transition of TA-PGs in aqueous solution, which suggested a structural dependence of the properties on the N-substituted groups and the "linkers" between 1,2,3-triazole ring and the tertiary amine groups in the side chains. In detail, the pH responsive properties of TA-PGs were basically determined by the hydrophobicity of the N-substituted groups in the side chains and the pH transition point (pHt) decreased as the increasing hydrophobicity of the N-substituted groups, while the temperature-responsiveness of TA-PGs were affected by either the N-substituted groups or the "linkers." TA-PGs with a moderate N-substituted amine group (e.g., DEA, PR, and PD) or a branched "linker" (e.g., iso-propylene and 2-methylpropylene group) were more likely to express the LCST-type phase transition tuned by pH variation. These structure-property relationships revealed in this study would help to develop the applications of TA-PGs in smart drug delivery systems. Copyright
- Xiao, Chunsheng,Cheng, Yilong,Zhang, Yu,Ding, Jianxun,He, Chaoliang,Zhuang, Xiuli,Chen, Xuesi
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p. 671 - 679
(2014/02/14)
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- NOVEL ARYLALKENE DERIVATIVES AND USE THEREOF AS SELECTIVE ESTROGEN RECEPTOR MODULATORS
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The invention provides novel ethylene derivatives represented by Formula I, which may be used as selective estrogen receptor modulators (SERMs) and useful in the prophylaxis and/or treatment of estrogen-dependent conditions or conditions.
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Paragraph 0236; 0312
(2013/07/19)
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- Aminophosphine-based chromium catalysts for selective ethylene tetramerization
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Chromium complexes of three new ligands, Ph2PN(Me)(CH 2)2-X [X = NMe2(PNN); PPh2 (PNP); Py (PNPy)], have been examined vis-a-vis their ability to promote ethylene tetramerization, (PNN)CrCl3(L) [L = THF (1); CH3CN (2)], (PNPy)CrCl3(L) [L = THF (3); CH3CN (4)], and (PNP)CrCl3(THF) (5). In the case of 2 and 4, it was possible to grow crystals suitable for X-ray diffraction. The reaction of 3 with Et3Al afforded the dinuclear [(HN(Me)(CH2)2Py)CrCl 2Et]2 (6) containing a trivalent chromium connected to an Et group. During the alkylation though, the ligand has been fragmented with removal of the side arm and protonation of the N atom of the remaining NP residue. All the complexes have been tested for ethylene oligomerization activity. Complex 1 displayed the highest selectivity for 1-octene, upon activation with DMAO in MeCy. Contrary to expectations, complex 6 is not a self-activating catalyst.
- Shaikh, Yacoob,Gurnham, Joanna,Albahily, Khalid,Gambarotta, Sandro,Korobkov, Ilia
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p. 7427 - 7433,7
(2020/10/15)
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- STYRYL SULFIDE DYES
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Disclosed are composition and method for dyeing keratin-containing fibers comprising or utilizing styryl sulfide dyes of formula (1), their salts, isomers, hydrates and other solvates, wherein R1, R′1, R2, R′2, R3, R′3, W1, W′1, W2, W′2, W3, W′3, W4, W′4, Q, Q′, Y1 and Y2 are defined in claims and disclosure.
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Page/Page column 31
(2009/08/14)
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- Facile conversion of cysteine and alkyl cysteines to dehydroalanine on protein surfaces: Versatile and switchable access to functionalized proteins
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An efficient and robust oxidative elimination of cysteine to dehydroalanine has been discovered. The reaction is induced by O-mesitylenesulfonylhydroxylamine (MSH) and is compatible with methionine. The key elimination has been executed on protein surfaces and allows ready access to different post-translationally modified proteins through conjugate addition of sulfur nucleophiles to dehydroalanine. Treatment of the resulting thioether with MSH results in regeneration of dehydroalanine, allowing a "functional switch" by subsequent addition of a different thiol. Copyright
- Bernardes, Goncalo J. L.,Chalker, Justin M.,Errey, James C.,Davis, Benjamin G.
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p. 5052 - 5053
(2008/10/09)
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- THIOL DYES
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Disclosed are thiol dyes of formula (I), wherein R1, R2, R3, R4 and R5 independently from each other are hydrogen; unsubstituted or substituted, straight-chain or branched, monocyclic or polycyclic, interrupted or uninterrupted C1-C14alkyl; C2-C14alkenyl; C6-C10aryl; C6-C10aryl-C1-C10alkyl; or C5-C10alkyl(C5-C10aryl); A is a residue of an organic dye; and Y1 is the direct bond; C1C10alkylene; C5-C10cycloalkylene; C5-C12arylene; or C5-C12arylene- (C1-C10alkylene). The compounds are used to dye hair with or without reducing agents. Furthermore, the present invention relates to compositions comprising thiol dyes of formula (I) and to process for the preparation of theses compounds.
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Page/Page column 37; 39-40; 42
(2008/06/13)
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- Synthesis and structure-activity relationships of 4-amino-5-chloro-N-(1,4- dialkylhexahydro-1,4-diazepin-6-yl)-2-methoxybenzamide derivatives, novel and potent serotonin 5-HT3 and dopamine D2 receptors dual antagonist
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In search of a dopamine D2 and serotonin 5-HT3 receptors dual antagonist as a potential broad antiemetic agent, a number of benzamides were prepared from 4-amino-5-chloro-2-methoxybenzoic acid derivatives and 6-amino-1,4-dialkylhexahydro-1,4-diazepines and evaluated for their binding affinity for the dopamine D2 and the serotonin 5-HT3 receptors using rat brain synaptic and rat cortical membranes, respectively. From the results of both in vitro receptor binding and in vivo biological assays for the dopamine D2 receptor, 1-ethyl-4-methylhexahydro-1,4- diazepine ring was selected as an optimum amine moiety. Introduction of one methyl group on the nitrogen atom at the 4-position and/or modification of the substituent at the 5-position of the 4-amino-5-chloro-2-methoxybenzoyl moiety caused a marked increase in the dopamine D2 receptor binding affinity along with a potent 5-HT3 receptor binding affinity. Among the compounds, 5-chloro-N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)-2-methoxy-4- methylaminobenzamide (82), 5-bromo (110), and 5-iodo (112) analogues exhibited a much higher affinity for the dopamine D2 receptor than that of metoclopramide (IC50=17.5-61.0 nM vs. 483 nM). In particular, 82 showed a potent antagonistic activity for both receptors in vivo tests. Optical resolution of the racemate 82 brought about a dramatic change in the pharmacological profile with the (R)-enantiomer exhibiting a strong affinity for both the dopamine D2 and the 5-HT3 receptors, while the corresponding (S)-enantiomer had a potent and selective serotonin 5-HT 3 receptor binding affinity.
- Hirokawa, Yoshimi,Harada, Hiroshi,Yoshikawa, Takashi,Yoshida, Naoyuki,Kato, Shiro
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p. 941 - 959
(2007/10/03)
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- Control of aminophosphine chelate ring-opening in Pt(II) and Pd(II) complexes: Potential dual-mode anticancer agents
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We show that bis(aminophosphine) complexes of the type [M(R1R2N(CH2)nPPh2)2 ]2+, M = Pt(II) or Pd(II), can exist in chelate ring-closed and ring-opened forms both in the solid state and in aqueous solution. The equilibrium between them in solution can be controlled by the nature of the groups R1 and R2 (H, Me, Bz, cyclohexyl), by the bridge length n, and by the pH and Cl- concentration. X-Ray crystal structures are reported for the ring-closed complexes cis-[Pt(H2N(CH2)2PPh2-P,N)2 ]Cl2, cis-[Pt(H2N(CH2)3PPh2-P,N)2 ]Cl2, and cis-[Pt(Me(H)N(CH2)2PPh2-P,N)2][HCl 2]2, the mono-ring-opened complex cis-[Pd(Me2N(CH2)2PPh2-N,P)Cl(Me 2NH(CH2)2PPh2-P)](NO3) 2, the di-ring-opened complex cis-[Pt(Me2N(CH2)3PPh2-P)2 CL2], and, for comparison, the monochelate cis-[Pd(Me2N(CH2)3PPh2-N,P)CL2 ]. These square-planar complexes exhibit varying degrees of distortion and variable M-N bond lengths dependent not only on the trans influence of P but also on steric effects within the complex, pH-induced chelate ring-opening of cis-[Pt(Me2N(CH2)2PPh2-P,N)2 ]CL2 had an associated pK value of 6.9. In contrast, complexes with R1 and R2 = H, n = 2 or 3 or R1 = H and R2 = Me, n = 2, are more difficult to ring-open. Thus the complexes cis-[Pt(Me(H)N(CH2)2-PPh2-P,N)2]CL 2 and cis-[Pt(H2N(CH2)3PPh2-P,N)2 ]CL2, had associated pK values of 2.1 and 2.9, respectively. These aminophosphine complexes may exhibit anticancer activity by two mechanisms: by disrupting mitochondrial membrane potentials as bis-chelated (ring-closed) lipophilic cations, or by direct binding to DNA bases as ring-opened complexes.
- Habtemanam, Abraha,Watchman, Beth,Potter, Brian S.,Palmer, Rex,Parsons, Simon,Parkin, Andrew,Sadler, Peter J.
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p. 1306 - 1318
(2007/10/03)
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- Synthesis and antitumor evaluation of 2,5-disubstituted-indazolo[4,3-gh]isoquinolin-6(2flr)-ones (9-aza-anthrapyrazoles)
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The synthesis and antitumor evaluation of 2,5-disubstituted-indazolo[4,3-gh]isoquinolin-6(2H)-ones (9-aza-APs) are described. The key intermediates in the synthesis are benz[g]isoquinoline5,10-diones which are substituted at positions 6 and 9 with groups of different nucleofugacity for SnAr displacements. The initial displacement of fluoride by a substituted hydrazine leads to the pyrazole analogues. Substitution of the remaining leaving group by an amine or BOC-protected amines leads to the 9-aza-APs 12. These analogues were converted into their maleate or hydrochloride salts 13. In two cases, namely, 13x and 13z, sidearm buildup was also employed in the synthetic pathway. In vitro evaluation of 9-aza-APs against the human colon tumor cell line LoVo uncovered for most of the compounds a cytotoxic potency lower than that of DuP-941 or mitoxantrone and comparable to that of doxorubicin. Only analogues 13c, 13n, and 13ff were as cytotoxic as DuP-941. Interestingly, while DuP-941 was highly cross-resistant in the LoVo cell line resistant to doxorubicin (LoVo/Dx), the 9-aza-APs carrying a distal lipophilic tertiary amine moiety in both chains were capable of overcoming the MDR resistance induced in this cell line. The 9-aza-APs show outstanding in vivo antitumor activity against both systemic P388 murine leukemia and MX-1 human mammary carcinoma transplanted in nude mice. At their optimal dosages, congeners 13a-c, 13f, 13n, 13q, 13x, and 13dd were highly effective against P388 leukemia with T/C% of 200-381, while the T/C% value of DuP-941 was 147. In the MX-1 tumor model, 24 compounds elicited percentages of tumor weight inhibitions (TWI) ranging from 50% to 99%. Congeners 13d, 13k, 131,13x, 13z, and 13ee emerged as the most effective ones, with TWI% 96, simliar to that of DuP-941 (TWI% = 95). On the basis of their efficacy profile in additional experimental tumors and lack of cardiotoxicity in preclinical models, two congeners have surfaced as potential clinical candidates.
- Paul Krapcho
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p. 5429 - 5444
(2007/10/03)
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- Synthesis and Biological Evaluation of 5-Fluoro-2'-deoxyuridine Phosphoramidate Analogs
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A series of alkylating phosphoroamidate analogs of 5-fluoro-2'-deoxyuridine has been prepared and their growth inhibitory activity evaluated against murine L1210 leukemia and B16 melanoma cells in vitro.These compounds were designed to undergo intracellular release of the phosphoramidate anions, which it was hoped would function as irreversible inhibitors of thymidylate synthase.The expectation was that binding of the nucleoside moiety would be followed by alkylation of the enzyme via the phosphoramidate.The chloride, bromide, iodide, and tosylate analogs were highlypotent inhibitors of L1210 cell proliferation, with increased inhibition observed at both higher drug concentrations and longer exposure times.Addition of thymidine completely reversed the inhibition for all compounds, suggesting that these compounds are acting via inhibition of thymidylate synthase.Although the nonalkylating morpholine analog 1f was ca. 50-fold less potent than the methyl(chloroethyl)amino compound, the piperidine analog 1g was only 2-fold less potent, confirming that nitrogen basicity may be as important as the presence of an alkylating group.Addition of thymidine reversed the growth inhibition of the morpholine and piperidine analogs, suggesting that these compounds may also undergo intracellular conversion to 5-fluoro-2'-deoxyuridine 5'-monophosphate.The thymidine and deoxyuridine derivatives 2 and 3 showed minimal growth inhibition in the L1210 assay.The alkylating analogs showed modest cytotoxicity against B16 melanoma cells, and the potency of the analogs was more dependent upon the alkylating moiety than on the 5-substituent.
- Fries, Kristin M.,Joswig, Carolyn,Borch, Richard F.
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p. 2672 - 2680
(2007/10/03)
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- Phosphoramidate analogs of 2'-deoxyuridine
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The present invention provides a series of cytotoxic phosphoramidate analogs of 5-fluoro-2'-deoxyuridine of the general formula (I): STR1 wherein R1 is H, F or (C1 -C4)alkyl; R2 is CH2 CH2 X wherein X is Cl, Br, I or p-toluenesulfonyl; R3 is (C1 -C4)alkyl or CH2 CH2 X wherein X is Cl, Br, I or p-toluenesulfonyl; or wherein R2 and R3, taken together with the N atom, can be a 5- or 6-membered heterocyclic ring which is aliphatic or aliphatic interrupted by a ring oxygen or a second ring nitrogen; R4 is H, one equivalent of a pharmaceutically-acceptable cation or (4,4,6-trimethyltetrahydro-1,3-oxazin-2-yl)ethyl, and the pharmaceutically-acceptable salts thereof.
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- Synthesis, characterization, and Ca2+ antagonistic activity of diltiazem metabolites.
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Diltiazem is a calcium antagonist widely used in the treatment of angina and hypertension. The contributions of metabolites of diltiazem to the vasorelaxant effects of diltiazem were investigated. The synthesis and spectroscopic characterization of eight major cis-diltiazem metabolites are described. Three of the compounds--N, O-didemethylated metabolite (21), O-demethylated metabolite (22), and diltiazem N-oxide (27)--have been recently reported and have not previously been synthesized. The identities of all eight synthetic metabolites have been verified with samples obtained from human urine using combined LC-MS/MS. The Ca2+ antagonistic activities of diltiazem and its metabolites (except 27) were studied on hamster aorta preparations depolarized with KCl. The order of potencies (IC50 +/- SE, microM) is as follows: diltiazem (0.98 +/- 0.47) greater than 17 (2.46 +/- 0.38) greater than or equal to 23 (3.27 +/- 1.02) greater than 26 (20.2 +/- 10.5) greater than 22 (40.4 +/- 15.4) greater than or equal to 25 (45.5 +/- 18.1) greater than 21 (112.2 +/- 33.2) greater than or equal to 24 (126.7 +/- 24.2). Structure-activity relationships are also discussed.
- Li,Farmer,Xie,Quilliam,Pleasance,Howlett,Yeung
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p. 3246 - 3253
(2007/10/02)
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- 2-AMINOPYRIMIDINE-4-CARBOXAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR APPLICATION IN URINARY THERAPEUTICS
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A compound of formula (I) STR1 in which n denotes 2, 3, 4, or 5, p denotes 0 or 1,m denotes 0, 1, 2, 3, 4, or 5, and R 1 denotes a hydrogen atom or a methyl group,each X, which may be identical or different to any other X if m is greater than 1, denotes fluorine, chlorine, methoxy, isopropyl or cyclopropyl,in the form of a free base or an acid addition salt.
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