- Preparation method of bisacodyl
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The present invention provides the preparation method shown in formula I., the preparation method of bisacodyl. The present invention provides a new method for the preparation of bisacodyl.
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Paragraph 0007-0008; 0011-0012
(2022/01/20)
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- Structure-based virtual screening, synthesis and biological evaluation of potential FAK-FAT domain inhibitors for treatment of metastatic cancer
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Focal adhesion kinase (FAK) is a tyrosine kinase that is overexpressed and activated in several advanced-stage solid cancers. In cancer cells, FAK promotes the progression and metastasis of tumours. In this study, we used structure-based virtual screening to filter a library of more than 210K compounds against the focal adhesion targeting FAK-focal adhesion targeting (FAT) domain to identify 25 virtual hit compounds which were screened in the invasive breast cancer line (MDA-MB-231). Most notably, compound I showed low micromolar antiproliferative activity, as well as antimigratory activity. Moreover, examination in a model of triple negative breast cancer (TNBC), revealed that, despite not effecting FAK phosphorylation, compound I significantly impairs proliferation whilst impairing focal adhesion growth and turnover leading to reduced migration. Further optimisation and synthesis of analogues of the lead compound I using a four-step synthetic procedure was performed, and analogues were assessed for their antiproliferative activity against three breast cancer (MDA-MB-231, T47D, BT474) cell lines and one pancreatic cancer (MIAPaCa2) cell line. Compound 5f was identified as a promising lead compound with IC50 values in the range of 4.59–5.28 μM in MDA-MB-231, T47D, BT474, and MIAPaCa2. Molecular modelling and pharmacokinetic studies provided more insight into the therapeutic features of this new series.
- Hiscox, Stephen E.,Jones, Samuel R.,Kandil, Sahar B.,Smith, Sonia,Westwell, Andrew D.
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- Radiosynthesis of the anticancer nucleoside analogue Trifluridine using an automated 18F-trifluoromethylation procedure
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Trifluoromethyl groups are widespread in medicinal chemistry, yet there are limited 18F-radiochemistry techniques available for the production of the complementary PET agents. Herein, we report the first radiosynthesis of the anticancer nucleoside analogue trifluridine, using a fully automated, clinically-applicable 18F-trifluoromethylation procedure. [18F]Trifluridine was obtained after two synthetic steps in 99%, and a molar activity of 0.4 GBq μmol-1 ± 0.05. Biodistribution and PET-imaging data using HCT116 tumour-bearing mice showed a 2.5 %ID g-1 tumour uptake of [18F]trifluridine at 60 minutes post-injection, with bone uptake becoming a prominent feature thereafter. In vivo metabolite analysis of selected tissues revealed the presence of the original radiolabelled nucleoside analogue, together with deglycosylated and phosphorylated [18F]trifluridine as the main metabolites. Our findings suggest a potential role for [18F]trifluridine as a PET radiotracer for elucidation of drug mechanism of action.
- King, Alice,Doepner, Andreas,Turton, David,Ciobota, Daniela M.,Da Pieve, Chiara,Wong Te Fong, Anne-Christine,Kramer-Marek, Gabriela,Chung, Yuen-Li,Smith, Graham
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p. 2986 - 2996
(2018/05/03)
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- Why are vinyl cations sluggish electrophiles?
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The kinetics of the reactions of the vinyl cations 2 [Ph2C=C+-(4-MeO-C6H4)] and 3 [Me2C=C+-(4-MeO-C6H4)] (generated by laser flash photolysis) with diverse nucleophile
- Byrne, Peter A.,Kobayashi, Shinjiro,Würthwein, Ernst-Urich,Ammer, Johannes,Mayr, Herbert
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supporting information
p. 1499 - 1511
(2017/02/10)
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- Synthesis and biological evaluation of aryloxyacetamide derivatives as neuroprotective agents
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A series of new aryloxyacetamide derivatives 10a-s and 14a-m are designed and synthesized. Their protective activities against the glutamate-induced cell death were investigated in differentiated rat pheochromocytoma cells (PC12 cells). Most compounds exhibited neuroprotective effects, especially for 10m, 10r, 14b and 14c, which showed potential protection of PC12 cells at three doses (0.1, 1.0, 10 μM). MTT assay, Hoechst 33342/PI double staining, and high content screening (HCS) revealed that pretreatment of the cells with 10m, 10r, 14b and 14c has significantly decreased the extent of cell apoptosis in a dose-dependent manner. The results of western blot analysis demonstrated these compounds suppressed apoptosis of glutamate-induced PC12 cells via caspase-3 pathway. These compounds can be lead compounds for further discovery of neuroprotective agents for treating cerebral ischemic stroke. Basic structure-activity relationships are also presented.
- Zhong, Yan,Xu, Yi,Zhang, Ai-Xia,Li, Xiao-Feng,Xu, Zhao-Ying,Li, Ping,Wu, Bin
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supporting information
p. 2526 - 2530
(2016/07/07)
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- Solid-phase synthesis of NH-1,2,3-triazoles using 4,4′- bismethoxybenzhydryl azide
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Readily available 4,4′-bismethoxybenzhydryl azide was found to be a useful building block for the synthesis of NH-1,2,3-triazoles through copper(I)-catalyzed cycloaddition reactions with solid-supported terminal alkynes, followed by acid-mediated deprotection. Peptide-containing NH-1,2,3-triazoles were obtained in good yield and excellent purity (typically >95%). Georg Thieme Verlag Stuttgart. New York.
- Cohrt, A. Emil,Le Quement, Sebastian T.,Nielsen, Thomas E.
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supporting information
p. 1891 - 1895
(2014/08/18)
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- Chlorination of benzylic and allylic alcohols with trimethylsilyl chloride enhanced by natural sodium montmorillonite
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A new and practical method for the efficient chlorination of tertiary, secondary, and primary benzylic and allylic alcohols is described. The method is characterized by the formation of hydrogen chloride from trimethylsilyl chloride and trace water, the formation of a carbenium ion through the protonation of an alcohol and subsequent dehydration, and the chlorination of the carbenium ion. During the process, sodium ion-exchanged montmorillonite plays a crucial role in capturing the generated hydrogen chloride, stabilizing the carbenium intermediate as well as promoting the chlorination.
- Tandiary, Michael Andreas,Masui, Yoichi,Onaka, Makoto
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supporting information
p. 2639 - 2643
(2015/01/09)
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- Development of small-molecule probes that selectively kill cells induced to express mutant RAS
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Synthetic lethal screening is a chemical biology approach to identify small molecules that selectively kill oncogene-expressing cell lines with the goal of identifying pathways that provide specific targets against cancer cells. We performed a high-throughput screen of 303,282 compounds from the National Institutes of Health-Molecular Libraries Small Molecule Repository (NIH-MLSMR) against immortalized BJ fibroblasts expressing HRASG12V followed by a counterscreen of lethal compounds in a series of isogenic cells lacking the HRASG12V oncogene. This effort led to the identification of two novel molecular probes (PubChem CID 3689413, ML162 and CID 49766530, ML210) with nanomolar potencies and 4-23-fold selectivities, which can potentially be used for identifying oncogene-specific pathways and targets in cancer cells.
- We?wer, Michel,Bittker, Joshua A.,Lewis, Timothy A.,Shimada, Kenichi,Yang, Wan Seok,MacPherson, Lawrence,Dandapani, Sivaraman,Palmer, Michelle,Stockwell, Brent R.,Schreiber, Stuart L.,Munoz, Benito
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supporting information; experimental part
p. 1822 - 1826
(2012/04/04)
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- Exploring post-translational arginine modification using chemically synthesized methylglyoxal hydroimidazolones
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The methylglyoxal-derived hydroimidazolones (MG-Hs) comprise the most prevalent class of non-enzymatic, post-translational modifications of protein arginine residues found in nature. These adducts form spontaneously in the human body, and are also present at high levels in the human diet. Despite numerous lines of evidence suggesting that MG-H-arginine adducts play critical roles in both healthy and disease physiology in humans, detailed studies of these molecules have been hindered by a lack of general synthetic strategies for their preparation in chemically homogeneous form, and on scales sufficient to enable detailed biochemical and cellular investigations. To address this limitation, we have developed efficient, multigram-scale syntheses of all MG-H-amino acid building blocks, suitably protected for solid-phase peptide synthesis, in 2-3 steps starting from inexpensive, readily available starting materials. Thus, MG-H derivatives were readily incorporated into oligopeptides site-specifically using standard solid-phase peptide synthesis. Access to synthetic MG-H-peptide adducts has enabled detailed investigations, which have revealed a series of novel and unexpected findings. First, one of the three MG-H isomers, MG-H3, was found to possess potent, pH-dependent antioxidant properties in biochemical and cellular assays intended to replicate redox processes that occur in vivo. Computational and mechanistic studies suggest that MG-H3-containing constructs are capable of participating in mechanistically distinct H-atom-transfer and single-electron-transfer oxidation processes. Notably, the product of MG-H3 oxidation was unexpectedly observed to disassemble into the fully unmodified arginine residue and pyruvate in aqueous solution. We believe these observations provide insight into the role(s) of MG-H-protein adducts in human physiology, and expect the synthetic reagents reported herein to enable investigations into non-enzymatic protein regulation at an unprecedented level of detail.
- Wang, Tina,Kartika, Rendy,Spiegel, David A.
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supporting information; experimental part
p. 8958 - 8967
(2012/07/02)
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- Photogeneration of benzhydryl cations by near-UV laser flash photolysis of pyridinium salts
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Laser flash irradiation of substituted N-benzhydryl pyridinium salts yields benzhydryl cations (diarylcarbenium ions) and/or benzhydryl radicals (diarylmethyl radicals). The use of 3,4,5-triamino-substituted pyridines as photoleaving groups allowed us to employ the third harmonic of a Nd/YAG laser (355 nm) for the photogeneration of benzhydryl cations. In this way, benzhydryl cations can also be photogenerated in the presence of aromatic compounds and in solvents which are opaque at the wavelength of the quadrupled Nd/YAG laser (266 nm). To demonstrate the scope and limitations of this method, the rate constants for the bimolecular reactions of benzhydryl cations with several substituted pyridines were determined in acetonitrile and with water in acetone. The obtained data agree with results obtained by stopped-flow UV-vis spectroscopic measurements. The rate constants for the reaction of the 4,4'-bis[methyl(2,2,2- trifluoroethyl)amino]benzhydrylium ion with 4- (dimethylamino)pyridine were also determined in dimethyl sulfoxide, N,N-dimethylformamide, and acetone. From the secondorder rate constants, we derived the nucleophilicity parameters N and sN for the substituted pyridines, as defined by the linear free energy relationship, log k2 = sN(N + E).
- Nigst, Tobias A.,Ammer, Johannes,Mayr, Herbert
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p. 8494 - 8499
(2013/01/14)
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- Design, synthesis and antifungal activity of some new imidazole and triazole derivatives
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Triazole and imidazole are incorporated into the structures of many antifungal compounds. In this study a novel series of 1,2,4-triazole, imidazole, benzoimidazole, and benzotriazole derivatives was designed as inhibitors of cytochrome P450 14α-demethylase (14DM). These structures were docked into the active site of MT-CYP51, using Autodock program. Sixteen compounds with the best binding energy were synthesized. The chemical structures of the new compounds were confirmed by elemental and spectral (1H-NMR and Mass) analyses. All compounds were investigated for antifungal activity against Candida albicans, Candida tropicalis, Candida glabrata, Candida parapeilosis, Candida kruzei, Candida dubliniensis, Aspergillus fomigatus, Aspergillus flavus, Microsporum canis, Microsporum gypseum, Trichophyton mentagrophyte, Epidermophyton floccosum. Some compounds showed excellent in-vitro antifungal activity against most of the tested fungi. Compounds 2, 9, and 10 had antifungal activity against several resistant fungi against fluconazole and itraconazole. A novel series of azole derivatives was designed and synthesized as inhibitors of cytochrome P450 14α-demethylase and the compounds were investigated for antifungal activity. Copyright
- Rezaei, Zahra,Khabnadideh, Soghra,Zomorodian, Kamiar,Pakshir, Kyvan,Kashi, Giti,Sanagoei, Narges,Gholami, Sanaz
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experimental part
p. 658 - 665
(2012/06/29)
-
- Ionizing power of aprotic solvents
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Rate constants for the heterolysis reactions (SN1) of a series of chloro-diarylmethanes in aprotic solvents (dimethyl sulfoxide (DMSO), acetonitrile, carboxamides, etc.) have been determined conductometrically in the presence of amines or triphenylphosphane, which trap the intermediate ion-pairs and suppress ion recombination. The operation of SN2 mechanisms can be excluded because the observed first-order rate constants become almost independent of the nature of the nucleophilic additive when a certain concentration of nucleophile is exceeded. The heterolysis rate constants are used to calculate nucleofugality parameters Nf and sf for chloride in aprotic solvents according to the linear free-energy relationship lgak (25 °C) = sf(Nf + Ef). Ionizing powers YBnCl of these solvents were calculated according to the Winstein-Grunwald equation. Because the heterolysis rate constants in aprotic solvents correlate only poorly with dielectric constants or empirical solvent parameters such as Gutmann's acceptor numbers or ETN values, the most common solvent polarity parameters do not reliably predict ionization rates in aprotic solvents. The kinetics of the heterolyses of chloro-diarylmethanes in aprotic solvents have been studied conductometrically by suppressing ion recombination with amine additives. In this way it became possible to determine the ionizing power of aprotic solvents and compare them to those of protic solvents. Copyright
- Streidl, Nicolas,Mayr, Herbert
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supporting information; experimental part
p. 2498 - 2506
(2011/06/10)
-
- Structure-activity relationships of diphenylpiperazine N-type calcium channel inhibitors
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A novel series of compounds derived from the previously reported N-type calcium channel blocker NP118809 (1-(4-benzhydrylpiperazin-1-yl)-3,3-diphenylpropan-1-one) is described. Extensive SAR studies resulted in compounds with IC50 values in the range of 10-150 nM and selectivity over the L-type channels up to nearly 1200-fold. Orally administered compounds 5 and 21 exhibited both anti-allodynic and anti-hyperalgesic activity in the spinal nerve ligation model of neuropathic pain.
- Pajouhesh, Hassan,Feng, Zhong-Ping,Ding, Yanbing,Zhang, Lingyun,Pajouhesh, Hossein,Morrison, Jerrie-Lynn,Belardetti, Francesco,Tringham, Elizabeth,Simonson, Eric,Vanderah, Todd W.,Porreca, Frank,Zamponi, Gerald W.,Mitscher, Lester A.,Snutch, Terrance P.
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scheme or table
p. 1378 - 1383
(2010/07/06)
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- Suppression of common-ion return by amines: A method to measure rates of fast SN1 reactions
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(Chemical Equation Presented) Rate constants for solvolyses of benzhydryl chlorides, which take place on the 10 ms to minute time scale, have been determined in aqueous acetone and acetonitrile by conductometry, using conventional conductometers as well as stopped-flow techniques. Secondary and tertiary amines were used to suppress ion recombination (common-ion return) thus giving access to the ionization rate constants k1. The observed common-ion rate depressions can be rationalized by the correlation equation for electrophile-nucleophile combinations, log k(20 °C) = s(E + N), where electrophiles (here: carbocations) are characterized by the parameter Eand nucleophiles (here: chloride anions and solvents) are characterized by N and s. 2009 American Chemical Society.
- Streidl, Nicolas,Antipova, Anna,Mayr, Herbert
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supporting information; experimental part
p. 7328 - 7334
(2010/01/16)
-
- 1,4-Dihydroindeno[1,2-c]pyrazoles with acetylenic side chains as novel and potent multitargeted receptor tyrosine kinase inhibitors with low affinity for the hERG ion channel
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The synthesis of a novel series of 1,4-dihydroindeno[1,2-c]pyrazoles with acetylene-type side chains is described. Optimization of those compounds as KDR kinase inhibitors identified 8, which displayed an oral activity in an estradiol-induced murine uterine edema model (ED50 = 3 mg/kg) superior to Sutent (ED50 = 9 mg/kg) and showed potent antitumor efficacy in an MX-1 human breast carcinoma xenograft tumor growth model (tumor growth inhibition = 90% at 25 mg/kg·day po). The compound was docked into a homology model of the homo-tetrameric pore domain of the hERG potassium channel to identify strategies to improve its cardiac safety profile. Systematic interruption of key binding interactions between 8 and Phe656, Tyr652, and Ser624 yielded 90, which only showed an IC50 of 11.6 μM in the hERG patch clamp assay. The selectivity profile for 8 and 90 revealed that both compounds are multitargeted receptor tyrosine kinase inhibitors with low nanomolar potencies against the members of the VEGFR and PDGFR kinase subfamilies.
- Dinges, Jürgen,Albert, Daniel H.,Arnold, Lee D.,Ashworth, Kimba L.,Akritopoulou-Zanze, Irini,Bousquet, Peter F.,Bouska, Jennifer J.,Cunha, George A.,Davidsen, Steven K.,Diaz, Gilbert J.,Djuric, Stevan W.,Gasiecki, Alan F.,Gintant, Gary A.,Gracias, Vijaya J.,Harris, Christopher M.,Houseman, Kathryn A.,Hutchins, Charles W.,Johnson, Eric F.,Li, Hu,Marcotte, Patrick A.,Martin, Ruth L.,Michaelides, Michael R.,Nyein, Michelle,Sowin, Thomas J.,Su, Zhi,Tapang, Paul H.,Xia, Zhiren,Zhang, Henry Q.
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p. 2011 - 2029
(2008/02/04)
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- Scaffold oriented synthesis. Part 1: Design, preparation, and biological evaluation of thienopyrazoles as kinase inhibitors
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We report the synthesis of kinase targeted libraries based on the thienopyrazole scaffold. Several thienopyrazole analogs have been identified as submicromolar inhibitors of KDR.
- Akritopoulou-Zanze, Irini,Darczak, Daria,Sarris, Kathy,Phelan, Kathleen M.,Huth, Jeffrey R.,Song, Danying,Johnson, Eric F.,Jia, Yong,Djuric, Stevan W.
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- Synthesis and insulin-sensitizing activity of (S)-2-ethoxy-3- phenylpropanoic acid derivatives
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A series of (S)-2-ethoxy-3-phenylpropanoic acid derivatives were synthesized and their insulin-sensitizing activities were evaluated in 3T3-L1 cells. Compounds 1b (EC30 = 9.43 × 10-3 μmol/L), 1d (EC30 = 7.45 × 10-3 μmol/L), 1e (EC 30 = 6.22 × 10-3 μmol/L), and 1f (EC30 = 7.76 × 10-3 μmol/L) exhibited more potent insulin-sensitizing activity than rosiglitazone (EC30 = 2.06 × 10-2 μmol/L).
- Cai, Xiao-Hua,Xie, Bing
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p. 1106 - 1109
(2007/10/03)
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- Synthesis and evaluation of methyl 2-methoxycarbonyl-3-phenylpropionate derivatives as a new type of angiotensin converting enzyme inhibitors
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Methyl 2-methoxycarbonyl-3-phenylpropionate derivatives were prepared, and their inhibitory activities for angiotensin converting enzyme (ACE) were evaluated. Compounds 5b (IC50 = 0.0039 μmol/L), 5d (IC 50 = 0.0027 μmol/L), 5e (IC50 = 0.0021 μmol/L), and 5f (IC50 = 0.0052 μmol/L) exhibited more potent ACE inhibitiory activity than the control drug Captopril (IC50 = 0.0075 μmol/L).
- Cai, Xiao-Hua,Xie, Bing,Guo, Hui
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p. 1110 - 1113
(2007/10/03)
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- Kinetics of the reactions of halide anions with carbocations: Quantitative energy profiles for SN1 reactions
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Rate constants for the reactions of Laser flash photolytically generated benzhydrylium ions (diarylcarbenium ions) with halide ions have been determined in various solvents, including neat and aqueous acetonitrile as well as some alcohols. Substitution of the rate constants into the correlation equation log k = s(N + E) yields the nucleophilicity parameters N for the halide ions in different solvents. Linear correlations with negative slopes are found between the nucleophilicity parameters N for Cl- and Br- in different solvents and the solvent ionizing powers Y of the corresponding solvents. Increasing halide solvation reduces the rates of carbocation/chloride combinations by approximately half as much as it increases the rates of ionizations of benzhydryl chlorides. Comparison of the solvent dependent nucleophilicity parameters N of halide anions and the nucleophilicity parameters N1 for solvents yields a quantitative prediction of common ion rate depression, as demonstrated by the analysis of a variety of literature reported mass-law constants α. Combination of the rate constants for the reactions of benzhydrylium ions with halide ions (k-1) reported in this work with the ionization constants of benzhydryl halides (k1) and the recently reported rate constants for the reactions of benzhydrylium ions with solvents (k2) yields complete quantitative free energy profiles for solvolysis reactions. The applicability of Hammond's postulate for interpreting solvolysis reactions can thus be examined quantitatively.
- Minegishi, Shinya,Loos, Robert,Kobayashi, Shinjiro,Mayr, Herbert
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p. 2641 - 2649
(2007/10/03)
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- 7-PHENYL-ISOQUINOLINE-5-SULFONYLAMINO DERIVATIVES AS INHIBITORS OF AKT (PROTEINKINASE B)
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The present invention relates to compounds Formula (I) as inhibitors of AKT activity, which are useful for the treatment of susceptible neoplasms and viral infections.
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Page/Page column 34
(2010/02/12)
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- Kinetic studies on the reactivity of triphenylmethyl cations adsorbed on silica, alumina, and aluminosilicate
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The apparent rate constants ka?2 of different surface-mediated reactions of three nucleophiles 1,4-cyclohexadiene, triethylsilane, and isobutylvinyl ether with triphenylmethylium ions have been determined for three different solid acid catalysts and various triphenylmethylium precursors (R1R2R3C-X, X = SCN, OH, Cl, or Br). Generation of triphenylmethylium ions [R1R2R3C+] was used for kinetic measurements when R1R2R3C-X derivates are chemisorbed to the solid acid catalysts. The catalysis of those surface-mediated reactions by a silica, an alumina, and an aluminosilicate has been studied in a slurry of dichloromethane at ambient temperature. The value of ka?2 increases in the order OH- - - - and silica s of the corresponding HX from R1R2R3C-X or the acidity of the solid acid (Adolph, S.; Spange, S.; Zimmermann, Y. J. Phys. Chem. B 2000, 104, 6429-6438) indicating the importance of the effective surface concentration of [R1R2R3C+] on the apparent rate constant. It is also shown that the specific rate constant of the surface-mediated reaction can be interpreted in terms of Mayr's nucleophilicity parameters of the ??-nucleophile (N) and the pKR+ values of the carbenium ion derived from polar reactions in homogeneous solution.
- Spange, Stefan,Adolph, Simone,Walther, Ralph,Zimmermann, Yvonne
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p. 298 - 305
(2007/10/03)
-
- Reactions between nitrile oxides and carbenium ions: Synthesis of benzoxazines, oximes, and amides through intramolecular ortho or ipso attack
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Reactions between nitrile oxides and benzylic carbocations are described. Different results were obtained when the carbocations were generated from the corresponding chlorides with different Lewis acids, with addition products such as benzoxazines, oximes, and amides being produced. Primary, secondary, and tertiary carbocations showed different reactivities. The product ratios strongly depended on the substituents on the aromatic ring of the benzylic carbocations. Evidence for the proposed mechanism is reported. Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.
- Auricchio, Sergio,Magnani, Caterina,Truscello, Ada M.
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p. 2411 - 2416
(2007/10/03)
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- Solid-phase synthesis of PhTX-3.2.4 and PhTX-2.3.3 derivatives
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A new solid-phase method for the synthesis of derivatives of the philanthotoxins is described. Diamines are attached as carbamates to hydroxymethyl polystyrene resin. Selective mono-alkylations by acid-labile, substituted benzhydryl chlorides, followed by reductive alkylations with Fmoc-protected amino aldehydes are employed to assemble the polyamine backbone. Different acid-stability of the benzhydrylic protective groups allows the selective removal from secondary amines for subsequent branching.
- J?nsson, Daniel
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p. 4793 - 4796
(2007/10/03)
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- Repetitive solid-phase synthesis of polyamines
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A repetitive solid-phase method for the synthesis of polyamines is described. Primary amino groups attached to a crosslinked polystyrene resin are monoalkylated by acid labile, benzhydryl-based alkyl chlorides. Reductive alkylation of the resulting secondary amino group by Fmoc-protected aminoaldehydes gives a N-benzhydryl polyamine backbone. Treatment of the resin with trifluoroacetic acid cleaves both the benzhydryl protective group and the polyamine derivative from the resin. By using benzhydryl protective groups with different acid stability, unbranched, branched and partly branched polyamines are synthesized.
- J?nsson, Daniel,Undén, Anders
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p. 3125 - 3128
(2007/10/03)
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- Synthesis and dopamine transporter binding affinities of 3α-benzyl-8-(diarylmethoxyethyl)-8-azabicyclo[3.2.1]octanes
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A series of 3α-benzyl-8-(diarylmethoxyethyl)-8-azabicyclo[3.2.1]octanes was synthesized and the binding affinities of the compounds were determined at the dopamine transporter. The unsubstituted analogue 7b (Ki=98 nM) was the most potent compou
- Bradley, Amy L,Izenwasser, Sari,Wade, Dean,Klein-Stevens, Cheryl,Zhu, Naijue,Trudell, Mark L
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p. 2387 - 2390
(2007/10/03)
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- Synthesis and dopamine transporter binding affinity of 2,6-dioxopiperazine analogues of GBR 12909
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A series of GBR 12909 analogues containing a 2,6-dioxopiperazine ring system were prepared and evaluated as ligands for the dopamine transporter. These less lipophilic analogues of GBR 12909 exhibited diminished in vitro binding affinities (Ki)
- Winfield, Leyte,Izenwasser, Sari,Wade, Dean,Trudell, Mark L.
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p. 102 - 115
(2007/10/03)
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- Competitive decay pathways of the radical ions formed by photoinduced electron transfer between quinones and 4,4′-dimethoxydiphenylmethane in acetonitrile
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The reactivity of the cation radical of (4-MeOC6H4)2CH2 photosensitized by 1,4-benzoquinone (BQ), 2,5-dichloro-1,4-benzoquinone (Cl2BQ), and tetrachloro-1,4-benzoquinone (chloranil, CA) was investigated in acetonitrile. The main photoreaction products obtained by steady-state irradiation were identified to be: (4-MeOC6H4)2CHOC6H4OH, sensitized by BQ; (4MeOC6H4)2CHCl, sensitized by Cl2BQ; (4-MeOC6H4)2CHOH, sensitized by CA. The mechanism of their formation was investigated by nanosecond laser flash photolysis that allowed transient species (radical ions, neutral radicals, and ions) to be detected and characterized in terms of absorption spectra, formation quantum yields, and decay rate constants. For all systems, the interaction between the triplet quinone (Q) and (4-MeOC6H4)2CH2 produced the corresponding radical ions (quantum yield φ ≥ 0.72) which mainly decay by back electron transfer processes. Less efficient reaction routes for the radical ions Q.- and (4-MeOC6H4)2CH2.+ were also: i) the proton-transfer process with the formation of the radical (4MeOC6H4)2CH. by use of Cl2BQ; ii) the hydrogen-transfer process with the formation of the cation (4-MeOC6H4)2CH+ in the case of CA. Instead, BQ sensitized a much higher yield of BQH. and (4MeOC6H4)2CH., mainly by the direct interaction of triplet BQ with (4MeOC6H4)2CH2. It was also shown that the presence of salts decreases significantly the rate of the back electron transfer process and enhances the quantum yields of formation of the neutral radicals and ions when Cl2BQ and CA are used, respectively. The behavior of BQ.-, Cl2BQ.-, and CA.- appears to be mainly determined by the Mulliken charges on the oxygen atom obtained from quantum mechanical calculations with the model B3LYP/6-311G(d,p). Spin densities seem to be much less important.
- Del Giacco, Tiziana,Baciocchi, Enrico,Lanzalunga, Osvaldo,Elisei, Fausto
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p. 3005 - 3013
(2007/10/03)
-
- Synthesis and pharmacological evaluation of some thiolupinine derivatives
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A small set of 9-(lupinylthio)xanthene, -thioxanthenes and α-(lupinylthio)diphenylmethanes was prepared and found to inhibit the angiotensin II-induced contractions of guinea pig ileum. Some of these compounds were also moderately active in vitro as tracheal relaxants and one compound was more active than aspirin against arachidonic acid-induced platelet aggregation.
- Novelli, Federica,Tasso, Bruno,Sparatore, Fabio
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p. 354 - 358
(2007/10/03)
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- Structure-activity relationship studies of novel 4-[2-[bis(4- fluorophenyl)methoxy]ethyl]-1-(3-phenylpropyl)piperidine analogs: Synthesis and biological evaluation at the dopamine and serotonin transporter sites
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Several analogs of the potent dopamine (DA) transporter ligand 4-[2- [bis(4-fluorophenyl)-methoxy]ethyl]-1-(3-phenylpropyl)piperidine, 1b, were made and biologically evaluated for their binding at the DA and serotonin (5HT) transporters in rat striatal membranes. Different alkyl chain lengths and substitutions were introduced in these molecules to generate an optimum activity and selectivity for the DA transporter. In general, unsubstituted and fluoro-substituted compounds were the most active and selective for the DA transporter. The compound 4-[2(diphenylmethoxy)ethyl]-1-benzylpiperidine, 9a, showed high potency and was the most selective for the DA transporter (5HT/DA = 49) in this series of compounds. Some of these novel analogs were found to be more selective in binding at the DA transporter than the original GBR 12909 molecule, 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3- phenylpropyl)piperidine.
- Dutta,Xu,Reith
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p. 749 - 756
(2007/10/03)
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- Novel 4'-Substituted and 4',4"-Disubstituted 3α-(Diphenylmethoxy)tropane Analogs as Potent and Selective Dopamine Uptake Inhibitors
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A series of 4'-substituted and 4',4"-disubstituted 3α-(diphenylmethoxy)tropane analogs were prepared as novel probes for the dopamine transporter.These compounds were evaluated in radiolabeled binding assays for the dopamine, norepinephrine, and serotonin transporters.All of these compounds monophasically displaced WIN 35,428 binding in rat caudate putamen with Ki values ranging from 11.8 to 2000 nM.The most potent compound in this series was 4',4"-difluoro 3α-(diphenylmethoxy)tropane 7c with Ki=11.8 nM.All of the compounds inhibited dopamine uptake in rat caudate putamen (IC50 = 24-4456 nM) which correlated significantly (r = 0.907; p > 0.0001) with binding affinities at the dopamine transporter.None of the compounds demonstrated high-affinity binding at the norepinephrine (Ki > 4800 nM) or serotonin (Ki > 690 nM)transporters.Therefore, the most potent dopamine uptake inhibitors in this series were highly selective for the dopamine transporter.Preliminary behavioral studies of several of these analogs (7a-e) suggested that the compounds did not display a cocaine-like behavioral profile, despite their ability to inhibit dopamine uptake.The present data coupled with the 3α-(diphenylmethoxy)tropane analogs may be interacting at a different active site than cocaine on the dopamine transporter and that an additional binding domain might be exploited for the identification of potential therapeutics for the treatment of cocaine abuse.
- Newman, Amy Hauck,Kline, Richard H.,Allen, Andrew C.,Izenwasser, Sari,George, Clifford,Katz, Jonathan L.
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p. 3933 - 3940
(2007/10/03)
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- Synthesis and pharmacological study of new calcium antagonists analogues of cinnarizine and flunarizine
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Several phosphonic diethyl esters were synthesized and their calcium antagonistic activity evaluated in vitro.The diethyl phosphonate group was condensed on substituted , , , , and groups.Despite the presence of the diethyl phosphonate moiety and the benzhydrylpiperazinyl group, both present in potent calcium antagonist structures, only 1 of the 19 synthesis compounds exhibited a calcium antagonistic profile. diethyl phosphonate / benzhydryl piperazine / calcium antagonist
- Younes, S.,Baziard-Mouysset, G.,Saqui-Sannes, G. de,Stigliani, J. L.,Payard, M.,et al.
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p. 943 - 948
(2007/10/02)
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- New applications of the protecting group di-(4-methoxyphenyl)methyl: N-protection of urethanes and uridines, and efficient removal by either ceric ammonium nitrate/silica or 2,3-dichloro-5,6-dicyanoquinone
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The protecting group di-(4-methoxyphenyl)methyl, removable by ceric ammonium nitrate on silica or 2,3-dichloro-5,6-dicyanoquinone, is shown to facilitate syntheses of urethanes (eg vinyl urethane, 1a) and uridine derivatives (eg 2-O-allyluridine, 8).
- AbuSbeih, Khaled,Bleasdale, Christine,Golding, Bernard T,Kitson, Sean L
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p. 4807 - 4810
(2007/10/02)
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- Kinetics of the reactions of laser-flash photolytically generated carbenium ions with alkyl and silyl enol ethers. Comparison with the reactivity toward alkenes, allylsilanes and alcohols
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Diarylcarbenium ions (benzhydryl cations) are generated from diarylmethyl chlorides by 20-ns laser pulses (248 nm) in acetonitrile solution at 20°C. The second-order rate constants for their reactions with n- and π-nucleophiles (anions, alcohols, water, alkenes, allylsilanes, alkyl and silyl enol ethers) are determined by monitoring the decay of the UV-vis transients at variable nueleophile concentrations. Only reactive nucleophiles (k2 > 106-107 L mol-1 s-1) can be investigated by this method because of the concomitant reactions of the carbenium ions with the solvent acetonitrile and the chloride ions in produced in the photoheterolysis. The largest observed values of k2 are ~2 × 1010 for reactions with anions and (2-4) × 109 L mol-1 s-1 for reactions with neutral nucleophiles. Alkoxy-substituted ethylenes are 300-105 times more reactive than the corresponding alkyl-substituted ethylenes. The reactivities of structurally analogous alkyl and silyl enol ethers differ by less than 1 order of magnitude. In sharp contrast to the situation previously observed for the reactions of benzhydryl cations with alkenes, the nucleophilic reactivities of the enol ethers correlate with their ionization potentials and not with the stabilities of the carbenium ions produced in the rate-determining step. The rate constants measured for the reactions of the flash photolytically generated benzhydryl cations with alkenes and allylsilanes agree well with those extrapolated from the reactivities of these nucleophiles toward less electrophilic benzhydryl cations, which have previously been determined by conventional techniques. Combination of the two sets of data yields a nucleophilicity scale with respect to the reference electrophile (p-H3CC6H4)2CH+.
- Bartl, J?rg,Steenken, Steen,Mayr, Herbert
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p. 7710 - 7716
(2007/10/02)
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- Thermochemical Study of the Addition of Carbenium Ions to Alkenes
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Scales of carbenium ion stabilities have been obtained from 1H NMR equilibrium studies of mixtures of partly ionized para-substituted diarylmethyl chlorides in CD2Cl2/BCl3 at -70 deg C and via calorimetric determination of the heats of ionization (ΔHi) of the alkyl chlorides (Ar2CHCl + BCl3 -> Ar2CH+BCl4-) in CH2Cl2/BCl3 at -70 deg C.The heats of the reactions of diarylmethyl tetrachloroborates with 2-methyl-1-pentene (Ar2CH+BCl4- + CH2=C(CH3)C3H7 -> Ar2CHCH2C(CH3)ClC3H7 + BCl3), which were determined by low-temperature calorimetry, increase from -53.1 kJ/mol for (H3CC6H4)2CH+BCl4- to -33.0 kJ/mol for the better stabilized (H3COC6H4)(H3CC6H4)CH+BCl4-.In contrast, the heats (ΔHa) of the Lewis acid catalyzed additions of the corresponding para-substituted diarylmethyl chlorides to 2-methyl-1-pentene are independent of the para substituents (ΔHa=-86.5 +/-2.7 kJ/mol).Similar values of ΔHa were obtained for the addition of p-anisylphenylmethyl chloride to trimethylethylene, styrene, β-methylstyrene, and isoprene. ΔHa is predominantly determined by the conversion of a ?(C=C) into a ?(C-C) bond, and the heats of addition of diarylmethyl tetrachloroborates to alkenes in CH2Cl2 are given by the equation ΔHb=(9.5 +/- 6.3 pKR+) kJ/mol.
- Schade, Christian,Mayr, Herbert,Arnett, Edward M.
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p. 567 - 571
(2007/10/02)
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- Ionisation and Dissociation of Diarylmethyl Chlorides in BCl3/CH2Cl2 Solution: Spectroscopic Evidence for Carbenium Ion Pairs
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The ionisation equilibria of diarylmethyl chlorides Ar2CHCl (Ar = p-CH3O-C6H4, p-PhO-C6H4, p-CH3-C6H4) reacting with BCl3 in CH2Cl2 to give ion-pairs Ar2CH(+)BCl4(-) (KI), and the dissociation of these (KD) were studied by conductimetry and spectro-photometry.The molar conductivities are almost independent of the nature of the aryl group (ca. 3.5E-3 Sm2/mol at -70 deg C).The ionisation constants KI increase strongly with increasing electron releasing ability of the p-substituents.The standard ionisation enthalpies and entropies for (p-CH3-C6H4)2CHCl and (p-PhO-C6H4)(Ph)CHCl, calculated from the KI at different temperatures are negative.The dissociation constants KD do not show a systematic dependence on the electron donating abilities of the substituents in the aryl groups.Small differences between the UV-vis absorption spectra of unpaired and paired ions were used to confirm the conductimetrically determined values of KD. - Key words: Carbocations / Electrochemistry / Ionisation / Spectroscopy, Visible / Thermodynamics
- Schneider, Reinhard,Mayr, Herbert,Plesch, Peter H.
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p. 1369 - 1374
(2007/10/02)
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- Stereoselective Reductions of Substituted Cyclohexyl and Cyclopentyl Carbon-Nitrogen ? Systems with Hydride Reagents
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Reductions of 3- and 4-substituted cyclohexyl imines, iminium salts, and enamines (via iminium ions) with various hydride reagents reveal that while small reagents (NaBH4, NaBH3CN) favor axial approach as observed with the corresponding ketones, even moderately bulky reagents (i.e., acetoxyboranes) attack preferentially from the equatorial side.This is in direct contrast to the results observed for the same reagents with the corresponding ketones and is interpreted as implying that additional steric interactions induced by the nitrogen substituents encumber axial attack by substituted hydride reagents and force approach from the equatorial direction.The very bulky tri-sec-butylborohydride anion affords highly stereodiscriminating equatorial attack.Reductions of 2-alkylcyclohexyl and 2-alkylcyclopentyl imines and enamines also proceed with high stereoselectivity to give cis-2-alkyl cyclic amines with both hindered and unhindered reagents.This is interpreted to be the result of (1) augmented steric interactions between nitrogen substituents and equatorial 2-alkyl groups (1,3-allylic strain) which induces conformational changes to favor the axial 2-alkyl conformer and (2) hindrance toward equatorial approach by reagents induced by axial alkyl substituents.The result is that equatorial approach is favored with equatorial 2-alkyl conformers and preferential axial approach with axial 2-alkyl conformers, leading to stereoselective production of cis-2-alkylamines. trans-2-n-Propyl-4-tert-butylcyclohexanone is reduced by LiBH(sec-Bu)3 preferentially from the axial direction in contrast to the usual highly selective equatorial attack observed with other cyclohexanones.
- Hutchins, Robert O.,Su, Wei-Yang,Sivakumar, Ramachandran,Cistone, Frank,Stercho, Yuriy P.
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p. 3412 - 3422
(2007/10/02)
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