- Synthesis and evaluation of new sesamol-based phenolic acid derivatives with hypolipidemic, antioxidant, and hepatoprotective effects
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The objective of this study is to synthesize a series of sesamol-based phenolic acid derivatives, which were designed by combination principle. The hypolipidemic activity of all these compounds was preliminarily screened by acute hyperlipidemic mice model induced by Triton WR 1339, in which compound T6 exhibited more significant reducing plasma TG and TC than fenofibrate. Compound T6 was also found to obviously decrease TG and TC both in the plasma and hepatic tissue of high-fat-diet-induced hyperlipidemic mice. Moreover, T6 showed hepatoprotective effects, which remarkable amelioration in characteristic liver enzymes was examined and the histopathological observation displayed that compound T6 inhibited lipids accumulation in the hepatic. The levels of PPAR-α receptor related to lipids metabolism in hepatic tissue were upregulated after T6 treatment. Other potent effects of T6 such as antioxidant and anti-inflammatory activity were also observed. On the bases of these findings, compound T6 may serve as an effective hypolipidemic and hepatoprotective agent. [Figure not available: see fulltext.]
- Xie, Yundong,Liu, Jiping,Shi, Yongheng,Bin Wang,Wang, Xiaoping,Wang, Wei,Sun, Meng,Xu, Xinya,He, Shipeng
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p. 1688 - 1702
(2021/07/26)
-
- Structure-supercooling property relationship of phenylethyl phenylacetate derivatives and analogue
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In this paper, three new compounds were synthesized by introduction of benzyloxy group to phenylethyl phenylacetate (PPA) and shorting the flexible ester linker. NMR spectra and mass spectra are achieved to confirm the structure of the compounds. The solid-liquid and liquid-solid phase change behaviors of PPA and these three compounds were explored by direct observation and differential scanning calorimetry (DSC) measurements. It was found that all four compounds would form supercooled liquids during a heating-cooling cycle. The supercooling degree is as large as 44 °C or above. The effects of benzyloxy group and the flexible linker on the phase transition processes as well as the supercooling degrees were discussed in detail with the computational optimized geometry of isolated molecules. It was revealed that the dihedral angles between adjacent phenyl rings play a significant role in tuning their phase transition temperatures. This work also discovers the high enthalpies of PPA derivatives and analogues in both solid-liquid and liquid-solid phase transition processes, making them great potentials for the thermal energy control of appropriate working temperature regions.
- Li, Wei,Liu, Dongzhi,Liu, Simin,Yin, Defei,Zhou, Xueqin
-
-
- Oxidation of Primary Alcohols and Aldehydes to Carboxylic Acids via Hydrogen Atom Transfer
-
The oxidation of primary alcohols and aldehydes to the corresponding carboxylic acids is a fundamental reaction in organic synthesis. In this paper, we report a new chemoselective process for the oxidation of primary alcohols and aldehydes. This metal-free reaction features a new oxidant, an easy to handle procedure, high isolated yields, and good to excellent functional group tolerance even in the presence of vulnerable secondary alcohols and tert-butanesulfinamides.
- Tan, Wen-Yun,Lu, Yi,Zhao, Jing-Feng,Chen, Wen,Zhang, Hongbin
-
supporting information
p. 6648 - 6653
(2021/09/08)
-
- Pd(OH)2/C, a Practical and Efficient Catalyst for the Carboxylation of Benzylic Bromides with Carbon Monoxide
-
A simple, efficient, cheap, and broadly applicable system for the carboxylation of benzylic bromides with carbon monoxide and water is reported. Upon simple reaction with only 2.5 wt % of Pearlman's catalyst and 10 mol % of tetrabutylammonium bromide in tetrahydrofuran at 110 °C for 4 h, a range of benzylic bromides can be smoothly converted to the corresponding arylacetic acids in good to excellent yields after simple extraction and acid-base wash. The reaction was found to be broadly applicable, scalable, and could be successfully extended to the use of ex situ-generated carbon monoxide and applied to the synthesis of the nonsteroidal anti-inflammatory drug diclofenac.
- Wakuluk-Machado, Anne-Marie,Dewez, Damien F.,Baguia, Hajar,Imbratta, Miguel,Echeverria, Pierre-Georges,Evano, Gwilherm
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p. 713 - 723
(2020/02/04)
-
- PdII-Catalyzed methoxylation of C(sp3)-H bonds adjacent to benzoxazoles and benzothiazoles
-
The Pd(OAc)2/PhI(OAc)2 catalyst system promotes the highly regioselective dehydrogenative methoxylation of a C(sp3)-H bond adjacent to benzoxazole and benzothiazole rings. The title transformation constitutes the first example of a Pd-catalyzed C(sp3)-H activating methoxylation at the proximal-selective α-position with regard to a directing auxiliary and provides expedient access to an important class of azole-decorated methyl ethers (up to 90% isolated yield). The synthetic practicality of the methodology was demonstrated by achieving α-methoxyacetic acids via the elimination of the benzoxazole auxiliaries and by obtaining the precursor of an O-methylated Breslow intermediate.
- Kumar, Jogendra,Gupta, Aniket,Bhadra, Sukalyan
-
supporting information
p. 3314 - 3318
(2019/04/01)
-
- Beyond the affinity for protein kinase C: Exploring 2-phenyl-3-hydroxypropyl pivalate analogues as C1 domain-targeting ligands
-
Over the past fifteen years, we reported the design and synthesis of different series of compounds targeting the C1 domain of protein kinase C (PKC) that were based on various templates. Out of the pivalate templates, 2-[4-(benzyloxy)phenyl]-3-hydroxypropyl pivalate (compound 1) emerged as the most potent and promising PKCα ligand, showing a Ki value of 0.7 μM. In the present contribution our efforts are aimed at better understanding which structural modifications of the pivalate template are allowed for its affinity to the C1 domain of PKC to be preserved or increased. To this aim, thirteen novel analogues of 1 were designed and their interaction with the target was evaluated in silico. Designed compounds were then prepared and fully characterized as well as their affinity for the α and δ isoforms of PKC evaluated. Additionally, in order to investigate the role of chirality in the ligand-target interaction, the pure enantiomers of the most interesting PKC ligands were prepared and their affinity for PKC isoforms was determined. Results from our study revealed that: i) the presence of the ester function seems to be essential for the ligand-target interaction; ii) only a few structural modifications at the ester group are allowed for the C1 domain affinity to be preserved; and iii) the [3H]PDBu replacement experiments showed that the C1 domain of PKC does not exhibit enantiopreference for the pure stereoisomers of tested compounds. Altogether our observations provide further insights into the ligand-target interactions of the PKC C1 domain and represent a step-forward in future development of more specific and effective PKC ligands. This journal is
- Rossi, Daniela,Talman, Virpi,Genn?s, Gustav Boije Af,Marra, Annamaria,Picconi, Pietro,Nasti, Rita,Serra, Massimo,Ann, Jihyae,Amadio, Marialaura,Pascale, Alessia,Tuominen, Raimo K.,Yli-Kauhaluoma, Jari,Lee, Jeewoo,Collina, Simona
-
p. 547 - 554
(2015/04/27)
-
- Designing new analogs for streamlining the structure of cytotoxic lamellarin natural products
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Despite the therapeutic potential of marine-derived lamellarin natural products, their preclinical development has been hampered by their lipophilic nature, causing very poor aqueous solubility. In order to develop more drug-like analogs, their structure was streamlined in this study from both the cytotoxic activity and lipophilicity standpoints. First, a modified total synthetic route was successfully devised to construct a library of 59 systematically designed lamellarin analogs, which were then subjected to cytotoxicity and log P determinations. Along with the 25 first-generation lamellarins previously synthesized in our laboratory, the structure-activity and structure-lipophilicity relationships were extensively evaluated. Our results clearly indicated the additional structural requirements around the lamellarin skeleton which, when combined with those reported previously, can provide invaluable guidance for further modifications to increase the aqueous solubility of these compounds.
- Tangdenpaisal, Kassrin,Worayuthakarn, Rattana,Karnkla, Supatra,Ploypradith, Poonsakdi,Intachote, Pakamas,Sengsai, Suchada,Saimanee, Busakorn,Ruchirawat, Somsak,Chittchang, Montakarn
-
p. 925 - 937
(2015/03/31)
-
- Synthesis and in vitro antitumor activity of asperphenamate derivatives as autophagy inducer
-
In an effort to improve the aqueous solubility and the antitumor activity of natural product asperphenamate, we have designed and synthesized three series of asperphenamate derivatives, including series I (simplifying molecular skeleton series), series II (introducing a hydroxyl group to A-phenyl ring series) and series III (disrupting molecular planarity series). All derivatives have displayed a significantly increased solubility compared with asperphenamate. Their growth inhibitory activities in vitro were screened by the standard MTT method in MCF-7, HeLa, and BEL-7402 cell lines. With the exception of the derivatives in series I, most of derivatives in series II and series III showed growth inhibitory activity. Among all derivatives, IM23b in series III showed the greatest potency in human breast cancer MCF-7 cells. The cellular potency of IM23b was approximately 1.5-fold more potent than that of cisplatin. The mechanism of cell death induced by IM23b in human breast cancer MCF-7 cells was further investigated. We concluded that the cell death was induced by autophagy instead of apoptosis or cell cycle arrest.
- Yuan, Lei,Li, Yanchun,Zou, Chunyang,Wang, Chao,Gao, Jian,Miao, Caixia,Ma, Enlong,Sun, Tiemin
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scheme or table
p. 2216 - 2220
(2012/04/18)
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- Synthesis and structure-activity relationships of tri-substituted thiazoles as RAGE antagonists for the treatment of Alzheimer's disease
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A series of thiazole derivatives were designed, and prepared to develop RAGE antagonist for the treatment of Alzheimer's disease (AD). SAR studies were performed to optimize inhibitory activity on Aβ-RAGE binding. SAR studies showed that introducing an amino group at part A was essential for inhibitory activity on Aβ-RAGE binding. Compounds selected from Aβ-RAGE binding screening displayed inhibitory activity on Aβ transport across BBB. They also showed inhibitory activity against Aβ-induced NF-κB activation. These results indicated that our derivatives had a potential as therapeutic agent for the treatment of AD.
- Lee, Yun Suk,Kim, Hee,Kim, Young-Ho,Roh, Eun Joo,Han, Hogyu,Shin, Kye Jung
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p. 7555 - 7561
(2013/02/21)
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- Synthesis of bis(tetronic acid)s via double Dieckmann condensation
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A practical, straightforward synthesis of several bis(tetronic acid)s from a common precursor, dimethyl l-tartrate, is described. It involves a double Dieckmann condensation using tetrabutylammonium fluoride. The radical scavenging capacities of these compounds are measured. Georg Thieme Verlag Stuttgart - New York.
- Thetiot-Laurent, Sophie A.-L.,Nadal, Brice,Le Gall, Thierry
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experimental part
p. 1697 - 1701
(2010/07/04)
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- An efficient chemoselective etherification of phenols in polyfunctional aromatic compounds
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A simple and efficient chemoselective alkylation of phenols in polyfunctional aromatic compounds with different alkyl halides in the presence of K2CO3/TBAB is reported. The method is successful with various hydroxy aromatic acids or oximes possessing other functional groups.
- Pandey, Jyoti,Mishra, Mridul,Bisht, Surendra Singh,Sharma, Anindra,Tripathi, Rama P.
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p. 695 - 698
(2008/09/17)
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- 2-Benzyl and 2-phenyl-3-hydroxypropyl pivalates as protein kinase C ligands
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A series of 2-benzyl and 2-phenyl-3-hydroxypropyl pivalates designed to incorporate the principal pharmacophores of phorbol esters have been synthesized and tested as PKC-α ligands. Among the analogues, 13c exhibited the most potent binding affinity with a Ki = 0.7 μM. The synthesized analogues were subjected to molecular modeling analysis based on two alternative models of the phorbol pharmacophore and a docking study of 13c was carried out.
- Lee, Jeewoo,Lee, Ju-Hyun,Kim, Su Yeon,Perry, Nicholas A.,Lewin, Nancy E.,Ayres, Jolene A.,Blumberg, Peter M.
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p. 2022 - 2031
(2007/10/03)
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- Novel, potent, selective, and orally bioavailable human βII-tryptase inhibitors
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The synthesis of novel [1,2,4]oxadiazoles and their structure-activity relationship (SAR) for the inhibition of tryptase and related serine proteases is presented. Elaboration of the P′-side afforded potent, selective, and orally bioavailable tryptase inhibitors.
- Sperandio, David,Tai, Vincent W.-F.,Lohman, Julia,Hirschbein, Bernie,Mendonca, Rohan,Lee, Chang-Sun,Spencer, Jeffrey R.,Janc, James,Nguyen, Margaret,Beltman, Jerlyn,Sprengeler, Paul,Scheerens, Heleen,Lin, Tong,Liu, Liang,Gadre, Ashwini,Kellogg, Alisha,Green, Michael J.,McGrath, Mary E.
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p. 4085 - 4089
(2007/10/03)
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- Highly chemoselective hydrogenation method using novel finely dispersed palladium catalyst on silk-fibroin: Its preparation and activity
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A palladium-fibroin complex (Pd/Fib) was prepared by soaking silk-fibroin in MeOH solution of Pd(OAc)2 for 2 days (under Ar atmosphere) - 4 days (under air). Pd(OAc)2 was gradually absorbed by fibroin and the rapid reduction of fibroin conjugated Pd(OAc)2 proceeded with MeOH as a reductant at room temperature to be the Pd(0) complex. Pd/Fib catalyzed chemoselective hydrogenation of acetylenes, olefins and azides in the presence of aromatic ketones and aldehydes, halides, N-Cbz protective groups and benzyl esters which are readily hydrogenated using Pd/C or Pd/C(en) as a catalyst.
- Ikawa, Takashi,Sajiki, Hironao,Hirota, Kosaku
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p. 2217 - 2231
(2007/10/03)
-
- New 3- and 4-hydroxyfuranones as anti-oxidants and anti-inflammatory agents
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Two series of new furanones substituted by methylsulfonylphenyl or methylsulfamidophenyl moieties were found to protect against oxidation damage by inhibiting or quenching free radicals and reactive oxygen species in in vitro experiments. The effect on lipid peroxidation was also examined. In addition, we investigated the activity of products in two models of inflammation: phorbol ester-induced ear edema in mice and carrageenan-induced paw edema in rat. The most powerful compounds and with reducing activity against DPPH (IC50 = 1779 and 57 μM, respectively), superoxide anion quenching capacity (IC50 = 511 and 49 μM, respectively), lipid peroxidation inhibitory effect and anti-inflammatory properties (about 50-65% inhibition of edema at 200 mg/kg ip in both tests used) were selected for further pharmacological and toxicological tests because of their attractive profile for the treatment of inflammatory diseases.
- Weber, Valerie,Rubat, Catherine,Duroux, Eliane,Lartigue, Claire,Madesclaire, Michel,Coudert, Pascal
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p. 4552 - 4564
(2007/10/03)
-
- Aminoalcohol derivatives
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The present invention relates to a compound formula [I]: wherein R1 is hydrogen or halogen, R2 is hydrogen or an amino protective group, R3 is hydrogen or lower alkyl, X is bond, —CH2— or —O—, and Y is ?in which R4 is lower alkoxycarbonyl, ?in which R5 is carboxy(lower)alkyl, etc., ?in which R6 is hydroxy, etc., and so on, or a salt thereof. The compound [I] of the present invention and pharmaceutically acceptable salts thereof are useful for the prophylactic and/or the therapeutic treatment of pollakiurea or urinary incontinence.
- -
-
Page/Page column 19
(2010/02/07)
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- AMINOALCOHOL DERIVATIVES AND THEIR USE AS BETA-3 ADRENERGIC RECEPTOR AGONISTS
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The present invention relates to a compound formula [I] or a salt thereof. The compound [I] of the present invention and pharmaceutically acceptable salts thereof are useful for the prophylactic and/or the therapeutic treatment of pollakiurea or urinary incontinence.
- -
-
Page/Page column 57-58
(2010/02/07)
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- Compositions and methods using compounds having cytochrome P450RAI inhibitory activity co-administered with vitamin A
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vitamin A, or a derivative of vitamin A having vitamin A like activity is co-administered with inhibitors of the CP450RAI1 and/or of CP450RAI2 enzymes for the purpose of treating diseases and conditions in mammals, including humans, which diseases or conditions are prevented, treated, ameliorated, or the onset of which is delayed by administration of retinoid compounds or by the mammalian organism's naturally occurring retinoic acid.
- -
-
-
- 4-[(8-Ethynyl, 8-vinyl or 8-ethynyl-methyl)-6-chromanoyl]-benzoic and 2-[4-[(8-ethynyl, 8-vinyl or 8-ethynyl-methyl)-6-chromanoyl]-phenyl]-acetic acid, their esters and salts having cytochrome P450RAI inhibitory activity
-
Compounds of Formula 1 1 wherein the variables are defined in the specification have cytochrome P450RAI-1 and P450RAI-2 inhibitory activity, and are suitable for treatment of mammals with conditions which are treatable with retinoids, or which are controlled by or responsive to the organism''s native retinoic acid. Formulations containing the compounds of the invention can also be co-administered with retinoids and/or Vitamin A to enhance or prolong the effects of medications containing retinoids, Vitamin A, or of the organism''s native retinoic acid.[From equivalent US6740676] Compounds of Formula 1: STR1wherein the variables are defined in the specification have cytochrome P450RAI-1 and P450RAI-2 inhibitory activity, and are suitable for treatment of mammals with conditions which are treatable with retinoids, or which are controlled by or responsive to the organism''s native retinoic acid. Formulations containing the compounds of the invention can also be co-administered with retinoids and/or Vitamin A to enhance or prolong the effects of medications containing retinoids, Vitamin A, or of the organism''s native retinoic acid.
- -
-
Page/Page column 10; 16
(2008/06/13)
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- 4-[(8-Substituted)-6-chromanoyl]-and 4-[8-substituted)-chroman-6-yl-ethynyl]-benzoic and phenylacetic acids, their esters and salts having cytochrome P450RAI inhibitory activity
-
Compounds of the formula 1where the variables are defined in the specification have cytochrome P450RAI-1 and P450RAI-2 inhibitory activity, and are suitable for treatment of mammals with conditions which are treatable with retinoids, or which are controlled by or responsive to the organism's native retinoic acid. Formulations containing the compounds of the invention can also be co-administered with retinoids and/or Vitamin A to enhance or prolong the effects of medications containing retinoids, Vitamin A, or of the organism's native retinoic acid.
- -
-
-
- A convenient synthesis of Δ7,8-Morphinan-6-one and its direct oxidation to 14-hydroxy-Δ7,8-morphinan-6-one
-
Synthesis of Δ7,8-morphinan-6-one by Grewe cyclization and bromoketalization reaction as crucial steps is described. Introduction of a hydroxyl group at 14-position is demonstrated by direct oxidation with MnO2 in the presence of silica gel.
- Passarella, Daniele,Consonni, Alessandra,Giardini, Alessandra,Lesma, Giordano,Silvani, Alessandra
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p. 1981 - 1983
(2007/10/03)
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- Non-peptidyl inhibitors of VLA-4 dependent cell binding useful in treating inflammatory, autoimmune, and respiratory diseases
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There is disclosed a genus of non-peptidyl compounds, wherein said compounds are VLA-4 inhibitors useful in treating inflammatory, autoimmune, and respiratory diseases, and wherein said compounds comprise a compound of Formula (1.0.0): and pharmaceutically acceptable salts and other prodrug derivatives thereof, wherein: A is (C1-C6) alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl optionally substituted with 0 to 3 R9; or is a member selected from the group consisting of the following radicals: A1-NHC(═O)NH-A2-, A1-NHC(═O)O-A2-, A1-OC(═O)NH-A2-, A1-NHSO2NH-A2-, A1-NHC(═O)-A2-, A1-C(═O)NH-A2-, A1-NHSO2-A2-, A1-SO2NH-A2-, A1-(CH2)r-A2-, where A1 and A2 are each independently selected from the group consisting of hydrogen, aryl, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, cycloalkyl, heteroaryl, and heterocyclyl substituted with 0 to 3 R9; B is a member independently selected from the group consisting of the following: E is a single bond; —O—; —NR10—; —CH═CH—; —CC—; —S(═)q; —CR11R12NR10—; or —CR11R12; X is —O—; —C(═O)—; —S(═O)q—; or —NR10—; X1, X2 and X3 are each independently selected from the group consisting of CH, CR9 or N; Y is a single bond; —C(═O)—; —C(═S)—; or —S(═O)2—; R7 is (C1-C6) alkyl; (CH2)kOR5; (CH2)kNR6C(═O)R5; (CH2)kNR6C(═O)OR5; (CH2)kNR6SO2R5; (CH2)kNR6R5; F; CF3; OCF3; aryl, substituted with 0 to 3 R9; heterocyclyl, substituted with 0 to 3 R9; heteroaryl, substituted with 0 to 3 R9; cycloalkyl, substituted with 0 to 3 R9; or R7 may be taken together with R8 to form a cycloalkyl or heterocyclyl ring; or R7 may be taken together with R11 to form a cycloalkyl or heterocyclyl ring; and R8 is hydrogen; F; (C1-C6) alkyl or (C1-C6) alkoxy.
- -
-
-
- Total synthesis of (2S,3s,4R)-plakoridine A
-
The β-amino ester 6 is synthesized via the diastereoselective Michael addition of the lithium amide derived from amine 5 to methyl (E)-2-hexenoate. This ester is converted to the pyrrolidinone 8 via an aldol condensation/deprotection/cyclization. Transformation of the lactam 8 into thiolactam 11 followed by Eschenmoser sulfide contraction provides (2S,3S,4R)-plakoridine A. (C) 2000 Elsevier Science Ltd.
- Ma, Dawei,Sun, Haiying
-
p. 1947 - 1950
(2007/10/03)
-
- Efficient synthesis of 1-Benzyloxyphenyl-3-phenylacetones
-
1-[(Benzyloxy)phenyl]-3-phenylacetones 1a-c have been conveniently synthesized by acylation of the PhCH2Li-DABCO complex with their respective N-methyl O-methyl hydroxamates 5a-c. In four steps, ketones 1a-c having ortho-, meta- and para-benzyloxy substituents were obtained in 42-51% overall yields from commercially available 2-(hydroxyphenyl)acetic acids.
- Mannekens,Tourwe,Lubell
-
p. 1214 - 1216
(2007/10/03)
-
- The formation of a novel Pd/C-ethylenediamine complex catalyst: Chemoselective hydrogénation without deprotection of the o-benzyl and ZV-Cbz groups
-
A Pd/C catalyst formed an isolable complex with ethylenediamine employed as the catalytic poison via one-to-one interaction between Pd metal and ethylenediamine, and this complex catalyst [Pd/ C(en)] chemoselectively hydrogenated a variety of reducible functionalities such as olefin, acetylene, nitro, benzyl ester, and azido in the presence of an O-benzyl or N-Cbz protective group. These findings reinforce the versatility potential of O-benzyl and N-Cbz as protective groups in organic synthesis, and the Pd/C(en) catalyst has been identified as a novel and chemoselective catalyst for the hydrogénation.
- Sajiki, Hironao,Hattori, Kazuyuki,Hirota, Kosaku
-
p. 7990 - 7992
(2007/10/03)
-
- Suppression effect of the Pd/C-catalyzed hydrogenolysis of a phenolic benzyl protective group by the addition of nitrogen-containing bases
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A mild and chemoselective hydrogenation method using 5% Pd/C for olefin, N-Cbz, benzyl ester and nitro functionalities distinguishing from the benzyl protective group for the phenolic hydroxyl group has been developed by the employment of 2,2'-dipyridyl as an additive. The suppressive effect on the benzyl ether hydrogenolysis was strongly influenced by the sorts of nitrogen- containing bases employed as an additive.
- Sajiki, Hironao,Kuno, Hiroko,Hirota, Kosaku
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p. 7127 - 7130
(2007/10/03)
-
- A novel type of Pd/C-catalyzed hydrogenation using a catalyst poison: Chemoselective inhibition of the hydrogenolysis for O-benzyl protective group by the addition of a nitrogen-containing base
-
A mild and chemoselective hydrogenation method for a variety of reducible functional groups distinguishing front aliphatic and aromatic' benzyl ethers was accomplished by the addition of an appropriate nitrogen- containing base to the Pd/C-catalyzed hydrogenation system.
- Sajiki, Hironao,Hirota, Kosaku
-
p. 13981 - 13996
(2007/10/03)
-
- Kinetics and Mechanism of the Alkaline Hydrolysis of Pentachlorophenyl ω-(p-Hydroxyphenyl)alkanoates
-
A kinetic study of the alkaline hydrolysis of pentachlorophenyl esters of ω-(p-hydroxyphenyl)alkanoic acids 3 shows that the dissociative route involving a spirodienone intermediate is not a feasible alternative to the normal associative BAC2 pathway.
- Cevasco, Giorgio,Thea, Sergio
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p. 269 - 272
(2007/10/03)
-
- Synthesis and protein kinase C inhibitory activities of balanol analogues with modification of 4-hydroxybenzamido moiety
-
A series of racemic balanol analogues with modification of the benzamido moiety of balanol have been synthesized and evaluated for their inhibitory activities against human protein kinase C isozymes (PKC-alpha, -beta I, -beta II, -gamma, -delta, -epsilon, and -eta). The structural modification includes replacement of the 4-hydroxyphenyl group with variously substituted phenyl rings, substitution of the amide linkage with a sulfonamide or an ester, and replacement of the 4-hydroxyphenyl substructure with a hydroxyl substituted indole or a hydroxybenzyl group. In general, these analogues were found to be less potent than balanol, but a number of analogues were identified with improved isozyme selectivity. The structure-activity relationship studies of these analogues also indicated that (1) the optimal general PKC inhibition requires a free 4-hydroxyl group in the benzamido portion of the molecule, (2) the amide linkage of the benzamido moiety is important for PKC inhibition, and (3) the conformation associated with the benzamido moiety seems to have a profound effect on PKC inhibition. The requirement of a free 4-hydroxyl group in conjunction with an appropriate conformation of the benzamido moiety for optimal PKC inhibition suggests that the 4-hydroxyphenyl group may be involved in a specific inhibitor-enzyme interaction important for PKC inhibition.
- Hu, Hong,Mendoza, Jose S.,Lowden, Christopher T.,Ballas, Lawrence M.,Janzen, William P.
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p. 1873 - 1882
(2007/10/03)
-
- Total syntheses of spidamine and joramine, polyamine toxins from the joro spider, Nephila clavata
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In order to confirm the structures of spidamine and joramine, identified from the venom of a spider (nephila clavata), we convergently synthesized both compounds, which have a common side chain of N-(L-asparaginyl)-N'-(3- aminopropyl-β-alanyl)-1,5-pentanediamine. A synthon of the common side chain was synthesized by starting with n-propanolamine which was converted to 7- azido-N-benzyloxycarbonyl-4-azaheptanoic acid N-hydroxysuccinimidyl ester. The ester was coupled with tert-butyloxycarbonyl-L-asparaginyl-1,5- pentanediamine to give the synthon of the common side chain. In the final synthesis of spidamine, the synthon of the common side chain was reacted with 2,4-dibenzyloxyphenylacetic acid N-hydroxysuccinimidyl ester, obtained by Willgerodt-kindler reaction of 2,4-dihydroxyacetophenone. The protected spidamine was catalytically hydrogenated to remove protective groups, affording spidamine itself in 13% yield from n-propanolamine. In the final synthesis of joramine, the synthon of the common side chain was reacted with 4-benzyloxyphenyl acetic acid N-hydroxysuccinimidyl ester. The protected joramine was also catalytically hydrogenated to produce joramine itself in 11% yield. The conformations of both synthesized compounds were analyzed by 1H-NMR and 13C-NMR. Their blocking activities on glutamate receptors were examined using lobster neuromuscular synapses.
- Chiba, Tadashige,Akizawa, Toshifumi,Matsukawa, Motomi,Nishi, Masatoshi,Kawai, Nobufumi,Yoshioka, Masanori
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p. 972 - 979
(2007/10/03)
-
- Polymer-Supported Mitsunobu Ether Formation and its Use in Combinatorial Chemistry
-
Aromatic hydroxy acids have been attached to a polymeric solid support and the phenolic hydroxy groups have been reacted with a variety of primary and secondary alcohols under the conditions of the Mitsunobu reaction (triphenylphosphine and diethyl azodicarboxylate) in tetrahydrofuran.In most cases the reaction provided a nearly quantitative yield of alkyl aryl ethers, as determined after cleaving theproduct from the resin.To demonstrate that the polymer-supported Mitsunobu reaction is useful for combinatorial library synthesis, we synthesized a number of model compounds and a simple three randomization step library composed of 4,200 different compounds.
- Krchnak, Viktor,Flegelova, Zuzka,Weichsel, Aleksandra S.,Lebl, Michal
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p. 6193 - 6196
(2007/10/02)
-
- The Effect of Carbonyl Containing Terminal Chains on Mesomorphic Properties in 4,4'-Disubstituted Phenylbenzoates and Phenylthiobenzoates. 4. Phenylbenzoates Containing A (CH2)nCO2R' Group (n = 0-2) on the Phenolic End
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The effect of a (CH2)nCO2R' group on the mesomorphic properties of the esters where X = alkyl or alkoxy, Y = (CH2)nCO2R'(R' = C7 and C9) and n = 0-2 has been studied by synthesizing these esters and determining their mesomorphic properties by hot-stage polarizing microscopy.The starting phenols were prepared by esterification of 4-hydroxybenzoic, phenylacetic or phenylpropionic acids.Both the benzyl and methoxycarbonyl protecting groups were tried with the latter giving higher yields when n = 0 because of better solubility of the protected acid.No mesophases were observed in the esters when n = 1, nematic and smectic A phases occurred when n = 2 and smectic A and C phases when n = 0.A few 1,4-cyclohexane diesters were also prepared using these phenols.The mesomorphic properties of these esters followed the same trend observed in the phenylbenzoates escept no C phases were observed.Comparisons of the transition temperatures for these esters with those for Y = R' showed that both small increases or decreases were observed for Y = CO2R'.However, the addition of a spacer methylene group (n = 1 and 2) always gave lower temperatures with the amount of lowering being much greater for n = 2 than n = 1.A comparison of transition temperatures for Y = CO2R', OCOR', COR' and OR' indicated that these temperatures were higher when Y = COR' as expected from dipole moment considerations but were lower when Y = CO2R' than when Y = OCOR', the opposite expected from these considerations.This trend was also observed in the cyclohexane diesters.Transition temperatures were always higher for the esters when Y has an oxygen atom adjacent to the benzene ring.Therefore, esters with Y = O(CH2)nCO2R', n = 1 and 2 were also synthesized.The phenols were prepared by alkylation of 4-benzyloxyphenol with the bromo esters followed by hydrogenolysis.However, these esters showed no mesophases except the cyclohexane diester with n = 2.
- Neubert, M. E.,Leung, K.,Jirousek, M. R.,Ezenylimba, M. C.,Sabol-Keast, S.,et al.
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- Substituted 1,5-dihydro-4-(N-methylhydroxylamino)-2H-pyrrol-2-ones
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Novel cyclic vinylogous N-hydroxy-N-methylureas are useful in the treatment of leukotriene mediated conditions such as asthma and rheumatoid arthritis.
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- SYNTHESIS OF ATR AND LIGHT SENSITIVE CIS-PHENOLIC CYCLOPROPANE DERIVATIVES
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The synthesis of several cis-phenolic cyclopropanes, 6, 7, 8 and 13 is described.These cyclopropanes are new potential antiestrogens.A hydrogenolysis study of precursors, 5b, 5c, 5d, 10, 11, and 12, and a novel method for the prevention of gem-dichlorocyclopropane ring-opening during hydrogenolysis are discussed.
- Afzal, Jalees,Magarian, Robert A.,Griffin, May,Pento, J. Thomas
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p. 3061 - 3068
(2007/10/02)
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- Quinoline hydroxamates and their use as modulators of arachidonic acid metabolic pathways
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This invention relates to new chemical compounds possessing valuable pharmaceutical activity, particularly as lipoxygenase inhibitors possessing anti-inflammatory and anti-allergic properties.
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- PREPARATION AND SOME REACTIONS OF 4- AND 5-ARYL-4,5-DIHYDROPYRIDAZIN-3(2H)-ONES
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Efficient preparations of 4- and 5-phenyl-4,5-dihydropyridazin-3(2H)-ones have been developed, the main reactions of these compounds have been studied, and the synthetic routes have been used to give analogues with substituents in the phenyl rings.In the best synthesis of the 4-phenyldihyropyridazinone (72 percent overall yield) the product was obtained from phenylacetic acid by three simple stages.This approach was applied in preparations of the 2- and 4-hydroxyphenyl compounds and, in conjunction with a recent method for amine protection, the 4-aminophenyl analogue.A four stage synthesis starting from benzaldehyde gave the 5-phenyldihydropyridazinone in 47 percent overall yield; hydroxybenzaldehydes were similarly converted into 5-(allyloxyphenyl)dihydropyridazinones.Oxidation to phenylpyridazinones occured more readily with the 4- and 5-phenyldihydropyridazinones than with the 6-phenyl isomer.The 4- and 5-dihydropyridazinones were smoothly reduced to tetrahydropyridazinones by hydrogenation over platinum but were uneffected by palladium in the presence of hydrazine or cyclohexene.
- Breukelman, Stephen P.,Meakins, G. Denis
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p. 1627 - 1636
(2007/10/02)
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- Process for preparing aryl acetic acid derivatives
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This invention relates to a process for preparing an aryl acetic acid derivative represented by the formula comprising hydrolyzing in an alkaline substance a dichloroethenyl compound represented by the formula
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- Dioxolanones as Synthetic Intermediates. Part 2. Synthesis of Tetronic Acids and Pulvinones
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The utility of 1,3-dioxolan-4-ones as intermediates in the synthesis of tetronic acids is examined.The reaction of dioxolanone (1) with lithium enolates of 2-substituted methyl or t-butyl acetates at -78 deg C in tetrahydrofuran afforded a general synthesis of 2-substituted tetronic acids (3) - (8).Treatment of (1) with the anions of 2-substituted acetonitriles led to formation of the corresponding 3-substituted-2-aminofuran-4(5H)-ones (13) and (14).A route to unsymmetrically substituted pulvinones by reaction of 5-arylidene-2,2-pentamethylene-1,3-dioxolan-4-ones with appropriately substituted phenylacetic ester anions has been devised.Thus, the preparation of the naturally occurring pigment 3',4',4-trihydroxypulvinone (18) was achieved via intermediate in which the phenolic groups were protected as benzyl ethers.The dioxolanone (26) has been used in the preparation of 2-acyl-4-benzylidenetetronic acids.
- Ramage, Robert,Griffiths, Gareth J.,Shutt, Fiona E.,Sweeney, John N. A.
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p. 1539 - 1545
(2007/10/02)
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- Biosynthesis. Part 24. Speculative Incorporation Experiments with 1-Benzylisoquinolines and a Logical Approach via C6-C2 and C6-C3 Precursors to the Biosynthesis of Hasubanonine and Protostephanine
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Many possible 1-benzyltetrahydroisoquinolines have been examined as possible advanced precursors of the alkaloids hasubanonine (1) and protostephanine (2) in Stephania japonica plants, but none was incorporated significantly.Administration of various precursor molecules having only one aromatic ring, such as tyrosine, has demonstrated that both alkaloids are derived from two different C6-C2 biogenetic units.The subsequent failure of further 1-benzyltetrahydroisoquinolines and bisphenethylamines to be incorporated suggested the intermediacy of either (a) modified 1-benzylisoquinolines or (b) trioxygenated C6-C2 building blocks.Precursors designed to examine the first possibility, such as 1-benzyl-3,4-dihydroisoquinolines or 1-benzyl-1-carboxytetrahydroisoquinolines, were not incorporated into (1) and (2) whereas two 3',4',5'-trioxygenated 2-phenylethylamines were incorporated.These findings allow further delineation of the requirements for later precursors of the alkaloids (1) and (2).
- Battersby, Alan R.,Jones, Raymond C. F.,Kazlauskas, Rymantas,Thornber, Craig W.,Ruchirawat, Somsak,Staunton, James
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p. 2016 - 2029
(2007/10/02)
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