- Chromium-Salen Complex/Nitroxyl Radical Cooperative Catalysis: A Combination for Aerobic Intramolecular Dearomative Coupling of Phenols
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We describe an aerobic intramolecular dearomative coupling reaction of tethered phenols using a catalytic system consisting of a chromium-salen (Cr-salen) complex combined with a nitroxyl radical. This novel catalytic system enables formation of various spirocyclic dienone products including those unable to be accessed by previously reported methods efficiently under mild reaction conditions.
- Nagasawa, Shota,Fujiki, Shogo,Sasano, Yusuke,Iwabuchi, Yoshiharu
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p. 6952 - 6968
(2021/05/29)
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- Fused pyrimidine derivatives substituted with a nitrogen-containing heterocyclic ring and their pharmaceutical use
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The present application relates to fused pyrimidine derivatives substituted with heterocycles containing nitrogen and to their medicinal use. Provided are a compound represented by chemical formula I, a solvate, a stereoisomer thereof, a pharmaceutically
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Paragraph 0559-0563
(2021/07/17)
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- Discovery and optimization of novel N-benzyl-3,6-dimethylbenzo[d]isoxazol-5-amine derivatives as potent and selective TRIM24 bromodomain inhibitors with potential anti-cancer activities
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Tripartite motif-containing protein 24 (TRIM24), recognized as an epigenetic reader for acetylated H3K23 (H3K23ac) via its bromodomain, has been closely involved in tumorigenesis or tumor progression of several cancers. Developing inhibitors of TRIM24 is significant for functional studies and drug discovery. Herein, we report the identification, optimization and evaluation of N-benzyl-3,6-dimethylbenzo[d]isoxazol-5-amines as TRIM24 bromodomain inhibitors starting from an in house library screening. Structure-based optimization leads to two potent and selective compounds 11d and 11h in an Alphascreen assay with IC50 values of 1.88 μM and 2.53 μM, respectively. The viability assay demonstrates the great potential of this series of compounds as inhibitors of proliferation of prostate cancer (PC) cells LNCaP, C4-2B. A colony formation assay further supports this inhibitory activity. Compounds 11d and 11h inhibit cell proliferation of other cancer types such as non-small cell lung cancer (NSCLC) cells A549 with IC50 values of 1.08 μM and 0.75 μM, respectively. These data suggests that compounds 11d and 11h are promising lead compounds for further research.
- Hu, Qingqing,Wang, Chao,Xiang, Qiuping,Wang, Rui,Zhang, Cheng,Zhang, Maofeng,Xue, Xiaoqian,Luo, Guolong,Liu, Xiaomin,Wu, Xishan,Zhang, Yan,Wu, Donghai,Xu, Yong
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- Naturally occurring Batatasins and their derivatives as α-glucosidase inhibitors
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Batatasins are endogenous plant hormones found in yams and other related plant species. These plants are widely consumed as botanical dietary supplements in many parts of the world. This study investigated the inhibitory effects and mechanisms of Batatasin I, III, IV, V against α-glucosidase regarding their antidiabetic activities. The results revealed that Batatasin I, III, IV inhibited α-glucosidase in a reversible and noncompetitive manner, with IC50 values of 2.55, 1.89 and 2.52 mM respectively, while Batatasin V completely abolished its inhibitory activity even at the highest concentrations tested. Furthermore, a class of Batatasin-derived compounds with different substitution patterns was synthesized and subjected to the assay to clarify the structure-activity relationships, which suggested that the hydroxyl at the C-2′ position may play a significant role in improving the inhibitory activities. Their probable binding modes and the specificity of the binding sites were studied using molecule docking simulation. It was concluded that Batatasins, especially Batatasin III and IV, are promising α-glucosidase inhibitors, which therefore could be used as functional food to alleviate postprandial hyperglycemia and as potential candidates for the development of antidiabetic agents.
- Hu, Wei-Ping,Cao, Guo-Dong,Zhu, Jin-Hua,Li, Jia-Zhong,Liu, Xiu-Hua
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p. 82153 - 82158
(2015/10/12)
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- Chemical synthesis and evaluation of 17α-alkylated derivatives of estradiol as inhibitors of steroid sulfatase
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Steroid sulfatase (STS) controls the levels of 3-hydroxysteroids available from circulating steroid sulfates in several normal and malignant tissues. This and the known involvement of active estrogens and androgens in diseases such as breast and prostate cancers thus make STS an interesting therapeutic target. Here we describe the chemical synthesis and characterization of an extended series of 17α-derivatives of estradiol (E2) using different strategies. A variant of the samarium-Barbier reaction with stoichiometric samarium metal and catalytic Kagan reagent formation was used for introducing low reactive benzyl substrates in position 17 of estrone (E1) whereas heterocyclic substrates were metalated and reacted with either the carbonyl or the 17-oxirane of E1. In vitro evaluation of the inhibitory potency of the new compounds against STS identified new inhibitors and allowed a more complete structure-activity relationship study of this family of 17α-derivatives of E2.
- Fournier, Diane,Poirier, Donald
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p. 4227 - 4237
(2011/11/12)
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- Biocatalytic organic synthesis of optically pure (S)-scoulerine and berbine and benzylisoquinoline alkaloids
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A chemoenzymatic approach for the asymmetric total synthesis of the title compounds is described that employs an enantioselective oxidative C-C bond formation catalyzed by berberine bridge enzyme (BBE) in the asymmetric key step. This unique reaction yielded enantiomerically pure (R)-benzylisoquinoline derivatives and (S)-berbines such as the natural product (S)-scoulerine, a sedative and muscle relaxing agent. The racemic substrates rac-1 required for the biotransformation were prepared in 4-8 linear steps using either a Bischler-Napieralski cyclization or a C1-Cα alkylation approach. The chemoenzymatic synthesis was applied to the preparation of fourteen enantiomerically pure alkaloids, including the natural products (S)-scoulerine and (R)-reticuline, and gave overall yields of up to 20% over 5-9 linear steps.
- Schrittwieser, Joerg H.,Resch, Verena,Wallner, Silvia,Lienhart, Wolf-Dieter,Sattler, Johann H.,Resch, Jasmin,MacHeroux, Peter,Kroutil, Wolfgang
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experimental part
p. 6703 - 6714
(2011/10/18)
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- Synthesis, in silico docking experiments of new 2-pyrrolidinone derivatives and study of their anti-inflammatory activity
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A new class of 2-pyrrolidinone derivatives was designed, synthesized, and tested for their antioxidant and anti-inflammatory activities. The compounds were evaluated for their inhibitory activity against LOX. The most potent among them, 14d [IC50 0.08 (±0.005) mM], and 14e [IC50 0.0705 (±0.003) mM], were also tested in vivo. The compound 14d induced equipotent inhibition against rat paw edema, which is very close to the effect produced by the commonly used standard, namely indomethacin (47%). The LOX inhibitory activity of the compound 14e proceeds in parallel to the % inhibitory value of lipid peroxidation meaning that this LOX inhibitory activity is supported by the lipid peroxidation inhibition. The molecular features that govern their bioactivity were explored through in silico docking experiments. The results showed that acidic moieties must be placed in certain distance and orientation in the active site of LOX enzyme in order to productively exhibit inhibitory activity. In addition, the 2-pyrrolidinone template significantly contributes in the inhibitory properties of the new compounds.
- Moutevelis-Minakakis, Panagiota,Papavassilopoulou, Eleni,Michas, George,Georgikopoulou, Kalliopi,Ragoussi, Maria-Eleni,Neophytou, Niki,Zoumpoulakis, Panagiotis,Mavromoustakos, Thomas,Hadjipavlou-Litina, Dimitra
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experimental part
p. 2888 - 2902
(2011/06/17)
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- Dual aromatase-steroid sulfatase inhibitors
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By introducting the steroid sulfatase inhibitory pharmacophore into aromatase inhibitor 1 (YM511), two series of single agent dual aromatase-sulfatase inhibitors (DASIs) were generated. The best DASIs in'vitro (JEG-3 cells) are 5, (IC50(aromatase) = 0.82 nM; IC 50(sulfatase) = 39 nM), and 14, (IC50(aromatase) = 0.77 nM; IC50(sulfatase) = 590 nM). X-ray crystallography of 5, and docking studies of selected compounds into an aromatase homology model and the steroid sulfatase crystal structure are presented. Both 5 and 14 inhibit aromatase and sulfatase in PMSG pretreated adult female Wistar rats potently 3 h after a single oral 10 mg/kg dose. Almost complete dual inhibition is observed for 5 but the levels were reduced to 85% (aromatase) and 72% (sulfatase) after 24 h. DASI 5 did not inhibit aldosterone synthesis. The development of a potent and selective DASI should allow the therapeutic potential of dual aromatase-sulfatase inhibition in hormone-dependent breast cancer to be assessed.
- Woo, L. W. Lawrence,Bubert, Christian,Sutcliffe, Oliver-B.,Smith, Andrew,Chander, Surinder K.,Mahon, Mary F.,Purohit, Atul,Reed, Michael J.,Potter, Barry V. L.
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p. 3540 - 3560
(2008/02/09)
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- Microwave-assisted cleavage of phosphate, phosphonate and phosphoramide esters
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A mild and rapid protocol for cleavage of phosphate, phosphonate and phosphoramide esters. The scope and limitations of this microwave-assisted reaction is explored here.
- Kishore Kumar,Saenz, David,Lokesh,Natarajan, Amarnath
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p. 6281 - 6284
(2007/10/03)
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- MACROCYCLIC TERTIARY AMINE BETA-SECRETASE INHIBITORS FOR THE TREATMENT OF ALZHEIMER'S DISEASE
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The present invention is directed to macrocyclic tertiary amine compounds represented by general formula (I), which are inhibitors of the beta-secretase enzyme and that are useful in the treatment of diseases in which the beta-secretase enzyme is involved, such as Alzheimer's disease. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the treatment of such diseases in which the beta-secretase enzyme is involved.
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Page/Page column 52
(2010/11/08)
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- Method and compositions for identifying anti-HIV therapeutic compounds
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Methods are provided for identifying anti-HIV therapeutic compounds substituted with carboxyl ester or phosphonate ester groups. Libraries of such compounds are screened optionally using the novel enzyme GS-7340 Ester Hydrolase. Compositions and methods relating to GS-7340 Ester Hydrolase also are provided.
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- Substituted γ-phenyl-Δ-lactams and uses related thereto
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γ-Phenyl-substituted Δ-lactams are disclosed. They may be formulated into pharmaceutical compositions, and/or used in the treatment or prevention of inflammation or other conditions or disease states.
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- Compound
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There is provided a compound of Formula I 1 wherein each T is independently selected from H, hydrocarbyl, —F—R, and a bond with one of D, E, P or Q, or together with one of P and Q forms a ring; Z is a suitable atom the valency of which is m; D, E and F are each independently of each other an optional linker group, wherein when Z is nitrogen E is other than CH2 and C═O; P, Q and R are independently of each other a ring system; and at least Q comprises a sulphamate group.
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Page/Page column 43
(2008/06/13)
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- Substituted gamma-phenyl-delta-lactams and uses related thereto
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gamma-Phenyl-substituted Delta-lactams are disclosed. They may be formulated into pharmaceutical compositions, and/or used in the treatment or prevention of inflammation or other conditions or disease states.
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- Substituted γ-phenyl-Δ-lactones and analogs thereof and uses related thereto
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γ-Phenyl-substituted Δ-lactones and analogs thereof, including lactams, are disclosed. They may be formulated into pharmaceutical compositions, and/or used in the treatment or prevention of inflammation or other conditions or disease states.
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- Synthesis, fungicidal activity, and QSAR of a series of 2- dichlorophenyl-3-triazolylpropyl ethers
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A series of new alkyl and arylalkyl ethers of 2-(2,4-dichlorophenyl)-3- (1H-1,2,4-triazol-1-yl)propanol, related to the fungicide tetraconazole, were synthesized and tested in vitro or in vivo against seven common pathogens in comparison with tetraconazol
- Arnoldi, Anna,Carzaniga, Raffaella,Morini, Gabriella,Merlini, Lucio,Farina, Gandolfina
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p. 2547 - 2555
(2007/10/03)
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- Thiepane compounds
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Tri- and tetra substituted thiepane compositions having use as immunogens, therapeutics, diagnostics and for other industrial purposes are disclosed. The compositions inhibit proteolytic activity of viral enzymes and are useful for the inhibition of such enzymes as well as in assays for the detection of such enzymes. Embodiments in which antigenic polypeptides are bonded to the compositions are useful in raising antibodies against the thiepane haptens or the polypeptide. Labeled thiepanes of this invention are useful as diagnostic reagents.
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- Synthesis and biological evaluation of two analogues of (S)-α-methyl- 3-carboxyphenylalanine
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Two analogues 2, 3 of (S)-α-methyl-3-carboxylphenylalanine 1 were synthesized to test their activity for metabotropic glutamate receptors (mGluRs). Both compounds 2 and 3 were inactive as antagonist for mGluRs, but 2 showed weak agonistic activity for GluR6 in contrast to that reported by Kemp and co-workers.
- Ma, Dawei,Ma, Zhaochun,Kozikowski, Alan P.,Pshenichkin, Sergey,Wroblewski, Jarda T.
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p. 2447 - 2450
(2007/10/03)
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- Thiepane compounds
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Tri- and tetra substituted thiepane and compositions having use as immunogens, therapeutics, diagnostics and for other industrial purposes are disclosed. The compositions inhibit proteolytic activity of viral enzymes and are useful for the inhibition of such enzymes as well as in assays for the detection of such enzymes. Embodiments in which antigenic polypeptides are bonded to the compositions are useful in raising antibodies against the thiepane haptens or the polypeptide. Labeled thiepanes of this invention are useful as diagnostic reagents.
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- Thiepane compounds
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Tri- and tetra substituted thiepane compositions having use as immunogens, therapeutics, diagnostics and for other industrial purposes are disclosed. The compositions inhibit proteolytic activity of viral enzymes and are useful for the inhibition of such enzymes as well as in assays for the detection of such enzymes. Embodiments in which antigenic polypeptides are bonded to the compositions are useful in raising antibodies against the thiepane haptens or the polypeptide. Labeled thiepanes of this invention are useful as diagnostic reagents.
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- Antithrombotic effects of the novel inhibitor of thrombin-induced platelet aggregation and thrombus formation, 3-[2-([1,1':2',1'']-terphenyl-4'-yl)ethyl]phenoxyacetic acid
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The new compound 3-[2-([1,1':2',1'']-terphenyl-4'-yl)ethyl]phenoxyacetic acid (F1070) was synthesized and its effects on platelet aggregation induced by thrombin, thrombin receptor agonist peptide (TRAP), ADP and collagen were evaluated in humans, guinea
- Miyamae, Tetsuhisa,Hashizume, Hirokazu,Ogawa, Tadashi,Okayama, Toru,Nukui, Eriko,Oshima, Kouichi,Morikawa, Tadanori,Hagiwara, Masaki
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- Synthesis and anti-HIV activity of dibenzylbutyrolactone lignans
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Five optically active dibenzylbutyrolactone lignans were synthesized through a lipase-catalyzed transesterification route and evaluated for their inhibitory activity against HIV-1 replication in acutely infected H9 cells. Compounds 1 and 2 demonstrated anti-HIV replication activity with an EC50 values of 2.2 and 0.16 μg/ml and a therapeutic index values of 9.1 and 5, respectively. Structure-antiviral activity relationships are discussed.
- Yang, Li-Ming,Lin, Shwu-Jiuan,Yang, Tsang-Hsiung,Lee, Kuo-Hsiung
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p. 941 - 944
(2007/10/03)
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- (-)-Arctigenin as a lead structure for inhibitors of human immunodeficiency virus type-1 integrase
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The natural dibenzylbutyrolactone type lignanelide (-)-arctigenin (2), an inhibitor of human irnmunodeficiency virus type-1 (HIV-1) replication in infected human cell systems, was found to suppress the integration of proviral DNA into the cellular DNA genome. In the present study 2 was tested with purified HIV-1 integrase and found to be inactive in the cleavage (3'- processing) and integration (strand transfer) assays. However, the semisynthetic 3-O-demethylated congener 9 characterized by a catechol substructure exhibited remarkable activities in both assays. Structure- activity relationship studies with 30 natural (1-6), semisynthetic (7-21), and synthetic (37-43, 45, 46) lignans revealed that (1) the lactone moiety is crucial since compounds with a butane-1,4-diol or tetrahydrofuran substructure and also lignanamide analogues lacked activity and (2) the number and arrangement of phenolic hydroxyl groups is important for the activity of lignanolides. The congener with two catechol substructures (7) was found to be the most active compound in this study. 7 was also a potent inhibitor of the 'disintegration' reaction which models the reversal of the strand transfer reaction. The inhibitory activity of 7 with the core enzyme fragment consisting of amino acids 50-212 suggests that the binding site of 7 resides in the catalytic domain.
- Eich, Eckart,Pertz, Heinz,Kaloga, Macki,Schulz, Jutta,Fesen, Mark R.,Mazumder, Abhijit,Pommier, Yves
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- MULTICYCLIC TERTIARY AMINE POLYAROMATIC SQUALENE SYNTHASE INHIBITORS
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This invention relates to polycyclic compounds containing two mono- and/or bicyclic rings and a basic tertiary amino group capable of forming an ammonium ion at biological pH and which reduces levels of serum cholesterol in the body without significantly reducing mevalonic metabolite synthesis. This invention relates also to pharmacological compositions and method of treatment for lowering serum cholesterol levels using the compounds of this invention. The compounds of this invention are described by the formula where Ar I is phenylene or naphthylene, Ar II is phenyl or naphthyl and A is 1-azabicyclo[2.2.2]octan-3-yl
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- Enantioselective synthesis of natural dibenzylbutyrolactone lignans (-)-enterolactone, (-)-hinokinin, (-)-pluviatolide, (-)-enterodiol, and furofuran lignan (-)-eudesmin via tandem conjugate addition to γ-alkoxybutenolides1,2
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A general and efficient method is described for the asymmetric synthesis of a variety of liguans. 5-(Menthyloxy)-2(5H)-furanones 5 proved to be excellent chiral synthons in this respect and could be transformed with complete stereoselectivity into a number of lignans. The addition of lithiated dithianes 7 to enantiomerically pure butenolides 5 was followed by quenching of the resulting lactone enolate anions with a benzylbromide (9) or with an aldehyde (6). This tandem addition quenching procedure gave the diastereomerically pure adducts 11, 26, or 27 in 50-67% yield, with a carbon skeleton as found in most natural lignans. As examples of the wide applicability of this method, the syntheses of the enantiomerically pure natural lignans (-)-hinokinin (23b), (-)-enterolactone (24a), (-)-pluviatolide (24c), and (-)-enterodiol (25) in overall yields of 29-37% from 5a and (-)eudesmin (30) in 16% overall yield from 5b are described.
- Van Oeveren,Jansen,Feringa
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p. 5999 - 6007
(2007/10/02)
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- Synthesis and Protein-Tyrosine Kinase Inhibitory Activity of Polyhydroxylated Stilbene Analogues of Piceatannol
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A series of hydroxylated trans-stilbene related to the antileukemic natural product trans-3,3',4,5'-tetrahydroxy stilbene (piceatannol) (1) has been prepared and tested for inhibition of the lymphoid cell lineage-specific protein-tyrosine kinase p56lck, which plays an important role in lymphocyte proliferation and immune function.A number of the analogues displayed enhanced enzyme inhibitory activity relative to the natural product.Reduction of the double bond bridging the two aromatic rings and benzylation of the phenolic hydroxyl groups was found to decrease activity significantly.The most potent compounds in the series proved to be trans-3,3',5,5'-tetrahydroxystilbene, trans-3,3',5-trihydroxystilbene, and trans-3,4,4'-trihydroxystilbene.
- Thakkar, Kshitij,Geahlen, Robert L.,Cushman, Mark
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p. 2950 - 2955
(2007/10/02)
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- Ruthenium Dioxide in Fluoro Acid Medium: II. Application to the Formation of Steganes Skeleton by Oxidative Phenolic Coupling
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Ruthenium (IV) dioxide dihydrate in fluoro acidic medium was found to be a very efficient agent for the oxidative coupling of the phenolic lignans (+/-)-presteganes A and B.Different attempts to oxidise the diphenolic dibenzylbutanolide (+/-)-HMPF were also carried out, but were unsuccessful.Likely explanation for these failures are given.
- Robin, Jean-Pierre,Landais, Yannick
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p. 819 - 830
(2007/10/02)
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- Synthesis and antirhinovirus activity of 6-(dimethylamino)-2-(trifluoromethyl)-9-(substituted benzyl)-9H-purines
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A series of 6-(dimethylamino)-2-(trifluoromethyl)-9-(substituted benzyl)purines was synthesized and tested for antirhinovirus activity. Most of the compounds were synthesized by alkylation of 6-chloro-2-(trifluoromethyl)-9H-purine with the appropriate benzyl halide followed by displacement of the chloro group with dimethylamine. Alternatively, 6-(dimethylamino)-2-(trifluoromethyl)purine was alkylated with the appropriate benzyl halide. Although several different aryl substituents provided compounds with IC50's = 0.03 μM against rhinovirus serotype 1B, no congener was significantly more active than the parent 2. Twenty-three compounds were tested against 18 other serotypes, but none exhibited a uniform profile of activity.
- Kelley,Linn,Selway
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p. 1757 - 1763
(2007/10/02)
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