- NITROGEN-CONTAINING COMPOUND, METHOD FOR MANUFACTURING THE SAME, AND OPTICAL FUNCTIONAL MATERIAL INCLUDING THE SAME
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PROBLEM TO BE SOLVED: To provide a novel nitrogen-containing compound having luminescence property. SOLUTION: A nitrogen-containing compound represented by the following formula (I) in which RA, RB, R1, R2, R3, R4, and X are either one of the following (1) and (2). SELECTED DRAWING: None COPYRIGHT: (C)2021,JPOandINPIT
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Paragraph 0152-0153
(2021/08/21)
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- Novel isoquinoline-oxazoline chiral ligand and preparation and application thereof (by machine translation)
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The invention relates to a novel isoquinoline-oxazoline chiral ligand as well as preparation and application thereof. Substituted radicals R in the general formula1 And R2 The isoquinoline-oxazoline chiral ligand disclosed by the invention can be used as a ligand and a metal to form a complex or a composition for asymmetric catalysis, and particularly the asymmetric Michael addition of the isoquinoline-oxazoline ligand and the metal palladium can effectively catalyze the asymmetric Michael addition of boric acid and nitroolefin, and has excellent stereoselectivity. (by machine translation)
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Paragraph 0021-0022; 0024
(2020/06/20)
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- Chemoenzymatic Approach to (S)-1,2,3,4-Tetrahydroisoquinoline Carboxylic Acids Employing D-Amino Acid Oxidase
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Optically pure 1,2,3,4-tetrahydroisoquinoline carboxylic acids constitute an important class of building blocks for the synthesis of natural products and synthetic pharmaceuticals. However, redox deracemization of racemic 1,2,3,4-tetrahydroisoquinoline carboxylic acids as an attractive method is still challenging for the lack of suitable oxidoreductases. Herein, a D-amino acid oxidase from Fusarium solani M-0718 (FsDAAO) with broad substrate scope and excellent enantioselectivity was exploited through genome mining, and applied for the kinetic resolution of a number of racemic 1- and 3-carboxyl substituted tetrahydroisoquinolines to yield the corresponding (S)-enantiomers with excellent enantiomeric excess (ee) values (up to >99%). By using FsDAAO in combination with ammonia-borane in one pot, deracemization of these racemic carboxyl-substituted tetrahydroisoquinolines was achieved with conversions up to >98% and >99% ee. Preparative-scale deracemization of racemic 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid and 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid was also demonstrated with good isolated yields (82% and 73%, respectively) and ee>99%. Our study provides an effective method for the synthesis of enantiomeric pure 1,2,3,4-tetrahydroisoquinoline carboxylic acids. This method is expected to provide access to chiral carboxyl-substituted 1,2,3,4-tetrahydroquinolines and 1,2,3,4-tetrahydro-?-carbolines. (Figure presented.).
- Ju, Shuyun,Qian, Mingxin,Xu, Gang,Yang, Lirong,Wu, Jianping
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supporting information
p. 3191 - 3199
(2019/05/15)
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- Neuroligin-2-derived peptide-covered polyamidoamine-based (PAMAM) dendrimers enhance pancreatic β-cells' proliferation and functions
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Pancreatic β-cell membranes and presynaptic areas of neurons contain analogous protein complexes that control the secretion of bioactive molecules. These complexes include the neuroligins (NLs) and their binding partners, the neurexins (NXs). It has been recently reported that both insulin secretion and the proliferation rates of β-cells increase when cells are co-cultured with full-length NL-2 clusters. The pharmacological use of full-length protein is always problematic due to its unfavorable pharmacokinetic properties. Thus, NL-2-derived short peptide was conjugated to the surface of polyamidoamine-based (PAMAM) dendrimers. This nanoscale composite improved β-cell functions in terms of the rate of proliferation, glucose-stimulated insulin secretion (GSIS), and functional maturation. This functionalized dendrimer also protected β-cells under cellular stress conditions. In addition, various novel peptidomimetic scaffolds of NL-2-derived peptide were designed, synthesized, and conjugated to the surface of PAMAM in order to increase the biostability of the conjugates. However, after being covered by peptidomimetics, PAMAM dendrimers were inactive. Thus, the original peptide-based PAMAM dendrimer is a leading compound for continued research that might provide a unique starting point for designing an innovative class of antidiabetic therapeutics that possess a unique mode of action.
- Munder, Anna,Moskovitz, Yoni,Meir, Aviv,Kahremany, Shirin,Levy, Laura,Kolitz-Domb, Michal,Cohen, Guy,Shtriker, Efrat,Viskind, Olga,Lellouche, Jean-Paul,Senderowitz, Hanoch,Chessler, Steven D.,Korshin, Edward E.,Ruthstein, Sharon,Gruzman, Arie
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supporting information
p. 280 - 293
(2019/03/02)
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- Multifunctional isoquinoline-oxazoline ligands of chemical and biological importance
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Multifunctional isoquinoline-oxazolines (MIQOXs) were conceived and synthesized from commercially available chiral amino acids. The multifunctional role of MIQOXs was demonstrated by Pd-catalyzed highly enantioselective addition of arylboronic acids to nitrostyrenes, and by the discovery of novel antifungal candidates.
- Li, Wei,Wang, Guotong,Lai, Jixing,Li, Shengkun
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supporting information
p. 5902 - 5905
(2019/05/27)
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- Design and synthesis of nanoscaled IQCA-TAVV as a delivery system capable of antiplatelet activation, targeting arterial thrombus and releasing IQCA
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Background: Arterial thrombosis has been associated with a series of pathological conditions, and the discovery of arterial thrombosis inhibitor is of clinical importance. Methods: By analyzing the pharmacophores of anti-platelet agents, thrombus targeting peptide and anti-thrombotic nano-systems 3S-1,2,3,4-tetrahydroisoquino- line-3-carbonyl-Thr-Ala- Arg-Gly-Asp(Val)-Val (IQCA-TAVV) was designed and prepared as a nano-scaled arterial thrombosis inhibitor. Results: In vitro the nanoparticles of IQCA-TAVV were able to adhere onto the surface of activated platelets, attenuate activated platelets to extend pseudopodia and inhibit activated platelets to form aggregators. In vivo IQCA-TAVV targeted arterial thrombus, dose depend- ently inhibited arterial thrombosis with a 1 nmol/kg of minimal effective dose, and the activity was ~1670 folds of that of aspirin. Conclusion: IQCA-TAVV represented the design, preparation and application of nanomedicine capable of adhering on the surface of activated platelets, attenuating platelet activation, targeting arterial thrombus and inhibiting arterial thrombosis.
- Wu, Jianhui,Zhu, Haimei,Yang, Guodong,He, Jianhong,Wang, Yuji,Zhao, Shurui,Zhang, Xiaoyi,Gui, Lin,Zhao, Ming,Peng, Shiqi
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p. 1139 - 1158
(2018/03/09)
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- Stereoselective synthesis of 1,3-disubstituted dihydroisoquinolines vial-phenylalanine-derived dihydroisoquinoline N-oxides
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The preparation of chiral pool-derived nitrone 3 and its use in the protecting-group free, stereoselective synthesis of a range of 1,3-disubstituted tetrahydroisoquinolines is described. Grignard reagent additions to nitrone 3 yielded trans-1,3-disubstituted N-hydroxytetrahydroisoquinolines 6 with good levels of selectivity, while 1,3-dipolar cycloadditions to this nitrone provided access to 3-(2-hydroxyalkyl)isoquinolines 12 as single diastereomers.
- Flores-Ferrándiz, Jesús,Carter, Nicholas,González-Soria, Maria José,Wasinska, Malgorzata,Gill, Daniel,Maciá, Beatriz,Caprio, Vittorio
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supporting information
p. 6961 - 6968
(2018/10/17)
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- Design and Discovery of Novel Chiral Antifungal Amides with 2-(2-Oxazolinyl)aniline as a Promising Pharmacophore
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Inspired by established succinate dehydrogenase inhibitors (SDHIs), our continuing efforts toward the discovery of chiral antifungal amides turned to the optimization of their polar regions with 2-(2-oxazolinyl)aniline as a known pharmacophore. Scaffold hopping and bioactivity-guided convergent synthesis enabled the identification of promising antifungal categories. Fine tuning of the substituents and chirality furnished seven amides (1s, 1t, 2d, 2h, 2j, 3k, and 2l) as antifungal candidates, with EC50 values lower than 5 mg/L. The first investigation of chiral amides of acyclic acids as SDHIs was conducted, and compound 2d was selected as a promising candidate against Botrytis cinerea, with a preventative efficacy of up to 93.9% at 50 mg/L, which is better than that of boscalid. The different binding models between compounds with different configurations were simulated for compound 2d and its diastereoisomers. The benefits of synthetic accessibility and cost-effectiveness highlight the practical potential for compound 2d as a good alternative to known SDHI fungicides.
- Zhang, Lu,Li, Wei,Xiao, Taifeng,Song, Zehua,Csuk, René,Li, Shengkun
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p. 8957 - 8965
(2018/09/10)
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- IQCA-TASS: a nano-scaled P-selectin inhibitor capable of targeting thrombus and releasing IQCA/TARGD(S)S in vivo
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Thrombosis is a serious threat to human health worldwide. Tetrahydroisoquinoline-3-carboxylic acid (IQCA) is an antithrombotic agent, while Thr-Ala-Arg-Gly-Asp(Ser)-Ser (TASS) can target thrombus. Herein, tetrahydro-isoquinoline-3-carbonyl-Thr-Ala-Arg-Gly-Asp(Ser)-Ser (IQCA-TASS) was designed with the aim towards the discovery of a nano-delivery system for targeting thrombus. In vitro, IQCA-TASS acted on P-selectin and down-regulated P-selectin expression. The IC50 values of IQCA-TASS against the platelet aggregation induced by four aggregators were less than 0.45 nM. In vivo, IQCA-TASS targeted thrombus, released IQCA and TASS inside the thrombus, showed dose-dependent anti-thrombotic action, of which the minimal effective dose was 1 nmol kg-1, and showed anti-inflammatory action. Even with the dose up to 1 μmol kg-1, a dose of 1000 times the minimal effective dose, IQCA-TASS still induced no toxic reaction. In rat plasma, IQCA-TASS formed nanoparticles with diameters of less than 41 nm. The interactions of the nanoparticles with both resting and activated platelets were imaged. IQCA-TASS should be a safe nano-medicine capable of targeting thrombus and releasing anti-thrombotic/anti-inflammatory pharmacophores in disease sites.
- Wu, Jianhui,Zhu, Haimei,Zhao, Ming,Wang, Yuji,Yang, Guodong,Wang, Yaonan,Zhao, Shurui,Gui, Lin,Zhang, Xiaoyi,Peng, Shiqi
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p. 917 - 927
(2017/02/10)
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- Environment-responsive multivalent isoquinoline-3-carboxylic acid conjugate, and preparation method and application thereof
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The invention discloses an environment-responsive multivalent isoquinoline-3-carboxylic acid conjugate, and a preparation method and application thereof, belonging to the field of isoquinoline-3-carboxylic acid conjugates. According to the invention, 3,3'-dithiopropane diacid is used as a linking arm for coupling four isoquinoline-3-carboxylic acids with tris(2-aminoethyl)amine so as to form an isoquinoline derivative; multivalent synergism of a plurality of pharmacophores on a drug carrier is exerted on the lesion site of a tumor, so the antitumor activity of the antitumor drug is substantially improved; and through the environmental redox response of a disulfide bond to tumors, intelligent targeted release of the antitumor drug to a tumor part is realized, and toxicity of the antitumor drug to normal tissue is effectively reduced.
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Paragraph 0023; 0027; 0028
(2017/09/01)
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- Anticancer activity of ruthenium(II) arene complexes bearing 1,2,3,4-tetrahydroisoquinoline amino alcohol ligands
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Ruthenium complexes offer potential reduced toxicity compared to current platinum anticancer drugs. 1,2,3,4-tetrahydrisoquinoline amino alcohol ligands were synthesised, characterised and coordinated to an organometallic Ru(II) centre. These complexes were evaluated for activity against the cancer cell lines MCF-7, A549 and MDA-MB-231 as well as for toxicity in the normal cell line MDBK. They were observed to be moderately active against only the MCF-7 cells with the best IC50 value of 34 μM for the cis-dia-stereomeric complex C4. They also displayed excellent selectivity by being relatively inactive against the normal MDBK cell line with SI values ranging from 2.3 to 7.4.
- Chelopo, Madichaba P.,Pawar, Sachin A.,Sokhela, Mxolisi K.,Govender, Thavendran,Kruger, Hendrik G.,Maguire, Glenn E. M.
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supporting information
p. 407 - 414
(2013/10/01)
-
- Design, synthesis and primary activity of thiomorpholine derivatives as DPP-IV inhibitors
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Thirteen thiomorpholine-bearing compounds were designed and synthesized as dipeptidyl peptidase IV (DPP-IV) inhibitors, with natural and non-natural l-amino acids as the starting materials. Their structures were characterized by 1H NMR, 13C NMR and HR-MS. The target compounds were screened for the DPP-IV inhibition, and the preliminary SAR result was obtained. Particularly, compounds 4c, 4d and 4f with good DPP-IV inhibition in vitro were further evaluated through a mouse oral glucose tolerance test (OGTT). The preliminary result showed the potential value for further studies on those thiomorpholine-bearing compounds as DPP-IV inhibitors.
- Han, Bei,Liu, Jing Long,Huan, Yi,Li, Peng,Wu, Qi,Lin, Zi Yun,Shen, Zhu Fang,Yin, Da Li,Huang, Hai Hong
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scheme or table
p. 297 - 300
(2012/05/20)
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- 2-Substituted (S)-2-(3,3-dimethyl-1-oxo-10,10a-dihydroimidazo[1,5-b] isoquinolin-2(1H,3H,5H)-yl)acetic acids: Conformational prediction, synthesis, anti-thrombotic and vasodilative evaluation
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(S)-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid (TIC) can inhibit thrombosis by inhibiting platelet aggregation. The investigation of amino acids modified TIC reveals that a stretching conformation is critical for high anti-thrombotic activity. The conformational modeling shows that introducing a ring into amino acid modified TIC results in a desirable stretching conformation. According to this hypothesis, we synthesized seventeen novel 2-substituted (S)-2-(3,3-dimethyl-1-oxo-10,10a-dihydroimidazo[1,5-b]isoquinolin- 2(1H,3H,5H)-yl)acetic acids (5a-q). In the in vitro anti-platelet aggregation assay, for ADP-induced platelet aggregation the IC50 values of 5a-q are 1.8-3.4-folds lower than that of TIC. In the in vivo anti-thrombotic assay, the effective dose of 5a-q was 167-folds lower than that of TIC. The vessel strip assay showed that 5a-q had mild vasorelaxation activity.
- Wang, Hong,Peng, Le,Zhao, Ming,Liu, Jiawang,Zhang, Xiaoyi,Wang, Yuji,Wu, Jianhui,Li, Li,Peng, Shiqi
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experimental part
p. 871 - 882
(2011/03/19)
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- A class of novel N-isoquinoline-3-carbonyl-l-amino acid benzylesters: Synthesis, anti-tumor evaluation and 3D QSAR analysis
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Isoquinoline-3-carboxylic acid (2) was modified with amino acid benzylesters and 18 novel N-isoquinoline-3-carbonylamino acid benzylesters (3a-r) were provided. The IC50 values of 3a-r against the proliferation of HL-60 and Hela cells were less than 1 × 10-8 M and 6 × 10-7 M, respectively. On S180 mice model 100 μmol/kg of 3a-r effectively inhibited the growth of the tumors. Using MFA based Cerius2 QSAR module, two equations (r, 0.989 and 0.987) were established to correlate the structure with the in vitro and in vivo activities. The benefit of this modification was supported with both the in vitro membrane permeation test and the in vivo anti-tumor assay. The in vitro membrane permeability of N-isoquinoline-3-carbonyl-l-threonine benzylester (3n) and N-isoquinoline-3-carbonyl-l-leucine benzylester (3q) was 2.5 fold higher than that of 2, and the in vivo anti-tumor activity of 3n, q was 4.4-fold higher than that of 2.
- Zheng, Meiqing,Yang, Yifan,Zhao, Ming,Zhang, Xiaoyi,Wu, Jianhui,Chen, Gong,Peng, Li,Wang, Yuji,Peng, Shiqi
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experimental part
p. 1672 - 1681
(2011/05/06)
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- A pictet-spengler cyclisation methodology for the construction of nonproteinogenic tetrahydroisoquinoline quaternary amino acids
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A simple highly stereoselective route to tetrahydroisoquinoline quaternary amino acids from phenylalanine is described. Georg Thieme Verlag Stuttgart · New York.
- Page, Philip C. Bulman,Parkes, Genna A.,Buckley, Benjamin R.,Wailes, J. Steven
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supporting information; experimental part
p. 3005 - 3007
(2012/01/05)
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- Design, synthesis and biological evaluation of new thalidomide analogues as TNF-α and IL-6 production inhibitors
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Several thalidomide analogues were synthesized and compared to thalidomide and its more active analogue, lenalidomide, for their ability to inhibit the production of the pro-inflammatory cytokine tumour necrosis factor (TNF)-α and interleukin (IL)-6 by LPS-activated peripheral blood mononuclear cells (PBMCs). Among these compounds, two analogues containing sulfonyl group displayed interesting downregulation of TNF-α and IL-6 production.
- Chaulet, Charlotte,Croix, Cécile,Alagille, David,Normand, Sylvain,Delwail, Adriana,Favot, Laure,Lecron, Jean-Claude,Viaud-Massuard, Marie-Claude
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scheme or table
p. 1019 - 1022
(2011/03/21)
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- New P-stereogenic triaminophosphines and their derivatives: Synthesis, structure, conformational study, and application as chiral ligands
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The synthesis, structural, and conformational studies of new P-chiral triaminophosphines, which feature an indolidine and a 1,2,3,4- tetrahydroquinolidine pattern, respectively, are reported. These compounds can feature very different 3D-structures, although they both could be seen a priori as close derivatives of the previously reported 3-phenyl-1,3-diaza-2- phosphabicyclo[3.3.0]octane. The consequences for the use of such compounds and their derivatives in asymmetric metal-catalysis are discussed on the basis of preliminary results in asymmetric cobalt-catalyzed [6+2] cycloaddition.
- Toselli, Nicolas,Fortrie, Remy,Martin, David,Buono, Gerard
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experimental part
p. 1238 - 1245
(2010/11/02)
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- A class of novel N-(3S-1,2,3,4-tetrahydroisoquinoline-3-carbonyl)-l-amino acid derivatives: their synthesis, anti-thrombotic activity evaluation, and 3D QSAR analysis
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To find new anti-thrombotic agents, a natural amino acid was introduced into the 3-position of anti-platelet aggregation active 3S-tetrahydroisoquinoline-3-carboxylic acid (THIQA), and 20 novel dipeptide derivatives, 3S-tetrahydroisoquinoline-3-carboxyamino acids (6a-t), targeting the intestinal peptide transport system were provided. In vitro anti-platelet aggregation assay of 6a-t indicated that their potencies of inhibiting adenosine diphosphate (ADP), arachidonic acid (AA), platelet-activating factor (PAF), and thrombin (TH) induced platelet aggregations were higher than that of THIQA, and the in vivo anti-thrombotic assay of 6a-t indicated that their potencies of inhibiting thrombogenesis in rats were also higher than that of THIQA. According to MFA based Cerius2 QSAR module, using training/test set of 6a,b,d,g-p/6c,e,f,q and training/test set of 6a-p/6q-t, two equations (r, 0.984 and 0.996) correlating the structures with in vitro or in vivo activity of 6a-t were established.
- Cheng, Shenling,Zhang, Xiaoyi,Wang, Wei,Zhao, Ming,Zheng, Meiqing,Chang, Heng Wei,Wu, Jianghui,Peng, Shiqi
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experimental part
p. 4904 - 4919
(2010/01/06)
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- (3S)-N-(l-Aminoacyl)-1,2,3,4-tetrahydroisoquinolines, a class of novel antithrombotic agents: Synthesis, bioassay, 3D QSAR, and ADME analysis
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To increase antithrombotic activity, 3S-tetrahydroisoquinoline-3-carboxylic acid (1) was modified with natural amino acids to form 19 novel dipeptide analogs, 3S-tetrahydroisoquinoline-3-carboxyamino acids (5a-s), targeting the intestinal peptide transport system. In vitro assay of 5a-s indicated that their potencies for inhibiting adenosine diphosphate (ADP), arachidonic acid (AA), platelet-activating factor (PAF), and thrombin (TH)-induced platelet aggregations were higher than that of 1. Additionally, in vivo assay of 5a-s indicated that their potencies for inhibiting thrombogenesis in rats were also higher than that of 1. Among the candidates, 5h with Ser attachment showed the most impressive features for further development. According to molecular field analysis based Cerius2 QSAR module, two equations (r, 0.961 and 0.988) correlating the structures with both in vitro and in vivo activities of 5a-s were established. ADMET calculations predict higher intestinal absorption for compounds 5a-s. Further investigation with 5h as a lead compound is underway.
- Zheng, Meiqing,Zhang, Xiaoyi,Zhao, Ming,Chang, Heng Wei,Wang, Wei,Wang, Yuji,Peng, Shiqi
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experimental part
p. 9574 - 9587
(2009/04/06)
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- Dual-acting agents that possess reversing resistance and anticancer activities: Design, synthesis, MES-SA/Dx5 cell assay, and SAR of Benzyl 1,2,3,5,11,11a-hexahydro-3,3-dimethyl-1-oxo-6H-imidazo[3′,4′:1,2]pyridin[3,4-b]indol-2-substitutedacetates
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Based on the structural analysis of fumitremorgin C (FTC), imidazoline and β-carboline amino acid benzylester, 14 novel 2-substitutedtetracyclic derivatives of tetrahydrocarboline 4a-n were prepared. We demonstrated that the exposure of MES-SA/Dx5 cells to some of 4a-n resulted in significant reduction of resistance of the cells against doxorubicin. This reduced resistance was accompanied by lowering of IC50 value to doxorubicin from 1.55 ± 0.26 μmol/L to 0.33 ± 0.05 μmol/L for 2-(2-butyl)-derivative 4c, to 1.03 ± 0.22 μmol/L for 2-methyl-derivative 4d, to 0.46 ± 0.04 μmol/L for 2-benzyl-derivative 4f, to 0.98 ± 0.25 μmol/L for 2-indole-3-yl-methyl-derivative 4h, to 0.36 ± 0.03 μmol/L for 2-benzyloxycarbonylmethyl-derivative 4i, to 0.77 ± 0.08 μmol/L for 2-benzyloxycarbonylethyl-derivative 4j, and to 0.77 ± 0.08 μmol/L for 2-benzyloxycarbonylamino-n-butyl-derivative 4l. Proliferation assays of 4a-n indicated 4c,f,i,j were able to inhibit the proliferation of doxorubicin resistant MES-SA/Dx5 cells. The SAR analysis revealed that the benzylester form and the tetracyclic structure of 4a-n were critical for both sensitizing doxorubicin and the cellular anti-proliferative effect.
- Liu, Jiawang,Cui, Guohui,Zhao, Ming,Cui, Chunying,Ju, Jingfang,Peng, Shiqi
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p. 7773 - 7788
(2008/03/15)
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- Asymmetric synthesis of unusual α-amino acids
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The synthesis of enantiomerically pure non-proteinogenic bis and cyclic amino acids 3a,b and achiral amino acid 3c using chiral NiII complex 1 and α,α′-dibromo-o-xylene as a bifunctional agent of alkylation is presented.
- Belokon, Yuri N.,Kochetkov, Konstantin A.,Borkin, Dmitry A.
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p. 132 - 134
(2007/10/03)
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- Tripeptidylpeptidase inhibitors
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A compound of formula wherein the substituents are defined as in the specification and salts or hydrates thereof is disclosed as well as a method of treating disorders associated with the inactivation or excessive degradation of cholecystokinin.
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-
- Evaluation of animal liver acetone powders for the resolution of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
-
Butyl, ethyl and methyl esters of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid were hydrolyzed stereoselectively under very mild conditions to give the corresponding (S)-acid and the unreacted (R)-ester using readily available animal liver (chicken, mouse, rat and rabbit) acetone powders.
- Sanchez, Remedios,Luna, Hector,Perez, Herminia I.,Manjarrez, Norberto,Solis, Aida
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p. 1399 - 1401
(2007/10/03)
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- Asymmetric pictet-spengler reactions: Synthesis of 1,2,3,4-tetrahydroisoquinoline carboxylic acid (Tic) chimeras
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A preparatively simple diastereoselective synthesis of the amino acid chimera (1S,3S)-1,2,3,4-tetrahydroisoquinoline-1,3-dicarboxylic acid from hexafluoroacetone-protected phenylalanine and glyoxylic acid hydrate via Pictet-Spengler reaction is described. The potential of the reaction of hexafluoroacetone-protected phenylalanine with other aldehydes was scrutinized.
- Spengler,Schedel,Sieler,Quaedflieg,Broxterman,Duchateau,Burger
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p. 1513 - 1518
(2007/10/03)
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- 1,5-dimethyl-4-phenylimidazolidin-2-one-derived iminic glycinimides: Useful new reagents for practical asymmetric synthesis of α-amino acids
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New 1,5-dimethyl-4-phenylimidazolidin-2-one-derived acyclic chiral iminic glycine reagents have been prepared and diastereoselectively alkylated with activated alkyl halides and electrophilic olefins in the presence of lithium chloride under (a) strong bases (LHMDS, KOBu(t)) and low temperature (-78 °C,) conditions; (b) solid-liquid phase-transfer catalysis reaction (LiOH, TBAB, -20 °C) conditions, and (c) in the presence of organic bases (DBU, BEMP, TMG, -20 °C). In the case of dielectrophiles C- and N-alkylation takes place to afford heterocyclic derivatives. Hydrolysis of alkylated products has been carried out (a) in two-step procedures with LiOOH or LiOH followed by acidic hydrolysis or Dowex purification, (b) in one single-step under refluxing water to give the corresponding α-amino acid, (c) in the presence of DBU in methanol to provide N-protected α-amino acids methyl esters, or (d) by a protection-hydrolysis procedure to afford N-Boc-protected α-amino acids. The chiral imidazolidinone has generally been recovered in good yield. This methodology has been shown to be useful for the synthesis of acyclic and heterocyclic (S)- and (R)-α-amino acids.
- Guillena,Najera
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p. 7310 - 7322
(2007/10/03)
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- Preparation and diastereoselective birch reduction-alkylation of chiral 3,4-dihydro-l (2h)-isoquinolinones. Enantiospecific syntheses and opioid receptor affinities of several hydro-2,3dimethyl-1H-7,12a-methanobenzo[6,7]cycloocta[l,2-c]pyridine-9-ols
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Synthetic procedures have been developed to provide 2,3-disubstituted-3,4-dihydro-1(2H)-isoquinolinones 6,10, and 15 from (1R,2S)-ephedrine, (1R,2R)-pseudoephedrine, and L-phenylalanine. Birch reduction of 6 and 10 gave enantiomerically related lactam enolates that were alkylated with methyl iodide, allyl bromide, benzyl bromide, p-benzyloxybenzyl bromide, and p-methoxybenzyl bromide to give 7a-7e, lia, and 11b with diastereoselectivities > 20:1. Birch reduction-methylation of 15 gave 19 with a diastereoselectivity of >35:1. Selective reduction of the disubstituted double bond in 19 with diimide and cleavage of the tert-butyldimethylsilyl ether gave 20b, from which iodoetherification under thermodynamic control gave the iodopyran 21a; iodoetherification of 20b under kinetic control gave the iodotetrahydrofuran 22. Enantiospecific syntheses of analogues of 24 (Schultz, A. G.; Kirincich, S. J.; Rahm, R. Tetrahedron Lett. 1995, 36, 4551-4554) have been developed. Tetracycle 24 is isomeric with the potent analgesic agent levorphanol, but the bridging of the hydroisoquinoline ring by the hydroxybenzyl unit in 24 is at C(7, isoquinoline numbering) and C(8a) rather than at C(1) and C(4a) as in levorphanol. The key step in the transformation of 7d and 7e to tetracyclic phenolic amines (-)-26 and (+)-28 is the Grewe-type cyclization of 7d to 25b and 7e to 25c. Ki values for the inhibition of binding to the μ-,δ-, and κ-opioid receptors by (-)-26, (+)-26, (+)-28, (-)-28, and (+)-32 are reported.
- Schultz, Arthur G.,Guzi, Timothy J.,Larsson, Erika,Rahm, Rainer,Thakkar, Kshitij,Bidlack, Jean M.
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p. 7795 - 7804
(2007/10/03)
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- Synthesis of the HIV-proteinase inhibitor Saquinavir: A challenge for process research
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The task of process research, namely developing efficient, economically and technically as well as ecologically feasible syntheses in time, is demonstrated on the HIV-proteinase inhibitor Saquinavir (1), a complex molecule comprising six stereo-centres. Based on the first 26-step research synthesis furnishing a 10% overall yield, process research established a new, short 11-step synthesis affording a 50% overall yield.
- Goehring, Wolfgang,Gokhale, Surendra,Hilpert, Hans,Roessler, Felix,Schlageter, Markus,Vogt, Peter
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p. 532 - 537
(2007/10/03)
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- Synthesis, molecular modeling, 2-D NMR, and biological evaluation of ILV mimics as potential modulators of protein kinase C
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To study the structural determinants required for protein kinase C (PKC) activation by indolactam V (ILV) for purposes of arriving at simpler versions of this PKC activator, four simplified analogues of ILV (4a-c and 14a) were synthesized. These analogues contain a benzene ring in place of the indole group of ILV and were designed for synthesis because molecular modeling studies revealed these simplified structures to possess readily accessible [ILV]-sofa-like conformations, thus mimicking the literature-reported bioactive conformation of ILV. During the course of designing these analogues, a more rigorous conformational search program (SysSearch) was developed to analyze the highly functionalized nine-membered lactam ring system present in ILV. The results of the molecular modeling studies using the SysSearch program on which the design of these analogues was based were confirmed by 2-D NMR and X-ray studies. The compounds of this series were constructed by use of the Mitsunobu reaction to generate the unique nine-membered lactam ring present in these structures. Two routes to compound 4a are presented, one of which utilizes the amino acid building blocks, L-valine and L-phenylalanine, to fix the stereochemistry of its two asymmetric centers. The biological studies reveal that these new analogues fail to modulate PKC activity, and thus they exclude the possibility that a benzene ring can serve as a surrogate of the indole ring of ILV. The present work therefore indicates that the nine-membered lactam ring moiety of ILV in an [ILV]sofa conformation is not a sufficient structural determinant for PKC activation.
- Kozikowski, Alan P.,Ma, Dawei,Pang, Yuan-Ping,Shum, Patrick,Likic, Vladimir,Mishra, Prasanna K.,Macura, Slobodan,Basu, Alakananda,Lazo, John S.,Ball, Richard G.
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p. 3957 - 3965
(2007/10/02)
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- Efficient synthesis of racemic and enantiomerically pure 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid and esters
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Racemic and optically pure 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids and esters were prepared, via base-catalyzed cyclization of 1,2-bis(halomethyl)benzenes 1a or b with diethyl 2-(acetylamino)malonate (2), subsequent decarboxylation and amide cleavage. The enantiomer resolution was achieved either by esterification with (-)-menthol followed by column chromatographic separation of the diastereomeric mixture or by diasteromeric salt separation of the benzylic ester with mandelic acid and base-catalyzed saponification of both esters.
- Kammermeier,Lerch,Sommer
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p. 1157 - 1160
(2007/10/02)
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- Asymmetric Transformation of (RS)-1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic Acid via Salt Formation with (1S)-10-Camphorsulfonic Acid
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Asymmetric transformation of (RS)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid by use of (1S)-10-camphorsulfonic acid as a resolving agent gave a salt of (S)-TIC with (S)-CS with 90percent optical purity in hexanoic acid.The TIC obtained from the salt was purified to give optically pure (S)-TIC in 80percent yield based on the starting (RS)-TIC.
- Shiraiwa, Tadashi,Furukawa, Tsuyoshi,Tsuchida, Tamotsu,Sakata, Shinji,Sunami, Michio,Kurokawa, Hidemoto
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p. 3729 - 3731
(2007/10/02)
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- Conformational restriction of the phenylalanine residue in a cyclic opioid peptide analogue: Effects on receptor selectivity and stereospecificity
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In an effort to determine the effect of side chain conformational restriction on opioid receptor selectivity, the cyclic phenylalanine analogues 2-aminoindan-2-carboxylic acid (Aic), 2-aminotetralin-2-carboxylic acid (Atc), and tetrahydroisoquinoline-3-carboxylic acid (Tic) were substituted for Phe in the potent cyclic opioid peptide analogue H-Tyr-D-Orn-Phe-Glu-NH2, which lacks significant opioid receptor selectivity. Compounds were tested in μ- and δ-opioid receptor representative binding assays and bioassays in vitro. The analogue H-Tyr-D-Orn-Aic-Glu-NH2 was found to be a potent agonist with high preference of μ receptors over δ receptors. Opening of the five-membered ring of Aic in the latter peptide, as achieved through substitution of C(α)-methylphenylalanine or o-methylphenylalanine, resulted in only slightly selective compounds, indicating that the high μ selectivity of the Aic analogue is exclusively the consequence of the imposed side chain conformational restriction. Both diastereoisomers of H-Tyr-D-Orn-(D,L)-Atc-Glu-NH2 were highly μ-selective and, in contrast to the weak affinity observed with the D-Phe3 analogue as compared to the L-Phe3 analogue, both had similar potency. Thus, stereospecificity was lost as a consequence of side chain conformational restriction. Further structure-activity data obtained with analogues containing L- or D-homophenylalanine (Hfe) or 3-(1'-naphthyl)alanine (Nap) in place of Phe3 and consideration of geometric interrelationships between Nap and the L and D isomers of Atc, Hfe, and Phe led to the proposal that the D-Phe3 and the D-Atc3 analogue may have different modes of binding to the receptor. The very low potency observed with H-Tyr-D-Orn-N(α)MePhe-Glu-NH2 (N(α)MePhe = N(α)-methylphenylalanine) and H-Tyr-D-Orn-Tic-Glu-NH2 indicated that N(α)-alkylation at the 3-position is detrimental to activity.
- Schiller,Weltrowska,Nguyen,Lemieux,Chung,Marsden,Wilkes
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p. 3125 - 3132
(2007/10/02)
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- Synthesis of Nonproteinogenic (R)- or (S)-Amino Acids. - Analogues of Phenylalanine, Isotopically Labelled and Cyclic Amino Acids from tert-Butyl 2-(tert-Butyl)-3-methyl-4-oxo-1-imidazolidinecarboxylate (Boc-BMI)
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The enantiomerically pure glycine derivatives (R)- and (S)-Boc-BMI, commercially available on a kg scale, are used as starting materials (Scheme 1) for the preparation of (i) open-chain amino acids such as α-deuterio amino acids (4,5), β-arylalanines (2), aspartic acid derivatives (6, 7a, 8), or ω-halo amino acids (7b,c, 12, 13, 16, 17, 19, 22), (ii) of α-aminocycloalkanecarboxylic acids (9, 11), and (iii) of heterocyclic α-amino acids (14, 15, 18, 20) containing azetidine, pyrrolidine, piperidine or perhydroazepine rings.Inversion by deprotonation/protonation ordeuteration allows to prepare either enantiomer of an amino acid from the same Boc-BMI enantiomer (Scheme 5).Effects of additives such as the cyclic urea DMPU, lithium salts, or secondeary amines upon the reactivity of lithium enolates are discussed and, in part, exploited.
- Seebach, Dieter,Dziadulewicz, Edward,Behrendt, Linda,Cantoreggi, Sergio,Fitzi, Robert
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p. 1215 - 1232
(2007/10/02)
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- N-Acylphenylalanines and Related Compounds. A New Class of Oral Hypoglycemic Agents
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N-Benzoyl-DL-phenylalanine (1) was found to possess hypoglycemic activity.A series of the analogues of compound 1 were prepared and evaluated for their blood glucose lowering activity.Both the steric effects of the phenylalanine moiety and the effects of variations in the acyl moiety were investigated.This study elucidated some of the structure-activity relationships and led to the development of N-(4-ethylbenzoyl)-D-phenylalanine (34), which was 50 times more potent than the initial compound 1.
- Shinkai, Hisashi,Toi, Koji,Kumashiro, Izumi,Seto, Yoshiko,Fukuma, Mariko,et al.
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p. 2092 - 2097
(2007/10/02)
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- Angiotensin converting enzyme inhibitors: N-substituted monocyclic and bicyclic amino acid derivatives
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The synthesis of N-(3-mercaptopropionyl)-N-arylglycines (14a-x), -N-arylalanines (15a,b), -N-cycloalkylglycines (16a-k), and -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids (17a-d), -1,2,3,4-tetrahydroquinoline-2-carboxylic acids (18a-f), and -indoline-2-carboxylic acids (19a-k) is described. In vitro inhibition of angiotensin converting enzyme (ACE) is reported for each compound, and the structure-activity relationship for each series is discussed. The in vivo inhibition of ACE and antihypertensive effects of representative compounds from each series are discussed. The most potent compound, 19d, had an in vitro ACE IC50 of 2.6 x 10-9 M and lowered blood pressure in spontaneous hypertensive rats 85 mm at a dose of 10 mg/kg po.
- Stanton,Gruenfeld,Babiarz,Ackerman,Friedmann,Yuan,Macchia
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p. 1267 - 1277
(2007/10/02)
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