- Synthesis, binding, and functional properties of tetrahydroisoquinolino-2-alkyl phenones as selective σ2R/TMEM97 ligands
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Sigma-2 receptor (σ2R/TMEM97) has been implicated to play important roles in multiple cellular dysfunctions, such as cell neoplastic proliferation, neuro-inflammation, neurodegeneration, etc. Selective σ2 ligands are believed to be promising pharmacological tools to regulate or diagnose various disorders. As an ongoing effort of discovery of new and selective σ2 ligands, we have synthesized a series of tetrahydroisoquinolino-2-alkyl phenone analogs and identified that 10 of them have moderate to potent affinity and selectivity for σ2R/TMEM97. Especially, 4 analogs showed Ki values ranging from 0.38 to 5.1 nM for σ2R/TMEM97 with no or low affinity for sigma-1 receptor (σ1R). Functional assays indicated that these 4 most potent analogs had no effects on intracellular calcium concentration and were classified as putative σ2R/TMEM97 antagonists according to current understanding. The σ2R/TMEM97 has been suggested to play important roles in the central nervous system. Based on published pharmacological and clinical results from several regarded σ2R/TMEM97 antagonists, these analogs may potentially be useful for the treatment of various neurodegenerative diseases.
- Xie, Xiao-Yang,Li, Yu-Yun,Ma, Wen-Hui,Chen, Ai-Fang,Sun, Yu-Tong,Lee, Ji Youn,Riad, Aladdin,Xu, Dao-Hua,Mach, Robert H.,Huang, Yun-Sheng
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Read Online
- The ethoxycarbonyl group as both activating and protective group in N-acyl-Pictet-Spengler reactions using methoxystyrenes. A short approach to racemic 1-benzyltetrahydroisoquinoline alkaloids
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We present a systematic investigation on an improved variant of the N-acyl-Pictet-Spengler condensation for the synthesis of 1-benzyltetrahydroisoquinolines, based on our recently published synthesis of N-methylcoclaurine, exemplified by the total syntheses of 10 alkaloids in racemic form. Major advantages are a) using ω-methoxystyrenes as convenient alternatives to arylacetaldehydes, and b) using the ethoxycarbonyl residue for both activating the arylethylamine precursors for the cyclization reaction, and, as a significant extension, also as protective group for phenolic residues. After ring closure, the ethoxycarbonyl-protected phenols are deprotected simultaneously with the further processing of the carbamate group, either following route A (lithium alanate reduction) to give N-methylated phenolic products, or following route B (treatment with excess methyllithium) to give the corresponding alkaloids with free N-H function. This dual use of the ethoxycarbonyl group shortens the synthetic routes to hydroxylated 1-benzyltetrahydroisoquinolines significantly. Not surprisingly, these ten alkaloids did not show noteworthy effects on TPC2 cation channels and the tumor cell line VCR-R CEM, and did not exhibit P-glycoprotein blocking activity. But due to their free phenolic groups they can serve as valuable intermediates for novel derivatives addressing all of these targets, based on previous evidence for structure-activity relationships in this chemotype.
- Bartel, Karin,Bracher, Franz,Geisslinger, Franz,Keller, Marco,Sauvageot-Witzku, Karl,Schaefer, Michael,Urban, Nicole
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supporting information
p. 2716 - 2725
(2022/01/12)
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- Structure–activity relationship and biological evaluation of berberine derivatives as PCSK9 down-regulating agents
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Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein and its deficiency markedly enhanced the survival rate of patient with cardiovascular diseases (CVDs). Forty berberine (BBR) derivatives were synthesized and evaluated for their activities on down-regulating the transcription of PCSK9 in HepG2 cells, taking BBR as the lead. Structure–activity relationship (SAR) analysis revealed that 2,3-dimethoxy moiety might be beneficial for activity. Among them, 9k displayed the most potent activity with IC50 value of 9.5 ± 0.5 μM, better than that of BBR. Also, it significantly decreased PCSK9 protein level at cellular level, as well as in the liver and serum of mice in vivo. Furthermore, 9k markedly increased LDLR expression and LDL-C clearance via down-regulating PCSK9 protein. The mechanism of action of 9k is targeting HNF1α and/or Sp1 cluster modulation upstream of PCSK9, a different one from BBR. Therefore, 9k might have the potential to be a novel PCSK9 transcriptional inhibitor for the treatment of atherosclerosis, worthy for further investigation.
- Fan, Tian-Yun,Yang, Yu-Xin,Zeng, Qing-Xuan,Wang, Xue-Lei,Wei, Wei,Guo, Xi-Xi,Zhao, Li-Ping,Song, Dan-Qing,Wang, Yan-Xiang,Wang, Li,Hong, Bin
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- Novel total syntheses of oxoaporphine alkaloids enabled by mild Cu-catalyzed tandem oxidation/aromatization of 1-Bn-DHIQs
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Novel total syntheses of oxoaporphine alkaloids such as liriodenine, dicentrinone, cassameridine, lysicamine, oxoglaucine and O-methylmoschatoline were developed. The key step of these total syntheses is Cu-catalyzed conversion of 1-benzyl-3,4-dihydro-isoquinolines (1-Bn-DHIQs) to 1-benzoyl-isoquinolines (1-Bz-IQs) via tandem oxidation/aromatization. This novel Cu-catalyzed conversion has been studied in detail, and was successfully used for constructing the 1-Bz-IQ core.
- Zheng, Bo,Qu, Hui-Ya,Meng, Tian-Zhuo,Lu, Xia,Zheng, Jie,He, Yun-Gang,Fan, Qi-Qi,Shi, Xiao-Xin
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p. 28997 - 29007
(2018/08/29)
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- 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
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p. 925 - 937
(2015/03/31)
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- β-selective C-H arylation of pyrroles leading to concise syntheses of lamellarins C and I
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The first general β-selective C-H arylation of pyrroles has been developed by using a rhodium catalyst. This C-H arylation reaction, which is retrosynthetically straightforward but results in unusual regioselectivity, could result in de novo syntheses of
- Ueda, Kirika,Amaike, Kazuma,Maceiczyk, Richard M.,Itami, Kenichiro,Yamaguchi, Junichiro
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supporting information
p. 13226 - 13232
(2015/03/30)
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- SAR based design of nicotinamides as a novel class of androgen receptor antagonists for prostate cancer
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Molecular knowledge of pure antagonism and systematic SAR study offered a direction for structural optimization of DIMN to provide nicotinamides as a novel series of AR antagonists. Nicotinamides with extended linear scaffold bearing sterically bulky alkoxy groups on isoquinoline end were synthesized for H12 displacement. AR binding affinity and molecular basis of antiandrogenic effect establish the optimized derivatives, 7au and 7bb, as promising candidates of second generation AR antagonists for advanced prostate cancer.
- Yang, Su Hui,Song, Chin-Hee,Van, Hue Thi My,Park, Eunsook,Khadka, Daulat Bikram,Gong, Eun-Yeung,Lee, Keesook,Cho, Won-Jea
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supporting information
p. 3414 - 3418
(2013/06/05)
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- FSH RECEPTOR ANTAGONISTS
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The invention relates to FSH receptor antagonist according to general formula (I) or a pharmaceutically acceptable salt thereof and to a pharmaceutical composition containing the same. The compounds can be used for the treatment and prevention of endometriosis, for the treatment and prevention of pre-menopausal and peri-menopausal hormone-dependent breast cancer, for contraception, and for the treatment of uterine fibroids and other menstrual-related disorders
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Page/Page column 80; 81
(2013/04/10)
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- Enantioselective synthesis of 1-vinyltetrahydroisoquinolines via Pd-catalyzed intramolecular asymmetric allylic amination reactions
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1-Vinyltetrahydroisoquinolines serve as versatile intermediates for the synthesis of a variety of naturally occurring isoquinoline alkaloids. 1-Vinyl-6,8-dimethoxytetrahydroisoquinoline 4 and 1-vinyl-5,6,7- trimethoxytetrahydroisoquinoline 6 with >90% ee by means of Pd-catalyzed intramolecular asymmetric allylic amination reactions, using MPN and BOP ligands, developed in our laboratory. The fine-tuning capability of the MPN and BOP ligands has played a significant role in the optimization of enantioselectivity. Interesting substituent effect as well as solvent effect on the product selectivity and enantioselectivity was observed. Plausible mechanisms are proposed, which can accommodate various findings, including the critical importance of the activation of the trifluoroamide moiety through its coordination to the Lewis acidic Pd2+ metal center.
- Chien, Chih-Wei,Shi, Ce,Lin, Chi-Feng,Ojima, Iwao
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experimental part
p. 6513 - 6523
(2011/09/20)
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- Biomimetic total synthesis of (±)-8-oxoerymelanthine
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(Chemical Equation Presented) Erymelanthine 1 and 8-oxoerymelanthine 2 are unique erythrina alkaloids containing a pyridine ring. We synthesized (±)-8-oxoerymelanthine 2 in 2.0% overall yield using the following key reactions. The characteristic 6-5-6-6-m
- Yoshida, Yuki,Mohri, Kunihiko,Isobe, Kimiaki,Itoh, Toshimasa,Yamamoto, Keiko
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scheme or table
p. 6010 - 6015
(2009/12/08)
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- Total synthesis of natural and unnatural lamellarins with saturated and unsaturated D-rings
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(Chemical Equation Presented) Twenty-eight natural and unnatural lamellarins with either a saturated or an unsaturated D-ring were synthesized according to our developed synthetic route. The key step involved the Michael addition/ring closure (Mi-RC) of the benzyldihydroisoquinoline and α-nitrocinnamate derivatives, which provided the 2-carboethoxypyrrole intermediates in moderate to good yields (up to 78% yield). Subsequent hydrogenolysis/lactonization furnished lamellarins with a saturated D-ring in excellent yields (up to 93% yield). DDQ oxidation of the saturated lamellarin acetates led directly to the corresponding unsaturated analogues in 54-95% yield. In addition, only two steps in our developed strategy require column chromatography.
- Ploypradith, Poonsakdi,Petchmanee, Thaninee,Sahakitpichan, Poolsak,Litvinas, Nichole D.,Ruchirawat, Somsak
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p. 9440 - 9448
(2007/10/03)
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- 1,2,3,4-TETRAHYDROISOQUINOLINE DERIVATIVES, PREPARATIONS THEREOF AND USES THEREOF
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Compounds of general formula (I) wherein D, E, R1, R2, R3, R4, R5, R6 and R7 are as defined in the specification, as well as salts, enantiomers thereof and pharmaceutical compositions including the compounds are prepared. They are useful in therapy, in particular in the management of pain.
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Page/Page column 43
(2008/06/13)
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- An α-aminomethyl carbanion equivalent via a novel Barbier reaction: (1H-naphtho[ 1,8-de]-1,2,3-triazin-2-yl)methyl anion
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A novel sonication-promoted Barbier reaction putatively generated the titled species from the corresponding naphthotriazinylmethyl chloride and magnesium in THF: its formal addition to a variety of carbonyl compounds in situ occurred in excellent yields. Subsequent catalytic hydrogenolysis of the triazine moiety demasked the amine, thus defining a route to various phenylethylamines (including the alkaloid 'mescaline'), or ethanolamines (in two cases), in excellent overall yields. (C) 2000 Elsevier Science Ltd.
- Chandrasekhar, Sosale,Sridhar, Malayalam
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p. 4685 - 4688
(2007/10/03)
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- Studies Directed Towards Total Syntheses of the Tropoloisoquinoline Alkaloids Grandirubrine and Imerubrine. I. Preparation of Two 4,5,6-Trimethoxycyclopentisoquinolin-7-ones and Their Response to Robinson Annulation Conditions
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In connection with efforts to develop total syntheses of the tropoloisoquinoline alkaloids grandirubrine (1) and imerubrine (2), preparations of tricyclic ketone (8) and the related ethoxycarbonyl system (47) are described.Of the various approaches to (8)
- Banwell, Martin G.,Bonadio, Anna,Turner, Kathleen A.,Ireland, Neil K.,Mackay, Maureen F.
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p. 325 - 351
(2007/10/02)
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