- 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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- Gene editing and synthetically accessible inhibitors reveal role for TPC2 in HCC cell proliferation and tumor growth
-
The role of two-pore channel 2 (TPC2), one of the few cation channels localized on endolysosomal membranes, in cancer remains poorly understood. Here, we report that TPC2 knockout reduces proliferation of cancer cells in vitro, affects their energy metabolism, and successfully abrogates tumor growth in vivo. Concurrently, we have developed simplified analogs of the alkaloid tetrandrine as potent TPC2 inhibitors by screening a library of synthesized benzyltetrahydroisoquinoline derivatives. Removal of dispensable substructures of the lead molecule tetrandrine increases antiproliferative properties against cancer cells and impairs proangiogenic signaling of endothelial cells to a greater extent than tetrandrine. Simultaneously, toxic effects on non-cancerous cells are reduced, allowing in vivo administration and revealing a TPC2 inhibitor with antitumor efficacy in mice. Hence, our study unveils TPC2 as valid target for cancer therapy and provides easily accessible tetrandrine analogs as a promising option for effective pharmacological interference.
- Bartel, Karin,Biel, Martin,Bracher, Franz,Chao, Yu-Kai,Chen, Cheng-Chang,Gegenfurtner, Florian A.,Geisslinger, Franz,Gerndt, Susanne,Gerwien, Aaron,Grimm, Christian,Nguyen, Ong Nam Phuong,Ortler, Carina,Schaefer, Michael,Urban, Nicole,Vollmar, Angelika M.,Zahler, Stefan,Zisis, Themistoklis,Müller, Christoph,Müller, Martin
-
p. 1119 - 27,1131
(2021/08/19)
-
- Vanadium-Catalyzed Oxidative Intramolecular Coupling of Tethered Phenols: Formation of Phenol-Dienone Products
-
A mild and efficient method for the vanadium-catalyzed intramolecular coupling of tethered free phenols is described. The corresponding phenol-dienone products are prepared directly in good yields with low catalyst loadings. Electronically diverse tethered phenol precursors are well tolerated, and the catalytic method was effectively applied as the key step in syntheses of three natural products and a synthetically useful morphinan alkaloid precursor.
- Gilmartin, Philip H.,Kozlowski, Marisa C.
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p. 2914 - 2919
(2020/04/10)
-
- Full-synthetic method of racemic tetrandrine
-
The invention discloses a full-synthetic method of racemic tetrandrine, and belongs to the technical field of drug synthesis. The full-synthetic method of the racemic tetrandrine comprises the steps that a synthetic route adopts a convergence synthesis method, a 5-bromovanillin, namely a compound 1 and 3-hydroxy-4-methoxyphenylacetic acid, namely a compound 5 are taken as starting materials to obtain a compound 4 and a compound 6 respectively, then the compound 4 and the compound 6 are taken as raw materials to synthesize a compound 11, a compound 19 is synthesized from the compound 11, and finally, the compound 11 reacts with the compound 19. The full-synthetic method of the racemic tetrandrine has the advantages that the synthetic efficiency is higher, the yield is higher, and the cost is lower; the reaction conditions are milder, the operation is simple and convenient, the industrial value is higher, and a reference is provided for the full-synthetic method of optical voidness tetrandrine.
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- PHENYL [A]INDOLE[2,3-G]QUINOLIZINE COMPOUNDS, PREPARATION METHOD THEREFOR, PHARMACEUTICAL COMPOSITION, AND APPLICATIONS THEREOF
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The present invention relates to phenyl [a]indole[2,3-g]quinolizine compounds represented by formula (I), a preparation method therefor, a pharmaceutical composition, and applications thereof. Specific applications are applications in the preparation of d
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- Benzo aza compound, preparation method and use thereof
-
Belonging to the field of pharmaceutical chemistry, the invention relates to a benzoazepine compound, a preparation method and application thereof, in particular to the benzoazepine compound, its preparation method and application in the field of treatment of nervous system diseases, especially application in the field of drug addiction related to dopamine D1 and D3 receptors. The benzoazepine compound and pharmacologically acceptable inorganic or organic salts thereof have a structure shown as formula (I). Results of drug experiments carried out by the invention show that the benzoazepine compound and its pharmacologically acceptable inorganic or organic salts have high antagonistic activity on dopamine D1 and D3, can be used as drug leads for further development of dopamine receptor antagonists with good selectivity and high activity, and can be used as potential drugs for treatment of drug addiction by dopamine D1, D3 receptor antagonists. (formula (I)).
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- Asymmetric total synthesis of tetrahydroprotoberberine derivatives and evaluation of their binding affinities at dopamine receptors
-
Cocaine addiction remains a serious challenge for clinical and medical research because there is no effective pharmacological treatment. L-THP, a natural product isolated from Corydalis yanhusuo W.T. Wang, is one of the most frequently used traditional herbs to treat drug addiction in China. Our laboratory first reported that its demethylated metabolites L-ICP, L-CD, and L-CP had high affinity at dopamine D1, D2, and D5 receptors. Here we report the chemical synthesis of these metabolites and other derivatives and their binding affinities at dopamine receptors. The synthesis of these bioactive metabolites will allow further in vivo study of their potential in treating cocaine addiction.
- Lee, David Y.W.,Liu, Jing,Zhang, Shuzhen,Huang, Peng,Liu-Chen, Lee-Yuan
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p. 1437 - 1440
(2017/03/08)
-
- ZrCl4-mediated synthesis of 1,2,3-triazoles from vinyl nitrates and their biological evaluation
-
A ZrCl4-mediated simple method for the conversion of vinyl nitrates to 1,2,3-triazoles in excellent yields is developed. The obtained new triazoles were evaluated for their antimicrobial activity.
- Sridhar, Gattu,Somnath, Mudavath,Sharma, Gangavaram V. M.,Prashanth, Thodupunuri
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p. 551 - 556
(2017/03/15)
-
- A Modular Access to (±)-Tubocurine and (±)-Curine - Formal Total Synthesis of Tubocurarine
-
Two consecutive Cu-catalyzed Ullmann-type C-O couplings permitted the first successful entry toward the curare alkaloids (±)-tubocurine and (±)-curine. Starting from vanillin, the synthetic sequence comprises 15 linear steps and includes a total of 24 transformations. In addition, the total synthesis of tubocurine represents a formal total synthesis of the famous arrow poison alkaloid tubocurarine.
- Otto, Nicola,Ferenc, Dorota,Opatz, Till
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p. 1205 - 1217
(2018/06/18)
-
- Functional reversal of (?)-Stepholidine analogues by replacement of benzazepine substructure using the ring-expansion strategy
-
(?)-Stepholidine is an active ingredient of the Chinese herb Stephania and naturally occurring tetrahydroprotoberberine alkaloid with mixed dopamine receptor D1 agonistic and dopamine receptor D2 antagonistic activities. In this work, a series of novel hexahydrobenzo[4,5]azepino [2,1-a]isoquinolines were designed and synthesized as ring-expanded analogues of (?)-Stepholidine. Initial pharmacological assays demonstrated that a benzazepine replacement was associated with significant increase in selectivity and functional reversal at dopamine receptor D1. Compound-(?)-15e (Ki?=?5.32?±?0.01?nm) is more potent than (?)-Stepholidine (Ki?=?13?nm) and was identified as a selective dopamine receptor D1 antagonist (IC50?=?0.14?μm). Moreover, molecular modeling suggested that (?)-15e might exert its dopamine receptor D1 antagonistic activities through interacting with the transmembrane helix 7 of dopamine receptor D1.
- Li, Wei,Zhang, Li,Xu, Lili,Yuan, Congmin,Du, Peng,Chen, Jiaojiao,Zhen, Xuechu,Fu, Wei
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p. 599 - 607
(2016/10/06)
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- N-METHYL-D-ASPARTATE RECEPTOR (NMDAR) POTENTIATORS, PHARMACEUTICAL COMPOSITIONS, AND USES RELATED THERETO
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This disclosure relates to tetrahydroisoquinolines, salts, and derivatives useful for managing mental or cognitive diseases or conditions of the brain or central nervous system. In certain embodiments, the disclosure relates to compounds and compositions
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- Synthetic approaches to pallimamine and analogues using direct imine acylation
-
The use of Direct Imine Acylation (DIA) methodology for the total synthesis of pallimamine is described, with three different synthetic routes examined. The construction of three advanced δ-lactam precursors, all utilising DIA, is described, along with attempts to progress these compounds further, using three distinct desymmetrisation strategies, two involving alcohol-aryl coupling, and a third involving an unusual diastereoselective lactonisation.
- Ronson, Thomas O.,Kitsiou, Christiana,Unsworth, William P.,Taylor, Richard J.K.
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p. 6099 - 6106
(2016/09/14)
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- ANTI-HIV COMPOUNDS
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This invention provides, among other things, tetrahydroisoquinolines useful for treating viral infections, pharmaceutical formulations containing such compounds, as well as methods of inhibiting the replication of a virus, such as HIV, or treating a disease, such as AIDS.
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-
Paragraph 0258
(2016/07/05)
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- C4 phenyl aporphines with selective h5-HT2B receptor affinity
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Abstract A group of aporphine alkaloids related to (±)-nantenine (1) and bearing a C4 phenyl and various C1 or N-substituents, was synthesized and evaluated for affinity to h5-HT receptors. In general, unlike nantenine, the analogs lack affinity for the h
- Kapadia, Nirav,Harding, Wayne W.
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p. 3451 - 3454
(2015/08/06)
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- DIARYL[A, G]QUINOLIZIDINE COMPOUND, PREPARATION METHOD THEREFOR, PHARMACEUTICAL COMPOSITION, AND USES THEREOF
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The present invention relates to a diarylo[a,g]quinolizidine compound of formula (I), enantiomer, diastereoisomer, racemate, mixture, pharmaceutically acceptable salt, crystalline hydrate or solvate thereof; the preparation method thereof, and uses thereof in preparing an experimental model drugs related to dopamine receptors and 5-HT receptors or a medicament for treating or preventing a disease related to dopamine receptors and 5-HT receptors.
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-
Paragraph 0053; 0054; 0247; 0248
(2015/03/28)
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- DIARYL[A, G]QUINOLIZIDINE COMPOUND, PREPARATION METHOD THEREFOR, PHARMACEUTICAL COMPOSITION, AND USES THEREOF
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The present invention relates to a diarylo[a,g]quinolizidine compound of formula (I), enantiomer, diastereoisomer, racemate, mixture, pharmaceutically acceptable salt, crystalline hydrate or solvate thereof; the preparation method thereof, and uses thereof in preparing an experimental model drugs related to dopamine receptors and 5-HT receptors or a medicament for treating or preventing a disease related to dopamine receptors and 5-HT receptors.
- -
-
Paragraph 0113; 0114; 0307; 0308
(2015/05/26)
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- Design, synthesis and evaluation of benzo[a]thieno[3,2-g]quinolizines as novel l-SPD derivatives possessing dopamine D1, D2 and serotonin 5-HT1A multiple action profiles
-
A novel scaffold derived from l-SPD with a substituted thiophene group in the D ring were designed, synthesized, and evaluated for their binding affinities at dopamine (D1, D2 and D3) and serotonin (5-HT1A and 5
- Li, Zeng,Huang, Jiye,Sun, Haifeng,Zhou, Shengbin,Guo, Lin,Zhou, Yu,Zhen, Xuechu,Liu, Hong
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p. 5838 - 5846
(2015/01/08)
-
- Synthesis and biological evaluation of 10-11C- dihydrotetrabenazine as a vesicular monoamine transporter 2 radioligand
-
In this study, we synthesized a new carbon-11-labeled radiotracer, 10- 11C-dihydrotetrabenazine (10-11C-DTBZ), and evaluated its potential as a vesicular monoamine transporter 2 (VMAT2) radioligand. The radiolabeled precursor 10-O-de
- Li, Xiaomin,Chen, Zhengping,Tang, Jie,Liu, Chunyi,Zou, Pei,Huang, Hongbo,Tan, Cheng,Yu, Huixin
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p. 313 - 319
(2014/05/20)
-
- HEXAHYDRODIBENZO[A,G]QUINOLIZINE COMPOUND, PREPARATION METHOD THEREOF, PHARMACEUTICAL COMPOSITION AND USE THEREOF
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The present invention relates to a novel hexahydrodibenzo[a,g]quinoline compound represented by general formula (I) and its derivatives, enantiomer, diastereoisomer, raceme and mixtures thereof, as well as pharmaceutically acceptable salts thereof. The pr
- -
-
Paragraph 0086
(2014/04/03)
-
- Asymmetric total synthesis and identification of tetrahydroprotoberberine derivatives as new antipsychotic agents possessing a dopamine D1, D2 and serotonin 5-HT1A multi-action profile
-
An effective and rapid method for the microwave-assisted preparation of the key intermediate for the total synthesis of tetrahydroprotoberberines (THPBs) including l-stepholidine (l-SPD) was developed. Thirty-one THPB derivatives with diverse substituents on A and D ring were synthesized, and their binding affinity to dopamine D1, D2 and serotonin 5-HT 1A and 5-HT2A receptors were determined. Compounds 18k and 18m were identified as partial agonists at the D1 receptor with Ki values of 50 and 6.3 nM, while both compounds act as D2 receptor antagonists (Ki = 305 and 145 nM, respectively) and 5-HT1A receptor full agonists (Ki = 149 and 908 nM, respectively). These two THPBs compounds exerted antipsychotic actions in animal models. Further electrophysiological studies employing single-unit recording in intact animals demonstrated that 18k-excited dopaminergic (DA) neurons are associated with its 5-HT1A receptor agonistic activity. These results suggest that these two compounds targeted to multiple neurotransmitter receptors may present novel lead drugs with new pharmacological profiles for the treatment of schizophrenia.
- Sun, Haifeng,Zhu, Liyuan,Yang, Huicui,Qian, Wangke,Guo, Lin,Zhou, Shengbin,Gao, Bo,Li, Zeng,Zhou, Yu,Jiang, Hualiang,Chen, Kaixian,Zhen, Xuechu,Liu, Hong
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p. 856 - 868
(2013/03/13)
-
- 8-Phenylisoquinolines And Pharmaceutical Composition Used In Treatment For Sepsis
-
A compound is provided. The compound includes a formula of:
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- Design, synthesis, and biological evaluation of Erythrina alkaloid analogues as neuronal nicotinic acetylcholine receptor antagonists
-
The synthesis of a new series of Erythrina alkaloid analogues and their pharmacological characterization at various nicotine acetylcholine receptor (nAChR) subtypes are described. The compounds were designed to be simplified analogues of aromatic erythrinanes with the aim of obtaining subtype-selective antagonists for the nAChRs and thereby probe the potential of using these natural products as scaffolds for further ligand optimization. The most selective and potent nAChR ligand to come from the series, 6,7-dimethoxy-2- methyl-1,2,3,4-tetrahydroisoquinoline (3c) (also a natural product by the name of O-methylcorypalline), displayed submicromolar binding affinity toward the α4β2 nAChR with more than 300-fold selectivity over α4β4, α3β4, and α7. Furthermore, this lead structure (which also has inhibitory activity at monoamine oxidases A and B and at the serotonin and norepinephrine transporters) showed antidepressant-like effect in the mouse forced swim test at 30 mg/kg.
- Crestey, Fran?ois,Jensen, Anders A.,Borch, Morten,Andreasen, Jesper Tobias,Andersen, Jacob,Balle, Thomas,Kristensen, Jesper Langgaard
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p. 9673 - 9682
(2014/01/06)
-
- Design, synthesis, and pharmacological evaluation of novel tetrahydroprotoberberine derivatives: Selective inhibitors of dopamine D 1 receptor
-
A series of new tetrahydroprotoberberine (THPB) derivatives were designed, synthesized, and tested for their binding affinity towards dopamine (D 1 and D2) and serotonin (5-HT1A and 5-HT 2A) receptors. Many of the THPB compounds exhibited high binding affinity and activity at the dopamine D1 receptor, as well as high selectivity for the D1 receptor over the D2, 5-HT 1A, and 5-HT2A receptors. Among these, compound 19c exhibited a promising D1 receptor binding affinity (Ki = 2.53 nM) and remarkable selectivity versus D2R (inhibition = 81.87%), 5-HT1AR (inhibition = 61.70%), and 5-HT2AR (inhibition = 24.96%). Compared with l-(S)-stepholidine (l-SPD) (D1 Ki = 6.23 nM, D2 Ki = 56.17 nM), compound 19c showed better binding affinity for the D1 receptor (2.5-fold higher) and excellent D2/D1 selectivity. Functional assays found compounds 18j, 18k, and 19c are pure D1 receptor antagonists. These results indicate that removing the C10 hydroxy group and introducing a methoxy group at C11 of the pharmacophore of l-SPD can reverse the function of THPB compounds at the D1 receptor. These results are in accord with molecular docking studies.
- Qian, Wangke,Lu, Weijian,Sun, Haifeng,Li, Zeng,Zhu, Liyuan,Zhao, Rui,Zhang, Lei,Zhou, Shengbin,Zhou, Yu,Jiang, Hualiang,Zhen, Xuechu,Liu, Hong
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p. 4862 - 4871
(2012/09/05)
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- Formal synthesis of the bisbenzylisoquinoline alkaloid berbamunine by asymmetric substitution of chiral organolithium compounds
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Asymmetric alkylation of enantiomeric tetrahydroisoquinolyl oxazolines was achieved with 96-97% diastereoselectivity. Removal of the oxazoline chiral auxiliary and further transformations provide a straightforward synthesis of the two synthetic intermediates that were previously synthesized by resolution, and which comprise a formal synthesis of berbamunine by Ullman coupling. ARKAT-USA, Inc.
- Gawley, Robert E.,Smith, Gregory A.
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p. 167 - 179
(2011/07/07)
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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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p. 6703 - 6714
(2011/10/18)
-
- Synthesis and biological evaluation of berberine analogues as novel up-regulators for both low-density-lipoprotein receptor and insulin receptor
-
Berberine (BBR) is a natural compound with up-regulating activity on both low-density-lipoprotein receptor (LDLR) and insulin receptor (InsR). This one-drug-multiple-target characteristic might be suitable for the treatment of metabolic syndrome. In searching for up-regulators effective for both LDLR and InsR expression, the structure-activity relationship (SAR) analysis for BBR analogues was done. Fourteen BBR analogues were designed, synthesized and biologically evaluated. SAR analysis revealed that appropriate modifications on the phenyl ring A or D of BBR might retain the up-regulatory activities on the expression of both LDLR and InsR. Among these compounds, compound 13a bearing 9-methoxy and 10-hydroxyl on the ring D showed promising activities on either LDLR or InsR gene expression. The 10-hydroxyl of 13a could be an arm to connect proper chemical groups for optimizing drug-bioavailability in vivo. Thus, 13a could be considered to be a parent compound to make pro-drugs for either blood lipids or glucose.
- Wang, Yan-Xiang,Wang, Yu-Ping,Zhang, Hao,Kong, Wei-Jia,Li, Ying-Hong,Liu, Fei,Gao, Rong-Mei,Liu, Ting,Jiang, Jian-Dong,Song, Dan-Qing
-
scheme or table
p. 6004 - 6008
(2010/06/16)
-
- E-Combretastatin and E-resveratrol structural modifications: Antimicrobial and cancer cell growth inhibitory β-E-nitrostyrenes
-
As part of a broad-based SAR investigation of E-resveratrol (strong sirtuin activator and antineoplastic) and the anticancer vascular-targeting combretastatin-type stilbenes, a series of twenty-three β-E-nitrostyrenes was synthesized in order to evaluate potential antineoplastic, antitubulin, and antimicrobial activities. The β-E-nitrostyrenes evaluated ranged from monosubstituted phenols to trimethoxy and 3-methoxy-4,5-methylenedioxy derivatives. Two of the β-nitrostyrenes were synthesized as water-soluble sodium phosphate derivatives (4t, 4v). All except four (4r, 4s, 4t, 4u) of the series significantly inhibited a minipanel of human cancer cell lines. All but eight led to an IC50 of 10 μM for inhibition of tubulin polymerization, and all except three (4l, 4t, 4v) displayed antimicrobial activity.
- Pettit, Robin K.,Pettit, George R.,Hamel, Ernest,Hogan, Fiona,Moser, Bryan R.,Wolf, Sonja,Pon, Sandy,Chapuis, Jean-Charles,Schmidt, Jean M.
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experimental part
p. 6606 - 6612
(2009/12/06)
-
- Total synthesis of natural and unnatural lamellarins with saturated and unsaturated D-rings
-
(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)
-
- An efficient synthesis of conjugated nitro-olefins using ceric ammonium nitrate
-
An efficient method for the synthesis of conjugated nitro-olefins from α,β-unsaturated acids under extremely mild conditions using ceric ammonium nitrate (CAN) at room temperature in acetonitrile in moderate to good yields is described.
- Sridhar Rao,Srinivas,Suresh Babu,Madhusudana Rao
-
p. 8141 - 8143
(2007/10/03)
-
- Amide compounds and use thereof
-
An amide compound given by formula [I]: wherein R1 represents a C1-C10 haloalkyl and so on, R2 represents a hydrogen and so on, X represents an oxygen or sulfur, Y represents an oxygen or sulfur, Ar represents an aromatic group, A represents an
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Page/Page column 18
(2010/01/31)
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- Structure-based approach to falcipain-2 inhibitors: Synthesis and biological evaluation of 1,6,7-Trisubstituted dihydroisoquinolines and isoquinolines
-
1,4,7-Trisubstituted isoquinolines were designed, synthesized and evaluated for their inhibition against Plasmodium falciparum cysteine protease falcipain-2. The 1-benzyloxyphenyl-dihydroisoquinoline and -isoquinoline derivatives were found to exhibit better activity against falcipain-2 than their corresponding 1-hydroxyphenyl or 1-methoxyphenyl analogues. The docking scores correlate with the IC50 values of compounds and give a high coefficient correlation of 0.94.
- Batra, Sanjay,Sabnis, Yogesh A.,Rosenthal, Philip J.,Avery, Mitchell A.
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p. 2293 - 2299
(2007/10/03)
-
- Iodine (III)-mediated generation of nitrogen-tethered orthoquinol acetates for the construction of oxygenated indole, quinoline, and phenanthridine alkaloid motifs
-
Functionalized indole and quinoline derivatives are conveniently prepared from nitrogen-tethered 2-methoxyphenols via phenyliodine(III) diacetate mediated oxidative acetoxylation, followed by a fluoride- or base-induced intramolecular nucleophilic addition reaction. This regioselective Michael-type addition step is further discussed in view of the rearrangement of orthoquinol acetate intermediates into paraquinol acetates that is sometimes observed in situ. Application of this methodology to the synthesis of a functionalized phenanthridine, and its potential for the construction of polyoxygenated lycorine-type alkaloid skeleta are here described.
- Pouysegu, Laurent,Avellan, Anne-Virginie,Quideau, Stephane
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p. 3425 - 3436
(2007/10/03)
-
- Synthesis of protoberberines using a silyl-directed Pictet-Spengler cyclization
-
Five naturally-occurring protoberberines have been synthesized in enantioenriched form by alkylation by two different 2-trimethylsilylbenzyl chlorides of four tetrahydroisoquinolines, derivatized with Meyers' formamidine valinol methyl ether chiral auxiliary. Silyl-directed Pictet-Spengler cyclization of the ensuing 3,4-dimethoxy-2-trimethylsilylbenzyl tetrahydroisoquinolines leads to four of the target protoberberines in excellent yield and complete regioselectivity. In the fifth case, the 3,4-methylenedioxy analog gives a mixture of protoberberine and a product of ring closure at C6 of the benzyl moiety in a 3:4 ratio.
- Cutter, Paul S,Miller, R.Bryan,Schore, Neil E
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p. 1471 - 1478
(2007/10/03)
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- An efficient synthesis of thalifoline
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An efficient multi-step approach for the synthesis of the isoquinolin-1-one alkaloid thalifoline (1) is described. The key intermediate carbamate 8a underwent a modified Bischler-Napieralski-type cyclization using Banwell's Tf2O/DMAP conditions to form the lactam 9a under mild conditions and in excellent yield.
- Wang, You-Chu,Georghiou, Paris E.
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p. 2187 - 2190
(2007/10/03)
-
- Syntheses and antitumor targeting G1 phase of the cell cycle of benzoyldihydroisoquinolines and related 1-substituted isoquinolines
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A series of 1-substituted 3,4-dihydroisoquinolines were synthesized and tested in vitro against the leukemia L 1210 cell line to evaluate their ability to perturb the cell cycle by arresting cells in the G1 phase. 1-Benzoylimines, 1-phenylimines, and 1-alkylimines were synthesized. The most powerful cytotoxic derivatives, 1-benzoyl-3,4-dihydroisoquinolines (1-26), were obtained from amides I via 1-benzyl-3,4-dihydroisoquinoline in good yield by a direct selective oxidation of the benzylic carbon of the corresponding imines through 10% Pd/C in acetonitrile. SAR studies let us to identify the essential structural features for cytotoxic activity. The most bioactive compounds (with IC50 5μM) were BzDHIQ (13, 22, 21, 8, 9, 11, 1, 20, 6, and 19), and they are characterized by the following: (i) An α-ketoimine moiety is necessary for potent antiproliferative activity (1-phenyl- and 1-alkyl-3,4-dihydroisoquinoline derivatives, 34-40, are less active). (ii) An hydrophobic, benzyloxy, alkyloxy, or allyloxy group at the C-6 position seems to be relevant for cytotoxicity. (iii) Regarding the influence of the benzoylic moiety, both the unsubstituted (13, 8, 9, 11, 1, and 6) and the 3′-monosubstituted (22, 21, 20, and 19) compounds were more potent than compounds with other substitutions.
- Bermejo, Almudena,Andreu, Inmaculada,Suvire, Fernando,Léonce, Stephane,Caignard, Daniel H.,Renard, Pierre,Pierré, Alain,Enriz, Ricardo D.,Cortes, Diego,Cabedo, Nuria
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p. 5058 - 5068
(2007/10/03)
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- Pictet-Spengler condensation of N-sulfonyl-β-phenethylamines with α- chloro-α-phenylselenoesters. New synthesis of 1,2,3,4- tetrahydroisoquinoline-1-carboxylates
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The reaction of N-sulfonyl-β-phenethylamines with α-chloro-a- phenylseleno acetate/propionate esters under Lewis acid promotion gives moderate to good yields of the corresponding 1,2,3, 4- tetrahydroisoquinoline-1-carboxylates. Varying degrees of diastereoselection were obtained using chiral sulfonamides and/or esters. Employing this strategy, the achievement of a new total synthesis of Calycotomine is reported.
- Silveira, Claudio C.,Bernardi, Carmem R.,Braga, Antonio L.,Kaufman, Teodoro S.
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p. 4969 - 4972
(2007/10/03)
-
- Biomimetic synthesis of the metabolites of trequinsin
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Six metabolites of Trequinsin isoquinolin-4-one. hydrochloride> are identified which have been synthesised from the parent molecule trequinsin 1.A base-promoted se
- Lal, Bansi,Souza, Eleanor Pinto de
-
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- SYNTHESIS OF 3-O-METHYLATED DERIVATIVES OF CATECHOLAMINES
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3-O-Methylated catecholamines, used in the radioenzyme method for the analysis of catecholamines in blood, were synthesized. The optimum conditions for the production of both the intermediate and the final products were determined. By the use of tetrabutylammonium bromide in the condensation of nitromethane with O-benzylvanilin it is possible to obtain a high yield of 1-(3-methoxy-4-benzyloxyphenyl)-2-nitroethanol. The latter is easily transformed at a palladium catalyst into methylnoradrenaline by reduction with ammonium formate. The reduction of 1-(3-methoxy-4-benzyloxyphenyl)-2-nitroethylene with hydrogen or its donors at a palladium catalyst takes place significantly more readily in the presence of ferric chloride.
- Kulikov, S. V.,Samartsev, M. A.
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p. 280 - 288
(2007/10/02)
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- THE ASYMMETRIC TOTAL SYNTHESIS OF (+)-RETICULINE
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The synthesis of the title compound was accomplished via chiral formamidines in 5 steps (30.4percent overall) and 98.6percent ee.
- Meyers, A. I.,Guiles, Joseph
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p. 295 - 301
(2007/10/02)
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- EFFICIENT SYNTHESES OF (E)-4-HYDROXY-5-METHOXY- AND (E)-5-HYDROXY-4-METHOXY-2,β-DINITROSTYRENES
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The key to efficient syntheses of the title compounds is chemoselective CF3CO2H debenzylation.The benzyl protecting group is necessary for regiospecific nitration.
- Mayer, Alice A.,Murphy, Bryan P.
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p. 423 - 430
(2007/10/02)
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- Synthesis of Heterocycles via Lactones: Part VI Condensation of Bromo Esters with β-Phenethylamines, a New Route to Berbines: Synthesis of (+/-)-Xylopinine, (+/-)-Scoulerine, Isocoptisine and Pseudoepitetrahydroberberine
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A new route involving the generation of a tricyclic lactam intermediate in one-step has been developed for the synthesis of 2,3,10,11-tetraoxygenated berbine alkaloids.Three such alkaloids have been synthesized besides scoulerine which is 2,9-dihydroxy-3,10-dimethoxyberbine (11).
- Pandey, G. D.,Tiwari, K. P.
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p. 272 - 275
(2007/10/02)
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- Cactus alkaloids. XXXIII. β-Phenethylamines from the Guatemalan cactus Pilosocereus maxonii
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TLC analysis of extracts of Pilosocereus maxonii (Rose) Byles and Rowley detected six identifiable alkaloids. Preparative TLC aided in the crystallization of the hydrochlorides of N-methyl-3,4-dimethoxyphenethylamine, N-methyl-3-methoxytyramine, and N,N-dimethyl-3-methoxytyramine. Traces of 3,4-dimethoxyphenethylamine (TLC and mass spectrometry), tyramine (TLC), and N-methyltyramine (TLC) were identified. While all of these compounds were isolated and/or detected previously in other cactus species this study is the first reported crystallization of N-methyl- and N,N-dimethyl-3-methoxytyramine from a natural source.
- Pummangura,Nichols,McLaughlin
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p. 1485 - 1487
(2007/10/05)
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