- Optimization and scale-up of the Grandberg synthesis of 2-methyltryptamine
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An efficient, safe, and cost-effective synthesis of 2-methyltryptamine (2), a key starting material in the synthesis of the histone deacetylase inhibitor LBH589 (1) is described. The reaction of Phenylhydrazine (7) with a stoichiometric amount of 5-chloro-2-pentanone (8) in aqueous ethanol at reflux furnished crude 2-methyltryptamine (2). The product 2 was obtained in 47% yield and >99% purity after crystallization from toluene.
- Slade, Joel,Parker, David,Girgis, Michael,Wu, Raeann,Joseph, Scott,Repic, Oljan
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Read Online
- An improved and efficient synthesis of panobinostat
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An improved and efficient method for the synthesis of panobinostat was developed. The commercially available starting material 4-(chloromethyl)benzaldehyde was converted to (E)-methyl 3-[4-(chloromethyl)phenyl]acrylate via the Wittig-Horner reaction and was then directly condensed with 2-(2-methyl-1H-indol-3-yl)ethanamine to afford the key intermediate (E)-methyl 3-[4-({[2-(2-methyl-1H-indol- 3-yl)ethyl]amino}methyl)phenyl]acrylate in a one-pot synthesis reactor. Subsequently a nucleophilic substitution reaction was carried out smoothly to generate the desired compound. The key intermediate and target compound were characterised by HRMS, 1H NMR and 13C NMR. This procedure is operationally simple and would be more suitable for industrial production.
- Chen, Shanwen,Zhang, Peiming,Chen, Huali,Zhang, Pu,Yu, Yu,Gan, Zongjie
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Read Online
- Development and pre-clinical testing of a novel hypoxia-activated KDAC inhibitor
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Tumor hypoxia is associated with therapy resistance and poor patient prognosis. Hypoxia-activated prodrugs, designed to selectively target hypoxic cells while sparing normal tissue, represent a promising treatment strategy. We report the pre-clinical efficacy of 1-methyl-2-nitroimidazole panobinostat (NI-Pano, CH-03), a novel bioreductive version of the clinically used lysine deacetylase inhibitor, panobinostat. NI-Pano was stable in normoxic (21% O2) conditions and underwent NADPH-CYP-mediated enzymatic bioreduction to release panobinostat in hypoxia (2). Treatment of cells grown in both 2D and 3D with NI-Pano increased acetylation of histone H3 at lysine 9, induced apoptosis, and decreased clonogenic survival. Importantly, NI-Pano exhibited growth delay effects as a single agent in tumor xenografts. Pharmacokinetic analysis confirmed the presence of sub-micromolar concentrations of panobinostat in hypoxic mouse xenografts, but not in circulating plasma or kidneys. Together, our pre-clinical results provide a strong mechanistic rationale for the clinical development of NI-Pano for selective targeting of hypoxic tumors.
- Skwarska, Anna,Calder, Ewen D.D.,Sneddon, Deborah,Bolland, Hannah,Odyniec, Maria L.,Mistry, Ishna N.,Martin, Jennifer,Folkes, Lisa K.,Conway, Stuart J.,Hammond, Ester M.
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p. 1258 - 13,1270
(2021/09/16)
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- Design of Hydrazide-Bearing HDACIs Based on Panobinostat and Their p53 and FLT3-ITD Dependency in Antileukemia Activity
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Here, we present a new series of hydrazide-bearing class I selective HDAC inhibitors designed based on panobinostat. The cap, linker, and zinc-binding group were derivatized to improve HDAC affinity and antileukemia efficacy. Lead inhibitor 13a shows picomolar or low nanomolar IC50 values against HDAC1 and HDAC3 and exhibits differential toxicity profiles toward multiple cancer cells with different FLT3 and p53 statuses. 13a indirectly inhibits the FLT3 signaling pathway and down-regulates master antiapoptotic proteins, resulting in the activation of pro-caspase3 in wt-p53 FLT3-ITD MV4-11 cells. While in the wt-FLT3 and p53-null cells, 13a is incapable of causing apoptosis at a therapeutic concentration. The MDM2 antagonist and the proteasome inhibitor promote 13a-triggered apoptosis by preventing p53 degradation. Furthermore, we demonstrate that apoptosis rather than autophagy is the key contributing factor for 13a-triggered cell death. When compared to panobinostat, 13a is not mutagenic and displays superior in vivo bioavailability and a higher AUC0-inf value.
- Li, Xiaoyang,Jiang, Yuqi,Peterson, Yuri K.,Xu, Tongqiang,Himes, Richard A.,Luo, Xin,Yin, Guilin,Inks, Elizabeth S.,Dolloff, Nathan,Halene, Stephanie,Chan, Sherine S. L.,Chou, C. James
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p. 5501 - 5525
(2020/06/10)
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- Facile in Vitro Biocatalytic Production of Diverse Tryptamines
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Tryptamines are a medicinally important class of small molecules that serve as precursors to more complex, clinically used indole alkaloid natural products. Typically, tryptamine analogues are prepared from indoles through multistep synthetic routes. In the natural world, the desirable tryptamine synthon is produced in a single step by l-tryptophan decarboxylases (TDCs). However, no TDCs are known to combine high activity and substrate promiscuity, which might enable a practical biocatalytic route to tryptamine analogues. We have now identified the TDC from Ruminococcus gnavus as the first highly active and promiscuous member of this enzyme family. RgnTDC performs up to 96 000 turnovers and readily accommodates tryptophan analogues with substituents at the 4, 5, 6, and 7 positions, as well as alternative heterocycles, thus enabling the facile biocatalytic synthesis of >20 tryptamine analogues. We demonstrate the utility of this enzyme in a two-step biocatalytic sequence with an engineered tryptophan synthase to afford an efficient, cost-effective route to tryptamines from commercially available indole starting materials.
- McDonald, Allwin D.,Perkins, Lydia J.,Buller, Andrew R.
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p. 1939 - 1944
(2019/07/08)
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- 5-(Cyano)dibenzothiophenium Triflate: A Sulfur-Based Reagent for Electrophilic Cyanation and Cyanocyclizations
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The synthesis of 5-(cyano)dibenzothiophenium triflate 9, prepared by activation of dibenzo[b,d]thiophene-5-oxide with Tf2O and subsequent reaction with TMSCN is reported, and its reactivity as electrophilic cyanation reagent evaluated. The scalable preparation, easy handling and broad substrate scope of the electrophilic cyanation promoted by 9, which includes amines, thiols, silyl enol ethers, alkenes, electron rich (hetero)arenes and polyaromatic hydrocarbons, illustrate the synthetic potential of this reagent. Importantly, Lewis acid activation of the reagent is not required for the transfer process. We additionally report herein biomimetic cyanocyclization cascade reactions, which are not promoted by typical electrophilic cyanation reagents, demonstrating the superior ability of 9 to trigger challenging transformations.
- Li, Xiangdong,Golz, Christopher,Alcarazo, Manuel
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supporting information
p. 9496 - 9500
(2019/06/27)
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- Novel Myocyte Enhancer Factor 2 (MEF2) modulators
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The present disclosure provides novel compounds capable of functioning as Myoctye Enhancer Factor 2 (MEF2) modulators, as well as compositions, pharmaceutical formulations, methods of synthesis and kits. Also provided are methods of treating a condition regulatable by MEF2 and/or MEF2 cofactors using the compounds, compositions, pharmaceutical formulations, and kits provided herein.
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Paragraph 0238; 0241-0242
(2019/08/20)
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- Panobinostat intermediate as well as synthesis and application thereof
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The invention belongs to the field of medicine synthesis and in particular relates to a panobinostat intermediate as well as synthesis and application thereof. The intermediate is shown as a formula II and is obtained by taking 2-methyltryptamine and 4-chloromethylbenzaldehyde to react; raw materials are cheap and easy to obtain, reaction conditions are moderate and the operation is simple; the intermediate is used as a raw material to prepare panobinostat, the cost is low, reaction steps are few, the purity is high, the reaction conditions are moderate and the operation is simple; the qualitycontrol and cost reduction of panobinostat crude drugs are facilitated. (The formula II is shown in the description.).
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Paragraph 0043-0045
(2018/12/02)
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- A handkerchief compared to department he and its key intermediate for the preparation of (by machine translation)
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The invention belongs to the field of drug synthesis, in particular to a handkerchief compared to department he and its key intermediate of the preparation method, the method to cheap 4 - halogenated methyl formaldehyde, 2 - a primary amine and phosphine acyl acetic acid methyl ester compound as raw material, in the same pot obtain key intermediate (E)- 3 - [4 - [[2 - (2 - methyl - 1 H - indole - 3 - 3 yl) ethylamine] methyl] phenyl] acrylic acid methyl ester, obtained by the reaction with hydroxylamine handkerchief compared to department he, the method not only raw materials are cheap and easily obtained, and the cost is low, and there are few reaction steps, high yield and purity, mild reaction conditions at the same time, the operation is simple, is easy for industrial production. (by machine translation)
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Paragraph 0027-0029
(2018/11/22)
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- PROCESS FOR THE PREPARATION OF 2-(E)-N-HYDROXY-3-[4-[[[2-(2-METHYL-1H-INDOL-3-YL) ETHYL]AMINO]METHYL]PHENYL]-2-PROPENAMIDE 2-HYDROXYPROPANOIC ACID (1:1) AND ITS POLYMORPHS THEREOF
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The present invention relates to novel amorphous and crystalline forms of 2-(E)-N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide and its lactate salt and also its process for the preparation thereof. (1a)
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Page/Page column 28
(2018/06/06)
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- Synthesis method of panobinostat
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The invention discloses a synthesis method of panobinostat. The synthesis method comprises a step of synthesizing 2-methyl tryptamine or hydrochloride thereof, namely taking 2-methylindole as a raw material, conducting reaction with chloroacetyl chloride or bromoacetyl bromide, and conducting reaction with potassium phthalimide to obtain the 2-methyl tryptamine. According to the technical scheme adopted by the invention, influence of toxic raw materials on the safety of a panobinostat product is avoided; meanwhile, the invention provides the synthesis method applicable to industrial production.
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Paragraph 0068; 0069; 0070
(2017/08/29)
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- An environmentally friendly protocol for oxidative halocyclization of tryptamine and tryptophol derivatives
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An environmentally friendly and efficient protocol (KX/oxone) for oxidative halocyclization of tryptamine/tryptophol derivatives was developed and demonstrated with 28 examples and concise total synthesis of cyclotryptamine alkaloid protubonines A and B. The distinct advantage of this protocol over all previous methods is that no organic byproduct is generated from a halogenating agent or oxidant, thus greatly reducing the environmental impact of halocyclization and facilitating the post-reaction purification.
- Xu, Jun,Tong, Rongbiao
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supporting information
p. 2952 - 2956
(2017/07/24)
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- Asymmetric fluorinative dearomatization of tryptamine derivatives
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An asymmetric fluorinative dearomatization reaction of tryptamine derivatives was developed by using a chiral anion phase transfer catalyst (PTC) system, and the preliminary results of the reaction mechanistic study were achieved. This method is characterized by a simple operation, facile introduction of a fluorine atom in a highly enantioselective manner and construction of two contiguous quaternary stereogenic centers.
- Liang, Xiao-Wei,Liu, Chuan,Zhang, Wei,You, Shu-Li
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supporting information
p. 5531 - 5534
(2017/07/07)
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- Iridium-catalyzed direct synthesis of tryptamine derivatives from indoles: Exploiting N-protected β-amino alcohols as alkylating agents
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The selective C3-alkylation of indoles with N-protected ethanolamines involving the "borrowing hydrogen" strategy is described. This method provides convenient and sustainable access to several tryptamine derivatives.
- Bartolucci, Silvia,Mari, Michele,Bedini, Annalida,Piersanti, Giovanni,Spadoni, Gilberto
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p. 3217 - 3222
(2015/03/30)
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- Asymmetric dearomatization of indoles through a Michael/Friedel-Crafts-Type cascade to construct polycyclic spiroindolines
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A highly efficient asymmetric dearomatization of indoles was realized through a cascade reaction between 2-isocyanoethylindole and alkylidene malonates catalyzed by a chiral N,N-dioxide/MgII catalyst. Fused polycyclic indolines containing three stereocenters were afforded in good yields with excellent diastereo- and enantioselectivities through a Michael/Friedel-Crafts/Mannich cascade. When 2-substituted 2-isocyanoethylindoles were used, spiroindoline derivatives were obtained through a Michael/Friedel-Crafts reaction.
- Zhao, Xiaohu,Liu, Xiaohua,Mei, Hongjiang,Guo, Jing,Lin, Lili,Feng, Xiaoming
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supporting information
p. 4032 - 4035
(2015/03/30)
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- The rearrangement of cyclopropylketone arylhydrazones. Synthesis of tryptamines and tetrahydropyridazines
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The cyclopropyliminium rearrangement of cyclopropylketone arylhydrazones may result in two possible products. The first one forms via cyclopropane ring-opening and ring-closure to give six-membered tetrahydropyridazines. The second is formed via ring-closure resulting in a five-membered ring and subsequent Grandberg rearrangement into a tryptamine. The product ratio depends on the nature of the starting hydrazones.
- Salikov, Rinat F.,Belyy, Aleksandr Yu.,Tomilov, Yury V.
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p. 5936 - 5939
(2015/01/08)
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- Rapid access to spirocyclized indolenines via palladium-catalyzed cascade reactions of tryptamine derivatives and propargyl carbonate
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We report the intermolecular palladium-catalyzed reaction of tert-butyl propargyl carbonate with tryptamine derivatives or other indole-containing bis-nucleophiles. The reaction proceeds under mild conditions and with low catalyst loadings to afford novel spiroindolenine products in good to high yields.
- Montgomery, Thomas D.,Nibbs, Antoinette E.,Zhu, Ye,Rawal, Viresh H.
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supporting information
p. 3480 - 3483
(2014/07/21)
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- Synthesis of tryptamine derivatives via a direct, one-pot reductive alkylation of indoles
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An efficient, one-pot reductive alkylation of indoles with N-protected aminoethyl acetals in the presence of TES/TFA is reported. It represents the first general method for the direct synthesis of tryptamine derivatives from indoles and nitrogen-functionalized acetals. This convergent and versatile approach employs safe and inexpensive reagents, proceeds under mild conditions, and tolerates several functional groups. The new procedure was efficiently applied to a gram-scale synthesis of both luzindole, a reference MT2-selective melatonin receptor antagonist, and melatonin.
- Righi, Marika,Topi, Francesca,Bartolucci, Silvia,Bedini, Annalida,Piersanti, Giovanni,Spadoni, Gilberto
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experimental part
p. 6351 - 6357
(2012/10/08)
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- Structural Characterization and Computer-Aided Optimization of a Small-Molecule Inhibitor of the Arp2/3 Complex, a Key Regulator of the Actin Cytoskeleton
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CK-666 (1) is a recently discovered small-molecule inhibitor of the actin-related protein 2/3 (Arp2/3) complex, a key actin cytoskeleton regulator with roles in bacterial pathogenesis and cancer cell motility. Although 1 is commercially available, the crystal structure of Arp2/3 complex with 1 bound has not been reported, making its mechanism of action uncertain. Furthermore, its relatively low potency increases its potential for off-target effects invivo, complicating interpretation of its influence in cell biological studies and precluding its clinical use. Herein we report the crystal structure of 1 bound to Arp2/3 complex, which reveals that 1 binds between the Arp2 and Arp3 subunits to stabilize the inactive conformation of the complex. Based on the crystal structure, we used computational docking and free-energy perturbation calculations of monosubstituted derivatives of 1 to guide optimization efforts. Biochemical assays of ten newly synthesized compounds led to the identification of compound 2, which exhibits a threefold increase in inhibitory activity invitro relative to 1. In addition, our computational analyses unveiled a surface groove at the interface of the Arp2 and Arp3 subunits that can be exploited for additional structure-based optimization.
- Baggett, Andrew W.,Cournia, Zoe,Han, Min Suk,Patargias, George,Glass, Adam C.,Liu, Shih-Yuan,Nolen, Brad J.
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scheme or table
p. 1286 - 1294
(2012/07/17)
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- Discovery of (2 E)-3-{2-butyl-1-[2-(diethylamino)ethyl]-1H-benzimidazol-5- yl}-N-hydroxyacrylamide (SB939), an orally active histone deacetylase inhibitor with a superior preclinical profile
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A series of 3-(1,2-disubstituted-1H-benzimidazol-5-yl)-N-hydroxyacrylamides (1) were designed and synthesized as HDAC inhibitors. Extensive SARs have been established for in vitro potency (HDAC1 enzyme and COLO 205 cellular IC 50), liver microsomal stability (t1/2), cytochrome P450 inhibitory (3A4 IC50), and clogP, among others. These parameters were fine-tuned by carefully adjusting the substituents at positions 1 and 2 of the benzimidazole ring. After comprehensive in vitro and in vivo profiling of the selected compounds, SB939 (3) was identified as a preclinical development candidate. 3 is a potent pan-HDAC inhibitor with excellent druglike properties, is highly efficacious in in vivo tumor models (HCT-116, PC-3, A2780, MV4-11, Ramos), and has high and dose-proportional oral exposures and very good ADME, safety, and pharmaceutical properties. When orally dosed to tumor-bearing mice, 3 is enriched in tumor tissue which may contribute to its potent antitumor activity and prolonged duration of action. 3 is currently being tested in phase I and phase II clinical trials.
- Wang, Haishan,Yu, Niefang,Chen, Dizhong,Lee, Ken Chi Lik,Lye, Pek Ling,Chang, Joyce Wei Wei,Deng, Weiping,Ng, Melvin Chi Yeh,Lu, Ting,Khoo, Mui Ling,Poulsen, Anders,Sangthongpitag, Kanda,Wu, Xiaofeng,Hu, Changyong,Goh, Kee Chuan,Wang, Xukun,Fang, Lijuan,Goh, Kay Lin,Khng, Hwee Hoon,Goh, Siok Kun,Yeo, Pauline,Liu, Xin,Bonday, Zahid,Wood, Jeanette M.,Dymock, Brian W.,Kantharaj, Ethirajulu,Sun, Eric T.
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supporting information; scheme or table
p. 4694 - 4720
(2011/09/15)
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- PROCESS FOR MAKING N-HYDROXY-3-[4-[[[2-(2-METHYL-1H-INDOL-3-YL)ETHYL]AMINO]METHYL]PHENYL]-2E-2-PROPENAMIDE AND STARTING MATERIALS THEREFOR
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N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide and starting materials therefor are prepared by new synthetic methods.
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Page/Page column 6
(2009/12/24)
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- PROCESS FOR MAKING SALTS OF N-HYDROXY-3-[4-[[[2-(2-METHYL-1H-INDOL-3-YL)ETHYL]AMINO]METHYL]PHENYL]-2E-2-PROPENAMIDE
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Salts of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide are prepared by various methods.
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Page/Page column 13-14
(2009/07/25)
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- Scale-up of microwave-promoted reactions to the multigram level using a sealed-vessel microwave apparatus
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A range of synthetic transformations have been scaled up successfully using a sealed-vessel multimode microwave unit. These include metal-catalyzed couplings, synthesis of heterocycles, reactions under an atmosphere of reactive gas and two-step one-pot procedures. Also, observations have been made along the way that are of use to chemists addressing scale-up of microwave-promoted reactions.
- Bowman, Matthew D.,Schmink, Jason R.,McGowan, Cynthia M.,Kormos, Chad M.,Leadbeater, Nicholas E.
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p. 1078 - 1088
(2013/01/03)
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- METHOD OF USE OF DEACETYLASE INHIBITORS
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The present invention provides methods of treating and/or preventing pathologic cardiac hypertrophy and heart failure comprising administering hydroxamate compounds which are deacetylase inhibitors.
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Page/Page column 25-26
(2008/06/13)
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- Novel and potent human and rat β3-adrenergic receptor agonists containing substituted 3-indolylalkylamines
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A novel series of 2-(3-indolyl)alkylamino-1-(3-chlorophenyl)ethanols was prepared and evaluated for in vitro ability to stimulate cAMP production in Chinese hamster ovary cells expressing cloned human β3-AR. The optically active 30a was found to be the most potent and selective human β3-AR agonist in this series with an EC50 value of 0.062 nM. In addition, 30a selectivity for human β3-AR was 210-fold and 103-fold that for human β2-AR and β1-AR, respectively. Furthermore, 30a showed potent agonistic activity at rat β3-AR.
- Harada, Hiroshi,Hirokawa, Yoshimi,Suzuki, Kenji,Hiyama, Yoichi,Oue, Mayumi,Kawashima, Hitoshi,Yoshida, Naoyuki,Furutani, Yasuji,Kato, Shiro
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p. 1301 - 1305
(2007/10/03)
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- A versatile linkage strategy for solid-phase synthesis of N,N-dimethyltryptamines and β-carbolines
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(matrix presented) Various tryptamines are captured by a vinylsulfonylmethyl polystyrene resin, generating a safety-catch linkage. β-Carbolines can be formed from 4 by a Pictet-Spengler reaction with the introduction of R1. Tryptamine 4 can also be derivatized by acylation or copper-mediated coupling to introduce R2. If X = Br, Suzuki coupling can be used to introduce R3. After derivatization, the indole derivatives are activated with methyl iodide and released under mild basic condition.
- Wu, Tom Y. H.,Schulte, Peter G.
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p. 4033 - 4035
(2007/10/03)
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- 48. Diastereoselective Spirocyclization of C-(Alkyloxycarbonyl)formimines of 2-Substituted 1H-Indole-3-ethanamines (= Tryptamines): Basic Studies
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C-(Alkoxycarbonyl)formimines of type 15-18 were derived from the 2-substituted tryptamines 2, 9, 10, and 11 and transformed with tosyl chloride into tricyclic 3-spiroindoles of types 19-22 (Scheme 3).The influence of the homochiral alkoxy moieties A-D on the stereochemical outcome of this reaction was studied.Good-to-excellent diastereoselectivities were observed with the (-)-8-(phenylmenth-3-yl)oxy group (B) as homochiral auxiliary.The structures of the tricycles 4, (2'R,3S)-19B, and (2'S,3R)-20C were established by X-ray analysis, the structures of the others by NOE and CD studies, and by chemical correlation.Possibilities to explain the steric course of the spirocyclizations are discussed.
- Freund, Ralf,Mahboobi, Siavosh,Noack, Klaus,Schoenholzer, Peter,Bernauer, Karl
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p. 439 - 454
(2007/10/02)
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- Intermolecular trapping by indole of a spiroindolenine intermediate formed during the Bischler-Napieralski cyclisation of N-acetyltryptamine
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The Bischler-Napieralski cyclisation of N-acetyltryptamine (1a) in the presence of indole (15) affords a moderate yield of the diastereomeric spiroindolines 9 and 10 suggesting the intermediacy of a spiroindolenine 2a in this reaction. Evidence is provided to show that the minor reaction products 2-methyltryptamine (11), tris-(3-indolyl)methane (12) and 6-[(o-aminophenyl) methyl]-5,11-dihydroindolo[3,2-b]carbazole (13) are derived from the spiroindolines 9 and 10.
- Frost, Jonathan R.,Gaudilliere, Bernard R.P.,Kauffmann, Elisabeth,Loyaux, Denis,Normand, Nadine,Petry, Genevieve,Poirier, Philippe,Wenkert, Ernest,Wick, Alexander E.
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p. 175 - 182
(2007/10/02)
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