2731-06-8Relevant academic research and scientific papers
Optimization and scale-up of the Grandberg synthesis of 2-methyltryptamine
Slade, Joel,Parker, David,Girgis, Michael,Wu, Raeann,Joseph, Scott,Repic, Oljan
, p. 721 - 725 (2007)
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.
An improved and efficient synthesis of panobinostat
Chen, Shanwen,Zhang, Peiming,Chen, Huali,Zhang, Pu,Yu, Yu,Gan, Zongjie
, p. 471 - 473 (2018)
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.
Development and pre-clinical testing of a novel hypoxia-activated KDAC inhibitor
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.
, p. 1258 - 13,1270 (2021/09/16)
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.
Design of Hydrazide-Bearing HDACIs Based on Panobinostat and Their p53 and FLT3-ITD Dependency in Antileukemia Activity
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
, p. 5501 - 5525 (2020/06/10)
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.
5-(Cyano)dibenzothiophenium Triflate: A Sulfur-Based Reagent for Electrophilic Cyanation and Cyanocyclizations
Li, Xiangdong,Golz, Christopher,Alcarazo, Manuel
supporting information, p. 9496 - 9500 (2019/06/27)
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.
Novel Myocyte Enhancer Factor 2 (MEF2) modulators
-
Paragraph 0238; 0241-0242, (2019/08/20)
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.
Facile in Vitro Biocatalytic Production of Diverse Tryptamines
McDonald, Allwin D.,Perkins, Lydia J.,Buller, Andrew R.
, p. 1939 - 1944 (2019/07/08)
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.
Panobinostat intermediate as well as synthesis and application thereof
-
Paragraph 0043-0045, (2018/12/02)
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.).
A handkerchief compared to department he and its key intermediate for the preparation of (by machine translation)
-
Paragraph 0027-0029, (2018/11/22)
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)
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
-
Page/Page column 28, (2018/06/06)
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)
