144073-15-4Relevant articles and documents
Non-Natural Linker Configuration in 2,6-Dipeptidyl-Anthraquinones Enhances the Inhibition of TAR RNA Binding/Annealing Activities by HIV-1 NC and Tat Proteins
Sosic, Alice,Saccone, Irene,Carraro, Caterina,Kenderdine, Thomas,Gamba, Elia,Caliendo, Giuseppe,Corvino, Angela,Di Vaio, Paola,Fiorino, Ferdinando,Magli, Elisa,Perissutti, Elisa,Santagada, Vincenzo,Severino, Beatrice,Spada, Valentina,Fabris, Dan,Frecentese, Francesco,Gatto, Barbara
, p. 2195 - 2207 (2018)
The HIV-1 nucleocapsid (NC) protein represents an excellent molecular target for the development of anti-retrovirals by virtue of its well-characterized chaperone activities, which play pivotal roles in essential steps of the viral life cycle. Our ongoing search for candidates able to impair NC binding/annealing activities led to the identification of peptidyl-anthraquinones as a promising class of nucleic acid ligands. Seeking to elucidate the inhibition determinants and increase the potency of this class of compounds, we have now explored the effects of chirality in the linker connecting the planar nucleus to the basic side chains. We show here that the non-natural linker configuration imparted unexpected TAR RNA targeting properties to the 2,6-peptidyl-anthraquinones and significantly enhanced their potency. Even if the new compounds were able to interact directly with the NC protein, they manifested a consistently higher affinity for the TAR RNA substrate and their TAR-binding properties mirrored their ability to interfere with NC-TAR interactions. Based on these findings, we propose that the viral Tat protein, sharing the same RNA substrate but acting in distinct phases of the viral life cycle, constitutes an additional druggable target for this class of peptidyl-anthraquinones. The inhibition of Tat-TAR interaction for the test compounds correlated again with their TAR-binding properties, while simultaneously failing to demonstrate any direct Tat-binding capabilities. These considerations highlighted the importance of TAR RNA in the elucidation of their inhibition mechanism, rather than direct protein inhibition. We have therefore identified anti-TAR compounds with dual in vitro inhibitory activity on different viral proteins, demonstrating that it is possible to develop multitarget compounds capable of interfering with processes mediated by the interactions of this essential RNA domain of HIV-1 genome with NC and Tat proteins.
Organic Nanotube with Subnanometer, pH-Responsive Lumen
Darnall, Shawn M.,Li, Changyi,Dunbar, Martha,Alsina, Marco,Keten, Sinan,Helms, Brett A.,Xu, Ting
, p. 10953 - 10957 (2019)
While many synthetic nanotubes with a hydrophobic lumen and fast molecular transport have been developed, decorating the interior of these channels with polar and/or responsive functional groups remains challenging. In transmembrane proteins like the aqua
Improved Scale-up Synthesis and Purification of Clinical Asthma Candidate MIDD0301
Arnold, Leggy A.,Cook, James M.,Knutson, Daniel E.,Mian, Md Yeunus,Roni, M. S. Rashid,Stafford, Douglas C.
, p. 1467 - 1476 (2020/11/23)
We report an improved and scalable synthesis of MIDD0301, a positive GABAA receptor modulator that is under development as oral and inhaled treatments for asthma. In contrast to other benzodiazepines in clinical use, MIDD0301 is a chiral compound that has limited brain absorption. The starting material to generate MIDD0301 is 2-amino-5-bromo-2′-fluorobenzophenone, which has a nonbasic nitrogen due to electron-withdrawing substituents in the ortho and para positions, reducing its reactivity toward activated carboxylic acids. Investigations of peptide coupling reagents on a multigram scale resulted in moderate yields due to incomplete conversions. Second, the basic conditions used for the formation of the seven-membered 1,4-diazepine ring resulted in racemization of the chiral center. We found that neutral conditions comparable to the pKa of the primary amine were sufficient to support the formation of the intramolecular imine but did not enable the simultaneous removal of the protecting group. Both difficulties were overcome with the application of the N-carboxyanhydride of d-alanine. Activated in the presence of an acid, this compound reacted with nonbasic 2-amino-5-bromo-2′-fluorobenzophenone and formed the 1,4-diazepine upon neutralization with triethylamine. Carefully designed workup procedures and divergent solubility of the synthesic intermediates in solvents and solvent combinations were utilized to eliminate the need for column chromatography. To improve compatibility with large-scale reactors, temperature-controlled slow addition of reagents generated the imidazodiazepine at -20 °C. All intermediates were isolated with a purity of >97% and impurities were identified and quantified. After the final hydrolysis step, MIDD0301 was isolated in a 44% overall yield and a purity of 98.9% after recrystallization. The enantiomeric excess was greater than 99.0%.
ESTROGEN RECEPTOR MODULATORS
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Paragraph 0215, (2017/11/04)
Compounds of Formula (I) are estrogen receptor alpha modulators, where the variables in Formula (I) are described in the disclosure. Such compounds, as well as pharmaceutically acceptable salts and compositions thereof, are useful for treating diseases or conditions that are estrogen receptor alpha dependent and/or estrogen receptor alpha mediated, including conditions characterized by excessive cellular proliferation, such as breast cancer.
Homochiral versus Heterochiral Trifluoromethylated Pseudoproline Containing Dipeptides: A Powerful Tool to Switch the Prolyl-Amide Bond Conformation
Chaume, Grégory,Simon, Julien,Lensen, Nathalie,Pytkowicz, Julien,Brigaud, Thierry,Miclet, Emeric
, p. 13602 - 13608 (2017/12/26)
The design of constrained peptides is of prime importance in the development of bioactive compounds and for applications in supramolecular chemistry. Due to its nature, the peptide bond undergoes a spontaneous cis-trans isomerism, and the cis isomers are much more difficult to stabilize than the trans forms. By using oxazolidine-based pseudoprolines (ψPro) substituted by a trifluoromethyl group, we show that the cis peptide bond can be readily switched from 0% to 100% in Xaa-ψPro dipeptides. Our results prove that changing the configuration of the Cα in Xaa or in ψPro is sufficient to invert the cis:trans populations while changing the nature of the Xaa side chain finely tuned the conformers ratio. Moreover, a strong correlation is found between the puckering of the oxazolidine ring and the peptide bond conformation. This finding highlights the role of the trifluoromethyl group in the stabilization of the peptide bond geometry. We anticipate that such templates will be very useful to constrain the backbone geometry of longer peptides.
Incorporation of CF3-pseudoprolines into peptides: A methodological study
Chaume, Gregory,Simon, Julien,Caupene, Caroline,Lensen, Nathalie,Miclet, Emeric,Brigaud, Thierry
, p. 10144 - 10153 (2013/11/06)
The peptide coupling reactions allowing the incorporation of trifluoromethyl substituted oxazolidine-type pseudoprolines (CF 3-ΨPro) into peptide chains have been studied. While standard protocols can be used for the peptide coupling reaction at the C-terminal position of the CF3-ΨPro, acid chloride activation has to be used for the peptide coupling reaction at the N-terminal position to overcome the decrease of nucleophilicity of the CF3-ΨPro. We demonstrate that the N-amidification of a diastereomeric mixture of CF3-ΨPro using Fmoc-protected amino acid chloride without base gave the corresponding dipeptides as a single diastereomer (6 examples). The ratio of the cis and trans amide bond conformers was determined by NMR study, highlighting the role of the Xaa side chains in the control of the peptide backbone conformation. Finally a tripeptide bearing a central CF3-ΨPro has been successfully synthesized.
Design, synthesis and preliminary biological evaluation of new hydroxamate histone deacetylase inhibitors as potential antileukemic agents
Guandalini,Cellai,Laurenzana,Scapecchi,Paoletti,Romanelli
supporting information; experimental part, p. 5071 - 5074 (2009/05/30)
This study concerns the synthesis of new histone deacetylase inhibitors (HDACi) characterized by a 1,4-benzodiazepine ring used as the cap, joined through an amide function or a triple bond as connection units, to a linear alkyl chain bearing the hydroxamate function as Zn2+-chelating group. Biological tests performed in human acute promyelocytic leukemia NB4 cells showed that new hybrids can induce histone H3/H4 acetylation, growth arrest, and also apoptosis. Notably, chiral compounds exhibit stereoselective activity.
Total synthesis of cyclosporin O by convergent approach employing Fmoc-amino acid chlorides mediated by zinc dust
Tantry, Subramanyam J.,Venkataramanarao, Rao,Chennakrishnareddy, Gundala,Sureshbabu, Vommina Venkata
, p. 9360 - 9363 (2008/03/14)
(Chemical Equation Presented) An epimerization free and efficient total synthesis of immunosuppressant cyclosporin O (CsO) by step-by-step assembly of amino acids in solution phase is reported. The couplings were performed by employing Fmoc-amino acid chl
Process development of a scaleable route to (2R)-[3-(2-Aminopropyl)-1H- indol-7-yloxy]-N,N-diethylacetamide: A key intermediate for AJ-9677, a potent and selective human and rat β3-adrenergic receptor agonist
Harada, Hiroshi,Fujii, Akihito,Odai, Osamu,Kato, Shiro
, p. 238 - 245 (2013/09/04)
(2R)-[3-(2-Aminopropyl)-1H-indol-7-yloxy]acetic acid (2) is the left-hand side segment of AJ-9677, which is a potent and selective human and rat β3-adrenergic receptor agonist. Herein, we describe the process development of a scaleable synthetic route to the corresponding N,N-diethylacetamide derivative 3 of 2 from 7-benzyloxy-1H-indole (4). Reaction of the indole Grignard reagent 12 generated from 4 and methylmagnesium bromide with the N-Fmoc-D-alanyl chloride 22, followed by reduction of the resulting crude 3-acylindole 26 with NaBH4 in a mixture of MeCN and 2-PrOH at refluxing temperature and subsequent treatment with oxalic acid gave the oxalate of the N-deprotected product, (2R)-3-(2-aminopropyl)-7-benzyloxy-1H- indole [(R)-7] as a crystalline material in 60% yield. After N-protection of the (R)-7 by Boc group, the (2R)-3-[2-(Boc-amino)propyl]-1H-indole 30 was hydrogenated to provide the (2R)-3-(2-aminopropyl)-7-hydroxy-1H-indole 31, which was subsequently alkylated with ClCH2CONEt2 to give 32 in 91% yield. Finally, treatment of 32 with oxalic acid afforded the desired 3 in 79% in >99% ee.
