144644-00-8Relevant articles and documents
Structure-Based Design of Inhibitors Selective for Human Proteasome β2c or β2i Subunits
Xin, Bo-Tao,Huber, Eva M.,De Bruin, Gerjan,Heinemeyer, Wolfgang,Maurits, Elmer,Espinal, Christofer,Du, Yimeng,Janssens, Marissa,Weyburne, Emily S.,Kisselev, Alexei F.,Florea, Bogdan I.,Driessen, Christoph,Van Der Marel, Gijsbert A.,Groll, Michael,Overkleeft, Herman S.
supporting information, p. 1626 - 1642 (2019/02/19)
Subunit-selective proteasome inhibitors are valuable tools to assess the biological and medicinal relevance of individual proteasome active sites. Whereas the inhibitors for the β1c, β1i, β5c, and β5i subunits exploit the differences in the substrate-binding channels identified by X-ray crystallography, compounds selectively targeting β2c or β2i could not yet be rationally designed because of the high structural similarity of these two subunits. Here, we report the development, chemical synthesis, and biological screening of a compound library that led to the identification of the β2c- and β2i-selective compounds LU-002c (4; IC50 β2c: 8 nM, IC50 β2i/β2c: 40-fold) and LU-002i (5; IC50 β2i: 220 nM, IC50 β2c/β2i: 45-fold), respectively. Co-crystal structures with β2 humanized yeast proteasomes visualize protein-ligand interactions crucial for subunit specificity. Altogether, organic syntheses, activity-based protein profiling, yeast mutagenesis, and structural biology allowed us to decipher significant differences of β2 substrate-binding channels and to complete the set of subunit-selective proteasome inhibitors.
A new type of chiral-pyridoxamines for catalytic asymmetric transamination of α-keto acids
Chen, Jianfeng,Zhao, Junyu,Gong, Xing,Xu, Dongfang,Zhao, Baoguo
supporting information, p. 4612 - 4615 (2016/09/23)
A new type of chiral pyridoxamines bearing an adjacent chiral stereocenter has been developed via multi-step synthesis. The pyridoxamines displayed catalytic activity in asymmetric transamination of α-keto acids to give a variety of optically active amino acids in 27–78% yields with 34–62% ee's under very mild conditions. This work provides a synthetic strategy to construct new chiral pyridoxamines using bromopyridine 7 as a key synthon and also represents an early example of the applications of chiral pyridoxamines in asymmetric catalysis.
Structure-guided design and optimization of dipeptidyl inhibitors of norovirus 3CL protease. Structure-activity relationships and biochemical, X-ray crystallographic, cell-based, and in vivo studies
Galasiti Kankanamalage, Anushka C.,Kim, Yunjeong,Weerawarna, Pathum M.,Uy, Roxanne Adeline Z.,Damalanka, Vishnu C.,Mandadapu, Sivakoteswara Rao,Alliston, Kevin R.,Mehzabeen, Nurjahan,Battaile, Kevin P.,Lovell, Scott,Chang, Kyeong-Ok,Groutas, William C.
, p. 3144 - 3155 (2015/04/27)
Norovirus infection constitutes the primary cause of acute viral gastroenteritis. There are currently no vaccines or norovirus-specific antiviral therapeutics available for the management of norovirus infection. Norovirus 3C-like protease is essential for viral replication, consequently, inhibition of this enzyme is a fruitful avenue of investigation that may lead to the emergence of antinorovirus therapeutics. We describe herein the optimization of dipeptidyl inhibitors of norovirus 3C-like protease using iterative SAR, X-ray crystallographic, and enzyme and cell-based studies. We also demonstrate herein in vivo efficacy of an inhibitor using the murine model of norovirus infection.
Aromatic Interactions in Organocatalyst Design: Augmenting Selectivity Reversal in Iminium Ion Activation
Holland, Mareike C.,Metternich, Jan Benedikt,Daniliuc, Constantin,Schweizer, W. Bernd,Gilmour, Ryan
supporting information, p. 10031 - 10038 (2015/07/07)
Substituting N-methylpyrrole for N-methyindole in secondary-amine-catalysed Friedel-Crafts reactions leads to a curious erosion of enantioselectivity. In extreme cases, this substrate dependence can lead to an inversion in the sense of enantioinduction. Indeed, these closely similar transformations require two structurally distinct catalysts to obtain comparable selectivities. Herein a focussed molecular editing study is disclosed to illuminate the structural features responsible for this disparity, and thus identify lead catalyst structures to further exploit this selectivity reversal. Key to effective catalyst re-engineering was delineating the non-covalent interactions that manifest themselves in conformation. Herein we disclose preliminary validation that intermolecular aromatic (CH-π and cation-π) interactions between the incipient iminium cation and the indole ring system is key to rationalising selectivity reversal. This is absent in the N-methylpyrrole alkylation, thus forming the basis of two competing enantio-induction pathways. A simple L-valine catalyst has been developed that significantly augments this interaction.
Design, synthesis, and SAR of a series of activated protein C (APC) inhibitors with selectivity against thrombin for the treatment of haemophilia
Bach, Peter,Knerr, Laurent,Fjellstr?m, Ola,Hansson, Kenny,Mattsson, Christer,Gustafsson, David
, p. 821 - 827 (2014/02/14)
A design strategy was used to identify inhibitors of activated protein C with selectivity over thrombin featured by a basic and/or aromatic functionality for binding to the S2 pocket. Our strongest inhibitor showed an IC 50-material value and selectivity for APC vs thrombin similar to a compound previously reported in the literature. However, in contrast to the reference compound, our compound showed a retained coagulant effect of thrombin with increasing substrate concentration in a modified Calibrated Automated Thrombogram (CAT) method. This was likely related to our compound being inactive against FVIIa, while the reference compound showed an IC50 of 8.9 μM. Thus, the higher selectivity of our compound against all relevant coagulation factors likely explained its higher therapeutic potential in comparison to the reference compound. The data indicate that at least a 100-fold selectivity over other serine proteases in the coagulation cascade will be required for an effective APC inhibitor.
Asymmetric fluorination of α-branched cyclohexanones enabled by a combination of chiral anion phase-transfer catalysis and enamine catalysis using protected amino acids
Yang, Xiaoyu,Phipps, Robert J.,Toste, F. Dean
supporting information, p. 5225 - 5228 (2014/05/06)
We report a study involving the successful merger of two separate chiral catalytic cycles: a chiral anion phase-transfer catalysis cycle to activate Selectfluor and an enamine activation cycle, using a protected amino acid as organocatalyst. We have demonstrated the viability of this approach with the direct asymmetric fluorination of α-substituted cyclohexanones to generate quaternary fluorine-containing stereocenters. With these two chiral catalytic cycles operating together in a matched sense, high enantioselectivites can be achieved, and we envisage that this dual catalysis method has the potential to be more broadly applicable, given the breadth of enamine catalysis. It also represents a rare example of chiral enamine catalysis operating successfully on α-branched ketones, substrates commonly inert to this activation mode.
Substituted 2-hydroxy-N-(arylalkyl)benzamides induce apoptosis in cancer cell lines
Imramovsky, Ale?,Jorda, Radek,Pauk, Karel,?ezní?ková, Eva,Du?ek, Jan,Hanusek, Ji?í,Kry?tof, Vladimír
supporting information, p. 253 - 259 (2013/10/01)
Variously substituted 2-hydroxy-N-(arylalkyl)benzamides were prepared and screened for antiproliferative and cytotoxic activity in cancer cell lines in vitro. Five compounds, out of 33 showed single-digit micromolar IC50 values against several human cancer cell lines. One of the most potent compounds N-((R)-1-(4-chlorophenylcarbamoyl)-2-phenylethyl)-5-chloro-2-hydroxybenzamide (6k) reduced proliferation and induced apoptosis in the melanoma cell line G361 in a dose-dependent manner, as shown by decrease in 5-bromo-2′- deoxyuridine incorporation and increase in several apoptotic markers, including subdiploid population increase, activation of caspases and site-specific poly-(ADP-ribose)polymerase (PARP) cleavage.
AMINO-ETHYL-AMINO-ARYL (AEAA) COMPOUNDS AND THEIR USE
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Page/Page column 142, (2009/10/06)
The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain amino-ethyl-amino-aryl (AEAA) compounds which, inter alia, inhibit protein kinase D (PKD) (e.g., PKD1, PKD2, PKD3). The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit PKD, and in the treatment of diseases and conditions that are mediated by PKD, that are ameliorated by the inhibition of PKD, etc., including proliferative conditions such as cancer, etc.
Rhodium/graphite-catalyzed hydrogenation of carbocyclic and heterocyclic aromatic compounds
Falini, Giuseppe,Gualandi, Andrea,Savoia, Diego
experimental part, p. 2440 - 2446 (2010/02/27)
Rhodium on graphite (Rh/Gr, C24Rh) was prepared by reaction of anhydrous rhodium trichloride with potassium graphite (C8K, 3 equivalents) and used as a heterogeneous catalyst for the hydrogenation of carbocyclic and heterocyclic aromatic compounds at room temperature and 1 atm of hydrogen pressure. The effect of substitution on the benzene ring was examined in a variety of derivatives, including those with alkyl, hydroxy, alkoxy, aryloxy, carboxy, amino, nitro, acyl, chloro, or functionalized alkyl groups. Reduction of carbonyl functions of aromatic aldehydes and ketones occurred with complete or partial cleavage of the benzylic C-O bond; this cleavage also occurred in the hydrogenation of benzylic alcohols and esters. Georg Thieme Verlag Stuttgart.
Direct platination as a route to conformationally restricted enantiopure C2-symmetric bisoxazoline pincer complexes
Fossey, John S.,Jones, Geraint,Motevalli, Majid,Nguyen, Huy V.,Richards, Christopher J.,Stark, Mark A.,Taylor, Helen V.
, p. 2067 - 2073 (2007/10/03)
(S)-3-Amino-4-cyclohexyl-2-methylbutan-2-ol 10 was synthesised in four-steps from (S)-2-amino-3-cyclohexanepropanoic acid (47% overall yield). Reaction of 10 with 1,3-bis(ethyl carboximidate)benzene gave (S,S)-1,3-bis(4′-cyclohexylmethyl-5
