- Discovery of a novel dipeptidyl boronic acid proteasome inhibitor for the treatment of multiple myeloma and triple-negative breast cancer
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A series of novel dipeptidyl boronic acid compounds were designed, synthesized and biologically investigated for the inhibition of the β5 subunit of 20S proteasome and several compounds showed high activities with IC50 values of less than 10 nM. Some of these compounds potently inhibited the multiple myeloma (MM) cancer cell lines with IC50 values of less than 10 nM. It was reported that the inhibition of both β2 and β5 subunits strongly increased the cytotoxicity of proteasome inhibitors in solid tumor cells, so some of the compounds were evaluated for the inhibition of the β2 subunit and the solid tumor triple-negative breast cancer cell line MDA-MB-231. The results showed that three compounds were active for both the β2 subunit and the triple-negative breast cancer cell line MDA-MB-231. The in vivo pharmacokinetic results showed that compound 8t had good biological parameters for both ig and iv administrations. An in vivo pharmacodynamic experiment showed that compound 8t inhibited the β5 subunit in whole blood more greatly than the marketed MLN9708 with the same dose at different time periods. A pathological analysis indicated that the injection of compound 8t in the tumor of a triple-negative breast cancer xenograft mice model led to tumor cell necrosis, nucleus condensation, deep staining, cell fragmentation, dissolution and neutrophil infiltration compared with the control group. The data in hand showed that compound 8t might be an effective candidate for the treatment of both MM and triple-negative breast cancer.
- Lei, Meng,Feng, Huayun,Bai, Enhe,Zhou, Hui,Wang, Jia,Qin, Yanru,Zhang, Haoyang,Wang, Xueyuan,Liu, Zhaogang,Hai, Ou,Liu, Jia,Zhu, Yongqiang
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p. 683 - 691
(2019/01/24)
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- A class of nitrogen-containing heterocyclic butane framework of non-natural amino acid derivative and its synthesis method (by machine translation)
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The invention belongs to the technical field of chemical synthesis, in particular discloses a containing azetidine skeleton of the synthesis method of the non-natural amino acid derivatives, its target product non-natural amino acid derivatives of the formula such as the specification of the Chinese (I), (II), (III), (IV) and (V) as shown in the, in the formula compound is a nitrogen-containing heterocyclic butane framework of non-naturalα-,β- Andγ- Amino acid derivatives, nitrogen atom are 2 - pyridine carboxylic acid protection; carboxyl methyl esterification; formula (I) in order to contain the azetidine framework of non-naturalα- Amino acid derivatives; (II) for the formula containing azetidine bridge ring skeleton of non-naturalα- Amino acid derivatives, wherein n=1 or 2; type (III) is a nitrogen-containing heterocyclic butane and ring skeleton of non-naturalα- Amino acid derivatives; formula (IV) is a nitrogen-containing heterocyclic butane bridge ring skeleton of non-naturalβ- Amino acid derivatives; type (V) is a nitrogen-containing heterocyclic butane and ring skeleton of non-naturalγ- Amino acid derivatives. The experiment of this invention result proves that: the compounds have potential hypolipidemic activity. (by machine translation)
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Paragraph 0043-0045
(2019/03/26)
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- SPIROCYCLIC INDOLINES AS IL-17 MODULATORS
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A series of substituted spirocyclic 2-oxoindoline derivatives, and analogues thereof, being potent modulators of human IL-17 activity, are accordingly of benefit in the treatment and/or prevention of various human ailments, including inflammatory and autoimmune disorders.
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Page/Page column 75
(2019/01/07)
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- Quantitative Modeling of Bis(pyridine)silver(I) Permanganate Oxidation of Hydantoin Derivatives: Guidelines for Predicting the Site of Oxidation in Complex Substrates
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The bis(pyridine)silver(I) permanganate promoted hydroxylation of diketopiperazines has served as a pivotal transformation in the synthesis of complex epipolythiodiketopiperazine alkaloids. This late-stage C-H oxidation chemistry is strategically critical to access N-acyl iminium ion intermediates necessary for nucleophilic thiolation of advanced diketopiperazines en route to potent epipolythiodiketopiperazine anticancer compounds. In this study, we develop an informative mathematical model using hydantoin derivatives as a training set of substrates by relating the relative rates of oxidation to various calculated molecular descriptors. The model prioritizes Hammett values and percent buried volume as key contributing factors in the hydantoin series while correctly predicting the experimentally observed oxidation sites in various complex diketopiperazine case studies. Thus, a method is presented by which to use simplified training molecules and resulting correlations to explain and predict reaction behavior for more complex substrates.
- Bischoff, Amanda J.,Nelson, Brandon M.,Niemeyer, Zachary L.,Sigman, Matthew S.,Movassaghi, Mohammad
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supporting information
p. 15539 - 15547
(2017/11/06)
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- 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
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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.
- 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.
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p. 3144 - 3155
(2015/04/27)
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- QUINAZOLINEDIONE CHYMASE INHIBITORS
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Disclosed are small molecule inhibitors which are useful in treating various diseases and conditions involving Chymase.
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Page/Page column 51-52
(2009/04/25)
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- Rhodium/graphite-catalyzed hydrogenation of carbocyclic and heterocyclic aromatic compounds
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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.
- Falini, Giuseppe,Gualandi, Andrea,Savoia, Diego
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experimental part
p. 2440 - 2446
(2010/02/27)
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