7479-01-8Relevant academic research and scientific papers
A new class of α-ketoamide derivatives with potent anticancer and anti-SARS-CoV-2 activities
An, Jing,Chen, Yiling,Ciechanover, Aaron,Fuk-Woo Chan, Jasper,Huang, Lina S.,Huang, Ziwei,Liang, Boqiang,Nie, Linlin,Wang, Juan,Warshel, Arieh,Wu, Meixian,Wu, Yi,Xu, Yan,Ye, Hui,Yuan, Shuofeng,Yuen, Kwok-Yung,Zhou, Jiao
, (2021/02/27)
Inhibitors of the proteasome have been extensively studied for their applications in the treatment of human diseases such as hematologic malignancies, autoimmune disorders, and viral infections. Many of the proteasome inhibitors reported in the literature target the non-primed site of proteasome's substrate binding pocket. In this study, we designed, synthesized and characterized a series of novel α-keto phenylamide derivatives aimed at both the primed and non-primed sites of the proteasome. In these derivatives, different substituted phenyl groups at the head group targeting the primed site were incorporated in order to investigate their structure-activity relationship and optimize the potency of α-keto phenylamides. In addition, the biological effects of modifications at the cap moiety, P1, P2 and P3 side chain positions were explored. Many derivatives displayed highly potent biological activities in proteasome inhibition and anticancer activity against a panel of six cancer cell lines, which were further rationalized by molecular modeling analyses. Furthermore, a representative α-ketoamide derivative was tested and found to be active in inhibiting the cellular infection of SARS-CoV-2 which causes the COVID-19 pandemic. These results demonstrate that this new class of α-ketoamide derivatives are potent anticancer agents and provide experimental evidence of the anti-SARS-CoV-2 effect by one of them, thus suggesting a possible new lead to develop antiviral therapeutics for COVID-19.
Application of proteasome inhibitor in inhibition of novel coronavirus
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Paragraph 0091-0094, (2021/06/22)
The invention provides application of a proteasome inhibitor in inhibition of a novel coronavirus or preparation of novel coronavirus inhibitors. The proteasome inhibitor has a structure represented by a formula (I) or isomers, pharmaceutically acceptable salts thereof and prodrugs thereof. According to the application, by applying the proteasome inhibitor to inhibition of the novel coronavirus, good inhibiting activity is obtained, and a novel treatment way of think is provided for diseases such as pneumonia caused by the novel coronavirus.
N-transfer reagent and method for preparing the same and its application
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Page/Page column 25; 49-50; 55-56, (2021/06/25)
Provided are a novel N-transfer reagent and a method for preparing the same and its application. The N-transfer reagent is represented by the following Formula (I): The various novel N-transfer reagents of the present invention can be quickly prepared by employing different nitrobenzene precursors. The N-transfer reagents can directly convert a variety of amino compounds into diazo compounds under mild conditions. Particularly, the N-transfer reagents can facilitate the synthesis of the diazo compounds. The application of synthesizing diazo compounds of the present invention can greatly decrease the difficulty in operation, increase the safety during experiments, reduce the cost of production and the environmental pollution, and enhance the industrial value of diazo compounds.
NovelN-transfer reagent for converting α-amino acid derivatives to α-diazo compounds
Lu, Guan-Han,Huang, Tzu-Chia,Hsueh, Hsiao-Chin,Yang, Shin-Cherng,Cho, Ting-Wei,Chou, Ho-Hsuan
supporting information, p. 4839 - 4842 (2021/05/25)
A novel universalN-transfer reagent for direct and effective transformation of α-amino ketones, acetamides, and esters to the corresponding α-diazo products under mild basic conditions has been developed. This one-step synthetic approach not only allows for generation of α-substituted-α-diazo carbonyl compounds from α-amino acid derivatives but also permits preparation of α-diazo dipeptides fromN-terminal dipeptides (32 examples, up to 91%).
Rhodium-Catalyzed Enantioselective Synthesis of Oxazinones via an Asymmetric Ring Opening-Lactonization Cascade of Oxabicyclic Alkenes
Yen, Andy,Pham, Anh Hoang,Larin, Egor M.,Lautens, Mark
supporting information, p. 7549 - 7553 (2019/10/02)
The rhodium-catalyzed asymmetric ring opening reaction of oxabicyclic alkenes is shown to be an efficient method for synthesizing chiral heterocycles. We demonstrate that the pairwise combination of chiral catalyst with chiral amino-acid-derived pronucleophiles results in a stereodivergent synthesis of diastereomeric hydroxyesters. A favorable conformational preference induces the subsequent lactonization of one diastereomer leading to the highly enantioselective synthesis of oxazinones.
Synthesis and structure-activity relationship of nitrile-based cruzain inhibitors incorporating a trifluoroethylamine-based P2 amide replacement
Gomes, Juliana C.,Cianni, Lorenzo,Ribeiro, Jean,dos Reis Rocho, Fernanda,da Costa Martins Silva, Samelyn,Batista, Pedro Henrique Jatai,Moraes, Carolina Borsoi,Franco, Caio Haddad,Freitas-Junior, Lucio H.G.,Kenny, Peter W.,Leit?o, Andrei,Burtoloso, Antonio C.B.,de Vita, Daniela,Montanari, Carlos A.
, (2019/09/30)
The structure-activity relationship for nitrile-based cruzain inhibitors incorporating a P2 amide replacement based on trifluoroethylamine was explored by deconstruction of a published series of inhibitors. It was demonstrated that the P3 biphenyl substituent present in the published inhibitor structures could be truncated to phenyl with only a small loss of affinity. The effects of inverting the configuration of the P2 amide replacement and linking a benzyl substituent at P1 were observed to be strongly nonadditive. We show that plotting affinity against molecular size provides a means to visualize both the molecular size efficiency of structural transformations and the nonadditivity in the structure-activity relationship. We also show how the relationship between affinity and lipophilicity, measured by high-performance liquid chromatography with an immobilized artificial membrane stationary phase, may be used to normalize affinity with respect to lipophilicity.
Tuning the reaction pathways of phenanthroline-Schiff bases: Routes to novel phenanthroline ligands
Ahmed, Muhib,Rooney, Denise,McCann, Malachy,Casey, Jamie,O'Shea, Katie,Twamley, Brendan
, p. 15283 - 15289 (2019/10/22)
Pyrido-phenanthrolin-7-one compounds are structural analogues of the cytotoxic alkaloid, ascididemin, and would be expected to have interesting biological activities. Synthetic strategies are reported for a novel simple route to form this class of ligand. 1,10-Phenanthrolin-5,6-dione reacts with l-phenylalanine alkyl esters and their para-substituted analogues to form both a phenanthroline-oxazine and a pyrido-phenanthrolin-7-one product. The nature of the major product is dependent on the electronic properties of the para substituent. Successful metal coordination to the pyrido-phenanthrolin-7-one ligand is also presented.
3, 5-disubstituted hydantoin compound as well as preparation method and application thereof
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Paragraph 0041; 0049; 0050; 0055; 0056, (2018/10/19)
The invention provides a 3, 5-disubstituted hydantoin compound as well as a preparation method and an application thereof. The structure of the compound is shown in formula I in the description. The application of the 3, 5-disubstituted hydantoin compound shown in the formula I or solvates, hydrates or salts of the compound in preparation of medicines for treating Alzheimer's disease, vascular dementia and other dementia diseases with memory impairment also belongs to the protection scope. Animal experiments prove that the compound has the effect of saving memory of animal models, has high safety, does not have mutagenicity, can stay in blood for several hours after oral administration and intravenous injection, and can enter the brain.
Pyrazole-based potent inhibitors of GGT1: Synthesis, biological evaluation, and molecular docking studies
Mansha, Muhammad,Kumari, Udayappan Udhaya,Cournia, Zoe,Ullah, Nisar
, p. 666 - 676 (2016/09/14)
In this study, a series of pyrazole-based structural analogues of GGTI-DU40 (1) have been synthesized and biologically evaluated for geranylgeranyltransferase 1 (GGT1) and farnesyltransferase (FT) inhibition. The screening results revealed that 2 (IC50?=?2.4?μM) and 5 (IC50?=?3.1?μM) are potent GGT1 inhibitors (GGTIs), possessing higher inhibitory activity compared to the control compound 1 (IC50?=?3.3?μM). The anti-proliferative efficacy of these compounds was further assayed against MDA-MB-231?cells which indicated a significantly higher activity of 2 (IC50?=?7.6?μM) compared to 1 (IC50?=?23.0?μM). To examine the capacity of the synthesized compounds to inhibit GGT1 in an intact cell, western blot analysis was performed on the MDA-MB-231?cell line, which revealed very high inhibitory cellular activity of 2 and 5 and demonstrated their capacity to inhibit prenylation of endogenous proteins. Molecular docking studies of 2 against the crystal structure of GGT1 complexed with a geranylgeranyl pyrophosphate (GGPP) Analog and a CaaX (C?=?cysteine, aa?=?aliphatic amino acids, and X?=?any amino acid) portion of the KKKSKTKCVIL peptide substrate revealed several hydrogen bonding interactions and π-π contacts between 2 and the binding pocket of GGT1. Together these data suggest that compound 2 could proceed to in?vivo investigation to further assess its efficacy and cytotoxicity.
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.
