2150-47-2Relevant academic research and scientific papers
Heterofunctionalized Cavitands by Macrocyclization of Sequence-Defined Foldamers
Meisel, Joseph W.,Hu, Chunhua T.,Hamilton, Andrew D.
, p. 7763 - 7767 (2019)
Macrocyclic hosts have long been the workhorses of molecular recognition. Despite the widespread use of container-shaped molecules as synthetic receptors, an efficient preparation of cavitands bearing multiple functional groups has not been realized. This Letter describes a new cavitand derived from a sequence-defined oligoamide foldamer scaffold. A solid-phase synthesis approach is reported, which enables the display of multiple chemically diverse functional groups on the cavitand rim.
ISOINDOLINE DERIVATIVES WHICH BIND TO AN ATP BINDING SITE
-
Paragraph 00195-00196, (2021/07/31)
The present invention relates to novel probe compounds of formulae I and II defined herein. The present invention also relates to methods of synthesising these novel probe compounds and to their use in assays and screens for determining the binding of a test molecule to the ATP-binding site of a target protein, such as, for example, the Mismatch Repair (MMR) component proteins PMS2 and MLH1, or for determining the location and/or quantity of such target proteins in a biological sample.
Optimization of pyrazolo[1,5-a]pyrimidines lead to the identification of a highly selective casein kinase 2 inhibitor
Berger, Benedict-Tilman,Celik, Ibrahim Ethem,Greco, Francesco Aleksy,Hanke, Thomas,Knapp, Stefan,Kr?mer, Andreas,Kurz, Christian Georg,Tjaden, Amelie
, (2020/09/09)
Casein kinase 2 (CK2) is a constitutively expressed serine/threonine kinase that has a large diversity of cellular substrates. Thus, CK2 has been associated with a plethora of regulatory functions and dysregulation of CK2 has been linked to disease development in particular to cancer. The broad implications in disease pathology makes CK2 an attractive target. To date, the most advanced CK2 inhibitor is silmitasertib, which has been investigated in clinical trials for treatment of various cancers, albeit several off-targets for silmitasertib have been described. To ascertain the role of CK2 inhibition in cancer, other disease and normal physiology the development of a selective CK2 inhibitor would be highly desirable. In this study we explored the pyrazolo [1,5-a]pyrimidine hinge-binding moiety for the development of selective CK2 inhibitors. Optimization of this scaffold, which included macrocyclization, led to IC20 (31) a compound that displayed high in vitro potency for CK2 (KD = 12 nM) and exclusive selectivity for CK2. X-ray analysis revealed a canonical type-I binding mode for IC20 (31). However, the polar carboxylic acid moiety that is shared by many CK2 inhibitors including silmitasertib was required for potency but limits the cellular activity of IC20 (31) and the cellular IC50 dropped to the low micromolar range. In summary, IC20 (31) represents a highly selective and potent inhibitor of CK2, which can be used as a tool compound to study CK2 biology and potential new applications for the treatment of diseases.
Design, synthesis, and in vitro evaluation of novel 1,3,4-oxadiazolecarbamothioate derivatives of Rivastigmine as selective inhibitors of BuChE
Fallah, Akram,Mohanazadeh, Farajollah,Safavi, Maliheh
, p. 341 - 355 (2019/12/30)
Rivastigmine has been prescribed for the therapy of Alzheimer’s disease (AD) symptoms. This drug is classified in the carbamate derivative group that has dual activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). According to the structure of Rivastigmine and its performance, a new series of 5-aryl-1,3,4-oxadiazole-2-carbamothioate compounds I–XI was synthesized using structure-based drug discovery approaches. For this purpose a set of these compounds were designed with computational docking method and their interactions with amino acid residues in the active sites of AChE and BuChE checked out. The structures of synthesized compounds were established by physicochemical and spectroscopic methods. The carbamoyl moiety of Rivastigmine structure was modified to carbamothioate and the effects of 1,3,4-oxadiazole heterocycle as a pharmacophoric nucleus were investigated. The potential of the synthesized compounds I–XI was evaluated against two most known agents of AD (AChE and BuChE) to determine their IC50 values. The results of the docking showed the range of binding affinity for the best poses of ten individual conformers for any compounds (I–XI) was between ?7.81 (VI) and ?6.75 (II) kcal/mol. The results of biological experiments displayed that most synthetic compounds (I–VIII) showed moderate to excellent selective activity range against BuChE (0.51–69.44 μM). In vitro cytotoxicity evaluation of these compounds (I–XI) by MTT assay on human dermal fibroblast (HDF) cell line exhibited no activity against HDF. The compound VI [S-(5-(p-tolyl)-1,3,4-oxadiazol-2-yl) ethyl(methyl)carbamothioate] showed the most stable binding affinity (?7.81 kcal/mol) and the lowest IC50 value (0.51 μM) in comparison with Rivastigmine with 7.72 μM and Donepezil with 5.20 μM against BuChE.
NOVEL COMPOUND HAVING HSP90 INHIBITORY ACTIVITY OR PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, AND MEDICAL USE THEREOF
-
Paragraph 0114; 0115; 0127; 0128; 0129; 0252; 0253; 0254, (2019/02/13)
The present invention relates to a novel compound having HSP90 inhibitory activity or a pharmaceutically acceptable salt thereof, and a medicinal use thereof, and composition comprising a dihydroxyphenyl compound or a benzamide compound, which is a novel compound having the HSP90 inhibitory activity of the present invention can effectively inhibit HSP90, and thus can be usefully used as a pharmaceutical composition for preventing or treating HSP90-mediated diseases or a health functional food for preventing or improving HSP90-mediated diseases, which selected from the group consisting of cancer diseases, degenerative neurological diseases and viral infections.
SOLID FOAM COMPRISING MESOGENIC LIGAND-FUNCTIONALIZED NANOPARTICLES AND METHODS OF MAKING AND USING THE SAME
-
Page/Page column 56-57, (2019/05/10)
Solid foam structures having multiple compartments comprising mesogenic ligand-functionalized nanoparticles are provided. Compositions that include these structures, as well as methods of making the structures are also provided. The structures, compositions and methods find use in a variety of applications, such as, photonics, luminescent coatings and multi-compartment encapsulation technologies.
NIRF turn-on nanoparticles based on the tumor microenvironment for monitoring intracellular protein delivery
Xu, Huaibao,Wang, Yi,Pei, Zhichao,Ji, Wei,Pei, Yuxin
supporting information, p. 14930 - 14933 (2019/12/24)
A dual responsive NIRF turn-on protein delivery system incorporating an NIRF turn-on probe and protein into one single nanoparticle has been constructed. It can be taken up efficiently by A549 cells, where protein release and NIRF recovery happen simultaneously in response to low pH and excessive H2O2. This work provides a novel system for monitoring intracellular protein delivery.
Design, synthesis, and biological evaluation of a series of resorcinol-based N-benzyl benzamide derivatives as potent Hsp90 inhibitors
Park, Sun You,Oh, Yong Jin,Lho, Yunmee,Jeong, Ju Hui,Liu, Kwang-Hyeon,Song, Jaeyoung,Kim, Soong-Hyun,Ha, Eunyoung,Seo, Young Ho
, p. 390 - 401 (2017/12/07)
Heat shock protein 90 (Hsp90) is a ubiquitous molecular chaperone that is responsible for the stabilization and maturation of many oncogenic proteins. Therefore, Hsp90 has emerged as an attractive target in the field of cancer chemotherapy. In this study, we report the design, synthesis, and biological evaluation of a series of Hsp90 inhibitors. In particular, compound 30f shows a significant Hsp90α inhibitory activity with IC50 value of 5.3 nM and an excellent growth inhibition with GI50 value of 0.42 μM against non-small cell lung cancer cells, H1975. Compound 30f effectively reduces the expression levels of Hsp90 client proteins including Her2, EGFR, Met, Akt, and c-Raf. Consequently, compound 30f promotes substantial cleavages of PARP, Caspase 3, and Caspase 8, indicating that 30f induces cancer cell death via apoptotic pathway. Moreover, cytochrome P450 assay indicates that compound 30f has weak inhibitory effect on the activities of five major P450 isoforms (IC50 > 5 μM for 1A2, 2C9, 2C19, 2D6, and 3A), suggesting that clinical interactions between 30f and the substrate drugs of the five major P450 isoforms are not expected. Compound 30f also inhibits the tumor growth in a mouse xenograft model bearing subcutaneous H1975 without noticeable abnormal behavior and body weight changes. The immunostaining and western immunoblot analysis of EGFR, Met, Akt in xenograft tissue sections of tumor further demonstrate a good agreement with the in vitro results.
Identification of N-Hydroxycinnamamide analogues and their bio-evaluation against breast cancer cell lines
Shukla, Akhilesh Kumar,Hamidullah,Shrivash, Manoj Kumar,Tripathi, Vishwa Deepak,Konwar, Rituraj,Pandey, Jyoti
, p. 475 - 483 (2018/08/21)
The present study demonstrates the identification of N-hydroxycinnamamide derivatives and their anticancer potential against human triple-negative breast cancer cell line MDA-MB?231, MCF-7 and non-malignant origin cell line, HEK-293 (human embryonic kidney). MTT assay was studied with HEK-293 cell line. Anticancer potential of the N-hydroxycinnamamide derivatives were compared with marked drug Tamoxifen through in vitro study. The compound numbers 3b and 3h exhibit most potent activity against antagonistic breast cancer cells (MDA-MB-231) with IC50 13μM and 5μM respectively. Compound 3h promotes DNA fragmentation and induction of apoptosis. Furthermore, loss of mitochondrial membrane potential induced by compound 3h. The major mechanism of compound 3h for anti-breast cancer activity was probably initiation of reactive oxygen species (ROS) in cancer cells thereby persuading apoptotic cell deaths in cancer cells.
Synergistic Photo-Copper-Catalyzed Hydroxylation of (Hetero)aryl Halides with Molecular Oxygen
Zhang, Xin,Wu, Ge,Gao, Wenxia,Ding, Jinchang,Huang, Xiaobo,Liu, Miaochang,Wu, Huayue
supporting information, p. 708 - 711 (2018/02/09)
Photoredox-mediated copper-catalyzed hydroxylation of (hetero)aryl halides (including chlorides, bromides, and iodides) with O2 at room temperature has been developed. Preliminary mechanistic studies indicate no arylcopper intermediate and that aryl radicals are involved in this procedure. 18O-labeling experiments confirm the hydroxyl oxygen atom originated from molecular oxygen.
