172531-36-1Relevant articles and documents
Bivalent ligands incorporating curcumin and diosgenin as multifunctional compounds against Alzheimer's disease
Chojnacki, Jeremy E.,Liu, Kai,Saathoff, John M.,Zhang, Shijun
, p. 7324 - 7331 (2015)
In an effort to combat the multifaceted nature of Alzheimer's disease (AD) progression, a series of multifunctional, bivalent compounds containing curcumin and diosgenin were designed, synthesized, and biologically characterized. Screening results in MC65 neuroblastoma cells established that compound 38 with a spacer length of 17 atoms exhibited the highest protective potency with an EC50 of 111.7 ± 9.0 nM. A reduction in protective activity was observed as spacer length was increased up to 28 atoms and there is a clear structural preference for attachment to the methylene carbon between the two carbonyl moieties of curcumin. Further study suggested that antioxidative ability and inhibitory effects on amyloid-β oligomer (AβO) formation may contribute to the neuroprotective outcomes. Additionally, compound 38 was found to bind directly to Aβ, similar to curcumin, but did not form complexes with the common biometals Cu, Fe, and Zn. Altogether, these results give strong evidence to support the bivalent design strategy in developing novel compounds with multifunctional ability for the treatment of AD.
Synthesis of the individual regioisomer of the bisadduct of fullerene C60 with tert-butyl 11-azido-3,6,9-trioxaundecanoate
Romanova,Yusupova,Balandina,Latypov,Yakhvarov,Nifant'Ev,Yashunskii,Sinyashina
, p. 1495 - 1500 (2007)
At 130 °C the reaction of fullerene C60 with 1-azido-9-tert-butoxycarbonyl-3,6,9-trioxanonane occurs regioselectively affording one regioisomer of the bisadduct.
TARGET PROTEIN EED DEGRADATION-INDUCING DEGRADUCER, PREPARATION METHOD THEREOF, AND PHARMACEUTICAL COMPOSITION FOR PREVENTING OR TREATING DISEASES RELATED TO EED, EZH2, OR PRC2, COMPRISING SAME AS ACTIVE INGREDIENT
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Paragraph 0245; 0248-0249, (2021/12/23)
The present invention relates to a target protein degradation-inducing Degraducer, a preparation method thereof, and a pharmaceutical composition for preventing or treating diseases related to EED, EZH2, or PRC2 comprising same as an active ingredient. A novel compound represented by formula 1, according to the present invention is a Degraducer compound that induces degradation of a target protein, i.e., embryonic ectoderm development (EED) or polycomb repressive complex 2 (PRC2), utilizing cereblon E3 ubiquitin ligase, von Hippel-Lindau tumor suppressor (VHL) E3 ubiquitin ligase, mouse double minute 2 homolog (MDM2) E3 ubiquitin ligase, and cellular inhibitor of apoptosis protein 1 (cIAP) E3 ubiquitin ligase, wherein the compound has an aspect of remarkably achieving target protein degradation-inducing activity through a ubiquitin proteasome system (UPS), and therefore there is a useful effect in that it is possible to provide a pharmaceutical composition for preventing or treating diseases or conditions related to a target protein, and a functional health food composition for preventing or improving same, comprising said compound as an active ingredient.
Erlotinib targeted degradation EGFR protein small molecule compound and preparation method and application thereof
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Paragraph 0048-0049; 0054, (2021/11/06)
The compound (EGFR) or a pharmaceutically acceptable salt or hydrate thereof, I comprises the compound and a preparation method and application thereof, and the pharmaceutical composition containing the compound can be applied to preparation and of drugs for preventing and/or treating cancer. To the invention, pomalidomide is selected as PROTACs to bind to E3 connecting enzyme, erlotinib is targeted EGFR small molecule compound, two-phase connection construction PROTACs, in-vitro anti-tumor activity test and in-vitro EGFR protein degradation activity show excellent EGFR-protein degradation activity.
GPX4 protein degradation agent, preparation method and application thereof, and antitumor cell drug
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Paragraph 0317-0318; 0327-0330, (2021/09/04)
The invention provides a GPX4 protein degradation agent, a preparation method thereof, and an anti-tumor cell drug, and belongs to the technical field of drug application. The GPX4 protein degradation agent provided by the invention has a protein degradation targeting chimera (PROTAC) molecular structure, a mother nucleus structure of the GPX4 protein degradation agent is used as a small molecule ligand for combining target protein, an A2 substituent is used as a small molecule ligand for combining an E3 ubiquitin ligase compound, and an A1 substituent is used as a connecting group for connecting the two ligands. The GPX4 protein degradation agent with the structure can specifically recognize GPX4 protein and effectively ubiquitinate and degrade the GPX4 protein, so that tumor cell ferroptosis is induced.
PROTEOLYSIS-TARGETING CHIMERAS
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Paragraph 00131; 00132, (2020/05/28)
The present disclosure provides compounds of the formula (I) wherein these compounds contain a ligand which binds to one or more target proteins such as CDK4 or CDK6 and a ligand which binds to the machinery associated with the ubiquitinating protein machinery. Also provided herein are methods of using these compounds in compositions or methods of treating patients with these compounds for the treatment of a disease or disorders such as cancer.
Discovery of a new class of PROTAC BRD4 degraders based on a dihydroquinazolinone derivative and lenalidomide/pomalidomide
Zhang, Fangqing,Wu, Zhenwei,Chen, Pan,Zhang, Jian,Wang, Tao,Zhou, Jinpei,Zhang, Huibin
, (2019/12/24)
BRD4 has emerged as an attractive target for anticancer therapy. However, BRD4 inhibitors treatment leads to BRD4 protein accumulation, together with the reversible nature of inhibitors binding to BRD4, which may limit the efficacy of BRD4 inhibitors. To address these problems, a protein degradation strategy based on the proteolysis targeting chimera (PROTAC) technology has been developed to target BRD4 recently. Herein, we present our design, synthesis and biological evaluation of a new class of PROTAC BRD4 degraders, which were based on a potent dihydroquinazolinone-based BRD4 inhibitor compound 6 and lenalidomide/pomalidomide as ligand for E3 ligase cereblon. Gratifyingly, several compounds showed excellent inhibitory activity against BRD4, and high anti-proliferative potency against human monocyte lymphoma cell line THP-1. Especially, compound 21 (BRD4 BD1, IC50 = 41.8 nM) achieved a submicromolar IC50 value of 0.81 μM in inhibiting the growth of THP-1 cell line, and was 4 times more potent than compound 6. Moreover, the mechanism study established that 21 could effectively induce the degradation of BRD4 protein and suppression of c-Myc. All of these results suggested that 21 was an efficacious BRD4 degrader for further investigation.
Development of small-molecule BRD4 degraders based on pyrrolopyridone derivative
Chen, Pan,Wang, Lixun,Wang, Tao,Xu, Changliang,Zhang, Huibin,Zhang, Jian,Zheng, Peiyuan,Zhou, Jinpei,Zhu, Peiyu
, (2020/04/30)
Bromodomain-containing protein 4 (BRD4) plays a crucial role in the epigenetic regulation of gene transcription and some BRD4 inhibitors have been advanced to clinical trials. Nevertheless, the clinical application of BRD4 inhibitors could be limited by drug resistance. As an alternative strategy, the emerging Proteolysis Targeting Chimeras (PROTACs) technology has the potential to overcome the drug resistance of traditional small-molecule drugs. Based on PROTACs approaches, several BRD4 degraders were developed and have been proved to degrade BRD4 protein and inhibit tumor growth. Herein, we present the design, synthesis, and biological evaluation of pyrrolopyridone derivative-based BRD4 degraders. Four synthesized compounds displayed comparative potence against BRD4 BD1 with IC50 at low nanomolar concentrations. Anti-proliferative activity of 32a against BxPC3 cell line (IC50 = 0.165 μM) was improved by about 7-fold as compared to the BRD4 inhibitor ABBV-075. Furthermore, degrader 32a potently induced the degradation of BRD4 and inhibited the expression of c-Myc in BxPC3 cell line in a time-dependent manner. The exploration of intracellular antitumor mechanism showed 32a induced cell cycle arrest and apoptosis effectively. All the results demonstrated that compound 32a could be considered as a potential BRD4 degrader for further investigation.
Solid-phase synthesis of a novel phalloidin analog with on-bead and off-bead actin-binding activity
Blanc, Antoine,Todorovic, Mihajlo,Perrin, David M.
supporting information, p. 385 - 388 (2019/01/09)
Specific effectors of actin polymerization have found use as dynamic probes of cellular morphology that may be used to gauge cellular response to stimuli and drugs. Of various natural products that target actin, phalloidin is one of the most potent and selective inhibitors of actin depolymerization. Phalloidin and related members of the phallotoxin family are macrocyclic heptapeptides bearing a characteristic and rigidifying transannular tryptathionine bridge. Here we describe a solid-phase synthesis of a new phalloidin analog as a prototype for library development with the potential for on- and off-bead screening. To validate our method, we labelled the phalloidin derivative with a fluorescent dye which stained actin in CHO cells. Furthermore, a bioassay was developed allowing actin polymerization on beads carrying a phalloidin derivative.
ADJUVANT COMPOUNDS
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, (2018/11/22)
Adjuvant compounds are described, as well as their conjugates comprising peptide antigens or other immunomodulatory moieties. Also described are methods of modulating immune responses in a subject in need thereof, as well as methods of treating cancer, viral or bacterial infections comprising administering the adjuvant compounds or the conjugates to a subject in need thereof.
