- Phthalimide–Oxy Derivatives for 3′- or 5′-Conjugation of Oligonucleotides by Oxime Ligation and Circularization of DNA by “Bis- or Tris-Click” Oxime Ligation
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A solid support and two phosphoramidites exhibiting a phthalimide–oxy group were synthesized. First, after treatment with hydrazine, the resulting 5′- and 3′-oxyamine oligonucleotides were conjugated with aldehyde derivatives by oxime ligation. Second, ol
- Meyer, Albert,Vasseur, Jean-Jacques,Dumy, Pascal,Morvan, Fran?ois
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Read Online
- Therapeutic effects of isothiocyanate prodrugs on rheumatoid arthritis
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Isothiocyanates 7a and 7b have poor stability and aqueous solubility. To address these problems, prodrugs 8a and 8b were synthesized. Prodrugs 8a and 8b were stable in HEPES buffer at pH 4.4, but released the active compounds 7a and 7b in HEPES buffer at
- Jiang, Yin,Li, Hui-Ying,Li, Xiao-Hui,Lu, Jun,Zhang, Quan,Bai, Cui-Gai,Chen, Yue
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Read Online
- In Vitro Photodynamic Studies of a BODIPY-Based Photosensitizer
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A new halogenated 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) derivative was designed as a singlet-oxygen photosensitizer (PS) for use as a photodynamic therapy (PDT) agent, and its photophysical properties were characterized. The PS, having two i
- Kim, Bosung,Sui, Binglin,Yue, Xiling,Tang, Simon,Tichy, Michael G.,Belfield, Kevin D.
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Read Online
- Synthesis and in vitro anticancer activity of zinc(II) phthalocyanines conjugated with coumarin derivatives for dual photodynamic and chemotherapy
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The combination of photodynamic therapy and chemotherapy is a promising strategy to overcome growing problems in contemporary medicine, such as low therapeutic efficacy and drug resistance. Four zinc(II) phthalocyanine-coumarin conjugates were synthesized and characterized. In these complexes, zinc(II) phthalocyanine was used as the photosensitizing unit, and a coumarin derivative was selected as the cytostatic moiety; the two components were linked via a tri(ethylene glycol) chain. These conjugates exhibit high photocytotoxicity against HepG2 human hepatocarcinoma cells, with low IC50 values in the range of 0.014-0.044 μm. The high photodynamic activities of these conjugates are in accordance with their low aggregation tendency and high cellular uptake. One of these conjugates exhibits high photocytotoxicity and significantly higher chemocytotoxicity. The results clearly show that the two antitumor components in these conjugates work in a cooperative fashion. As shown by confocal microscopy, the conjugates can localize in the mitochondria and lysosomes, and one of the conjugates can also localize in the cell nuclei.
- Zhou, Xiao-Qin,Meng, Lu-Bo,Huang, Qi,Li, Jun,Zheng, Ke,Zhang, Feng-Ling,Liu, Jian-Yong,Xue, Jin-Ping
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Read Online
- The dynamic covalent reaction based on diselenide-containing crown ether irradiated by visible light
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A novel diselenide-containing crown ether (BC7Se2) was fabricated, which can polymerize to form cyclic oligomers through intermolecular dynamic covalent reaction by irradiation of visible light. The size and distribution of oligomers are relate
- Shang, Jie,Gong, Hanlin,Zhang, Qian,Cui, Zhiliyu,Li, Shuangran,Lv, Ping,Pan, Tiezheng,Ge, Yan,Qi, Zhenhui
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Read Online
- Persistent room-temperature phosphorescence or high-contrast phosphorescent mechanochromism: polymorphism-dependent different emission characteristics from a single gold(i) complex
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Luminophores with persistent room-temperature phosphorescence (p-RTP) or effective phosphorescent mechanochromism features have significant potential applications in the field of optoelectronic materials. Until now, p-RTP and remarkable phosphorescent mechanochromism phenomena have been observed in some luminescent molecules with different molecular structures. However, separately realizing p-RTP and high-contrast phosphorescent mechanochromism in different polymorphs from a single luminophore is still a valuable and challenging topic. In this work, two polymorphs1Band1YGof a new gold(i) complex with blue and yellow-green luminescence, respectively, are reported. Interestingly,1Bexhibits high-contrast phosphorescent mechanochromic behavior, while1YGexhibits a persistent room-temperature phosphorescence effect. This is the first example of simultaneously obtaining double-purpose crystalline materials with a high-contrast phosphorescent mechanochromism or persistent room-temperature phosphorescence feature from a single luminophore.
- Chen, Zhao,Liu, Sheng Hua,Wang, Xiao-Yan,Yin, Jun,Yin, Ya
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Read Online
- Mitochondrion-targeting PEGylated BODIPY dyes for near-infrared cell imaging and photodynamic therapy
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A series of 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene-based photosensitizers (AmBXI, X = H, M, Br) featuring a cationic mitochondrion-targeting group and near-infrared (NIR) absorption was synthesized. After extending the photosensitizers' π conjugation via Knoevenagel reaction, both the absorbance and emission maxima of AmBXI shifted to the phototherapeutic wavelength range (650-900 nm). Theoretical computations indicate that the introduction of bromine atoms promotes spin-orbit coupling, so that for each additional bromine atom in AmBXI an increase in singlet oxygen quantum yield would be expected (0.3%, 2.2%, and 4.1%, for AmBHI, AmBMI, and AmBBrI, respectively). Moreover, AmBXI photosensitizers exhibited low cytotoxicity in the dark and high phototoxicity, with the half maximal inhibitory concentrations of AmBBrI found to be 46.93 nM and 22.84 nM, while those of AmBMI were 129.7 nM and 58.34 nM in HeLa and MCF-7 cancer cells, respectively. Notably, introduction of a single bromine atom was enough to produce a cytotoxic effect. Furthermore, the presence of a quaternary ammonium group in AmBXI enabled the dyes to localize and stain the negatively charged mitochondria. The results presented herein indicate the straightforward and facile synthesis of NIR-light triggered mitochondrion-targeting photosensitizers. This journal is
- Badon, Isabel Wen,Cho, Sung,Kang, Dongho,Kim, Chanwoo,Kim, Ho-Joong,Lee, Joomin,Lim, Jong Min,Mai, Duy Khuong,Vales, Temmy Pegarro,Yang, Jaesung
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p. 1196 - 1209
(2022/03/02)
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- Discovery of novel potent covalent inhibitor-based EGFR degrader with excellent in vivo efficacy
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Although several Epidermal growth factor receptor (EGFR) inhibitors have been approved for the treatment of non-small-cell lung cancers (NSCLC), acquired drug resistance and side effects largely encumbered their application in clinic. The emerging technology Proteolysis targeting chimera (PROTAC) could be an alternative strategy to overcome these problems. Here, we reported the discovery of Dacomitinib-based EGFR degraders. Promising compound 13 can effectively induce degradation of EGFRdel19 with DC50 value of 3.57 nM in HCC-827 cells, but not to other EGFR mutant, wild-type EGFR protein and the same family receptors (HER2 and HER4). Of note, 13 is the first EGFR-PROTAC to evaluate antitumor effect in vivo, and exhibited excellent antitumor efficacy (TGI = 90%) at a dose of 30 mg/kg without causing observable toxic effects. The preliminary mechanism study demonstrated that 13 can efficiently induce EGFR protein degradation through ubiquitin proteasome pathway and inhibit phosphorylation of downstream pathways in vitro and in vivo, which indicated that 13 exerted antitumor effect by degradation of EGFR protein in tumor tissue. Overall, our study provided further evidence to validate EGFR-PROTACs as a promising strategy for lung cancer therapy.
- Cui, Jiaqi,Du, Yu,Huang, Lei,Niu, Jing,Shi, Shi,Xu, Yungen,Zhu, Qihua
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supporting information
(2022/01/26)
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- HETEROBIFUNCTIONAL MOLECULES AS TEAD INHIBITORS
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The invention relates to compounds and methods of using said compounds, as well as pharmaceutical compositions containing such compounds, for treating diseases and conditions mediated by TEAD, such as cancer.
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Paragraph 0275-0276; 0339-0340
(2021/09/11)
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- MODULAR CHEMICAL PROBE FOR DETECTION OF AMINO ACID CITRULLINE IN PHYSIOLOGICAL SAMPLES
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An improved chemical probe for the detection of the amino acid citrulline combines: 1) a reactive head formed of 1,3-dicarbonyl moiety that reacts with a citrulline side chain in an improved manner compared to currently used 1,2-dicarbonyl moieties; and 2) a modular action of the probe where citrulline side chains are labeled first using reactive heads described above, and attachment of a read-out subunit or tag, be it a fluorophore, a nanoparticle, or an antigen is performed separately. The modular nature of the chemical probe increases the sensitivity of the probes due to their smaller size. Additionally, the chemical probes of the present disclosure allow the same sample to be analyzed using a variety of read-out methods.
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Page/Page column 16
(2021/01/29)
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- Selenacrown Macrocycle in Aqueous Medium: Synthesis, Redox-Responsive Self-Assembly, and Enhanced Disulfide Formation Reaction
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Organic selenides are famous for their coordination and catalytic functions in the organic phase, albeit challenging for aqueous medium. Herein, the combination of a hydrophilic body of crown ether and substitution of one oxygen atom with a selenium one provides a new type of design route for organic selenide entities with charming functions in aqueous solution. The selenacrown ether C9Se presented here intrinsically shows an amphiphile-like property. Its nanosphere structure in water readily expands the catalysis of organic selenide to aqueous substrates in thiol/disulfide conversion.
- Shang, Jie,Li, Bo,Shen, Xin,Pan, Tiezheng,Cui, Zhiliyu,Wang, Yangxin,Ge, Yan,Qi, Zhenhui
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p. 1430 - 1436
(2021/01/13)
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- Pd(II)-Mediated C?H Activation for Cysteine Bioconjugation
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Selective bioconjugation remains a significant challenge for the synthetic chemist due to the stringent reaction conditions required by biomolecules coupled with their high degree of functionality. The current trailblazer of transition-metal mediated bioconjugation chemistry involves the use of Pd(II) complexes prepared via an oxidative addition process. Herein, the preparation of Pd(II) complexes for cysteine bioconjugation via a facile C?H activation process is reported. These complexes show bioconjugation efficiency competitive with what is seen in the current literature, with a user-friendly synthesis, common Pd(II) sources, and a more cost-effective ligand. Furthermore, these complexes need not be isolated, and still achieve high conversion efficiency and selectivity of a model peptide. These complexes also demonstrate the ability to selectively arylate a single surface cysteine residue on a model protein substrate, further demonstrating their utility.
- Frost, Christopher G.,Kociok-K?hn, Gabriele,Lubben, Anneke T.,Reeksting, Shaun B.,Tilden, James A. R.
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supporting information
(2022/01/19)
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- GPX4 protein degradation agent, preparation method and application thereof, and antitumor cell drug
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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.
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Paragraph 0274; 0282-0284
(2021/09/04)
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- Erlotinib targeted degradation EGFR protein small molecule compound and preparation method and application thereof
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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.
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Paragraph 0048-0052
(2021/11/06)
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- Discovery of a new class of PROTAC BRD4 degraders based on a dihydroquinazolinone derivative and lenalidomide/pomalidomide
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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.
- Zhang, Fangqing,Wu, Zhenwei,Chen, Pan,Zhang, Jian,Wang, Tao,Zhou, Jinpei,Zhang, Huibin
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- Targeting G Protein-Coupled Receptors with Magnetic Carbon Nanotubes: The Case of the A3 Adenosine Receptor
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The A3 adenosine receptor (AR) is a G protein-coupled receptor (GPCR) overexpressed in the membrane of specific cancer cells. Thus, the development of nanosystems targeting this receptor could be a strategy to both treat and diagnose cancer. Iron-filled carbon nanotubes (CNTs) are an optimal platform for theranostic purposes, and the use of a magnetic field can be exploited for cancer magnetic cell sorting and thermal therapy. In this work, we have conjugated an A3AR ligand on the surface of iron-filled CNTs with the aim of targeting cells overexpressing A3ARs. In particular, two conjugates bearing PEG linkers of different length were designed. A docking analysis of A3AR showed that neither CNT nor linker interferes with ligand binding to the receptor; this was confirmed by in vitro preliminary radioligand competition assays on A3AR. Encouraged by this result, magnetic cell sorting was applied to a mixture of cells overexpressing or not the A3AR in which our compound displayed indiscriminate binding to all cells. Despite this, it is the first time that a GPCR ligand has been anchored to a magnetic nanosystem, thus it opens the door to new applications for cancer treatment.
- Pineux, Florent,Federico, Stephanie,Klotz, Karl-Norbert,Kachler, Sonja,Michiels, Carine,Sturlese, Mattia,Prato, Maurizio,Spalluto, Giampiero,Moro, Stefano,Bonifazi, Davide
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p. 1909 - 1920
(2020/09/11)
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- Pegylated triarylmethanes: Synthesis, antimicrobial activity, anti-proliferative behavior and in silico studies
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We describe herein the synthesis, characterization and biological studies of novel PEGylated triarylmethanes. Non-symmetrical and symmetrical triarylmethanes series have been synthesized by Friedel-Crafts hydroxyalkylation or directly from bisacodyl respectively followed by a functionalization with PEG fragments in order to increase bioavailability and biological effectiveness. The antimicrobial activity was investigated against Gram-positive and Gram-negative foodborne pathogens and against Candida albicans, an opportunistic pathogenic yeast. The anti-biocidal activity was also studied using Staphylococcus aureus as a reference bacterium. Almost all PEGylated molecules displayed an antifungal activity comparable with fusidic acid with MIC values ranging from 6.25 to 50 μg/mL. Compounds also revealed a promising antibiofilm activity with biofilm eradication percentages values above 80% for the best molecules (compounds 4d and 7). Compounds 7 and 8b showed a modest antiproliferative activity against human colorectal cancer cell lines HT-29. Finally, in silico molecular docking studies revealed DHFR and DNA gyrase B as potential anti-bacterial targets and in silico predictions of ADME suggested adequate drug-likeness profiles for the synthetized triarylmethanes.
- Abdmouleh, Fatma,Ali, Mamdouh Ben,Arbi, Mehdi El,Ferroud, Clotilde,Goya-Jorge, Elizabeth,Guenineche, Léna,Lagarde, Nathalie,Liagre, Bertrand,Martin, Frédérique,Ricco, Christophe,Riccobono, Charlotte,Veitía, Maité Sylla-Iyarreta
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supporting information
(2020/01/31)
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- IRAK DEGRADERS AND USES THEREOF
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The present invention provides compounds, compositions thereof, and methods of using the same.
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Paragraph 00962; 001756-001758
(2020/06/19)
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- A synthetic 2,3-diarylindole induces microtubule destabilization and G2/M cell cycle arrest in lung cancer cells
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The anticancer potential of a synthetic 2,3-diarylindole (PCNT13) has been demonstrated in A549 lung cancer cells by inducing both apoptosis and autophagic cell death. In this report, we designed to connect a fluorophore to the compound via a hydrophilic linker for monitoring intracellular localization. The best position for linker attachment was identified from cytotoxicity and effect on cell morphology of newly synthesized PCNT13 derivatives bearing hydrophilic linker. Cytotoxicity and effect on cell morphology related to the parental compound were used to identify the optimum position for linker attachment in the PCNT13 chemical structure. The fluorophore-PCNT13 conjugate was found to localize in the cytoplasm. Microtubules were found to be one of the cytosolic target proteins of PCNT13, as the compound could inhibit tubulin polymerization in vitro. A molecular docking study revealed that PCNT13 binds at the colchicine binding site on the α/β-tubulin heterodimer. The effect of PCNT13 on microtubule dynamics caused cell cycle arrest in the G2/M phase as analyzed by flow cytometric analysis.
- Thanaussavadate, Bongkotrat,Ngiwsara, Lukana,Lirdprapamongkol, Kriengsak,Svasti, Jisnuson,Chuawong, Pitak
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supporting information
(2019/11/14)
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- Tetra-(benzo-24-crown-8)-phthalocyanines as a platform for supramolecular ensembles: Synthesis and interaction with viologen
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The synthesis of a series of novel tetra-(benzo-24-crown-8)-phthalocyanines (Mg(II), Ni(II) and Co(II)) as well as a modified procedure for the free-base ligand and its Zn(II) and Cu(II) complexes are reported. The tendency of these phthalocyanines to und
- Efimov, Nikolay N.,Gorbunova, Yulia G.,Minin, Vadim V.,Safonova, Evgeniya A.,Tsivadze, Aslan Yu.,Ugolkova, Elena A.,Weiss, Jean,Wytko, Jennifer A.
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- Lenalidomide-based small-molecular compound targeting to EGFR protein degradation, and preparation and application thereof
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The invention relates to a lenalidomide-based small-molecular compound targeting to EGFR protein degradation, and preparation and application thereof, and provides a compound targeting to ubiquitination induced EGFR protein degradation and shown as a form
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Paragraph 0050; 0051; 0055; 0056; 0057
(2020/09/09)
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- POLYCYCLIC COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OF RAPIDLY ACCELERATED FIBROSARCOMA POLYPEPTIDES
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The present disclosure relates to bifunctional compounds, ULM— L—PTM, which find utility as modulators of Rapidly Accelerated Fibrosarcoma (RAF, such as c-RAF, A- RAF and/or B-RAF; the target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand which binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein RAF, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein, or the constitutive activation of the target protein, are treated or prevented with compounds and compositions of the present disclosure.
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Paragraph 1156; 1157
(2020/03/29)
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- PYRIDAZINE DERIVATIVES AS SMARCA2/4 DEGRADERS
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The present invention provides pyridazine derivatives of formula (I), which are therapeutically useful as SMARCA2/4 degraders. These compounds are useful in the treatment and/or prevention of diseases or disorders dependent upon SMARCA2/4 in a mammal. The present invention also provides preparation of the compounds and pharmaceutical compositions comprising at least one of the pyridazine derivatives of formula (I) or a pharmaceutically acceptable salt, or a stereoisomer thereof.
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Page/Page column 105; 106
(2019/11/12)
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- The effect of monosaccharides on self-assembly of benzenetricarboxamides
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The interaction between monosaccharides exhibits an important role in the assembly of monosaccharide-containing molecules. In this work, three common monosaccharides, glucose, galactose and mannose, are employed to investigate the effect of monosaccharide on the self-assembly of benzenetricarboxamide (BTA) core-containing molecules. In the presence of monosaccharides, three benzenetricarboxamide derivatives aggregate into different ordered structures. When alanine linkers are introduced to these molecules between the core and the monosacchride, morphologies of three types of monosaccharide BTAs turned to disordered, meanwhile their structures become similar with the increase of the length of alanine linkers, indicating the disappearance of the monosaccharide effects.
- Wang, Jue,Qi, Wenjing,Chen, Guosong
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supporting information
p. 587 - 591
(2019/01/04)
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- BI-FUNCTIONAL MOLECULES TO DEGRADE CIRCULATING PROTEINS
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The present invention is directed to bi-functional compounds which find use as pharmaceutical agents in the treatment of disease states and/or conditions which are through.macrophage migration inhibitory factor (MIF) or immunoglubin G (IgG). The present invention is also directed to pharmaceutical compositions which comprise these bi- functional compounds as well as methods for treating disease states and/or conditions which are mediated through MIF/lgG or where MIF/lgG is a contributing factor to the development and perpetuation of diseases and/or conditions, especially including autoimmune diseases and cancer, among others. The purpose of the present invention is to provide a molecular strategy to lower plasma MIF/lgG level in patients with autoimmune diseases or certain types of cancers. The b.i -functional molecule construct is comprised of a MIF/IgQ-targeting motif, that is derived from small molecule MIF/lgG ligands, and an ASGPr- targeting motif that binds to hepatocyte asialoglycoprotein receptor { ASGPr). The compounds selectively bind MIF or IgG in plasma and subsequently engage the endo-lysosomal pathway of hepatocytes through ASGPr. As a consequence, MIF/igG is internalized and degraded by hepatocytes, thus resulting in potential attenuation of corresponding disease symptoms which are modulated through MIF/igG.
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Page/Page column 76
(2019/11/04)
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- BIFUNCTIONAL SMALL MOLECULES TO TARGET THE SELECTIVE DEGRADATION OF CIRCULATING PROTEINS
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The present invention is directed to bifunctional small molecules which contain a circulating protein binding moiety (CPBM) linked through a linker group to a cellular receptor binding moiety (CRBM) which is a membrane receptor of degrading cell such as a hepatocyte or other degrading cell. In embodiments, the (CRBM) is a moiety which binds to asialoglycoprotein receptor (an asialoglycoprotein receptor binding moiety, or ASGPRBM) of a hepatocyte. In additional embodiments, the (CRBM) is a moiety which binds to a receptor of other cells which can degrade proteins, such as a LRP1, LDLR, FcyRI, FcRN, Transferrin or Macrophage Scavenger receptor. Pharmaceutical compositions based upon these bifunctional small molecules represent an additional aspect of the present invention. These compounds and/or compositions may be used to treat disease states and conditions by removing circulating proteins through degradation in the hepatocytes or macrophages of a patient or subject in need of therapy. Methods of treating disease states and/or conditions in which circulating proteins are associated with the disease state and/or condition are also described herein.
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Page/Page column 69; 82
(2019/11/04)
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- Compound for targeted ubiquitin degradation of EGFR protein as well as pharmaceutical composition and application thereof
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The invention discloses a compound for targeted ubiquitin degradation of EGFR protein or a pharmaceutically acceptable salt thereof, and also discloses a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof and
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Paragraph 0043; 0048-0050
(2019/07/04)
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- Compound for targeting decomposition of EGFR proteins and preparing method and application of compound
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The invention discloses a compound for targeting decomposition of EGFR proteins with a structure shown in a formula or a pharmaceutically acceptable salt of the compound. In the formula, R representsC1-C6 alkyl groups, m is an integer of 1-7, and n is an integer of 1-6. The invention further discloses a preparing method of the compound, a drug composition comprising the compound or the pharmaceutically acceptable salt of the compound and a pharmaceutically acceptable carrier and a preparation prepared from the drug composition. The compound shows an excellent EGFR degradation effect and goodanti-tumor activity. Therefore, the invention further discloses application of the compound in preparing drugs for preventing or/and treating cancers. The compound has a huge application prospect in the field of medical treatment.
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Paragraph 0044-0045; 0049-0051
(2019/10/01)
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- IRAK DEGRADERS AND USES THEREOF
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The present invention provides compounds, compositions thereof, and methods of using the same.
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Paragraph 2425; 2426
(2019/07/10)
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- Discovery of a series of selective and cell permeable beta-secretase (BACE1) inhibitors by fragment linking with the assistance of STD-NMR
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Two β-secreatase (BACE1) inhibitors from natural products (cinnamic acid and flavone) were linked to furnish potent, cell permeable BACE1 inhibitors with noncompetitive mode of inhibition, with the assistance of saturated transfer difference (STD)-NMR technique. Some of these conjugates also exhibited selective BACE1 inhibition over other aspartyl proteases such as BACE-2 and renin, as well as poor cytotoxicity. Taken together, conjugates 4 represent a new series of BACE inhibitors warrants further investigation for their potential in Alzheimier's disease therapy.
- Fang, Wei-Shuo,Sun, De-yang,Yang, Shuang,Cheng, Chen,Moschke, Katrin,Li, Tianqi,Sun, Shanshan,Lichtenthaler, Stefan F.,Huang, Jian,Wang, Yinghong
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supporting information
(2019/09/30)
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- F-labeled aggregation-induced emission (AIE) fluorescent/positron emission tomography (PET) dual-mode probe, and preparation method and application thereof
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The invention discloses an F-labeled aggregation-induced emission (AIE) fluorescent/positron emission tomography (PET) dual-mode probe, and a preparation method and application thereof. The compound is denoted as F-TPE-TEG, and has a following str
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Paragraph 0042; 0046; 0047
(2019/07/10)
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- MODULATORS OF PROTEOLYSIS AND ASSOCIATED METHODS OF USE
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The present disclosure relates to bifunctional compounds, which find utility as modulators of Kirsten rat sarcoma protein (target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand which binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation, accumulation, and/or overactivation of the target protein are treated or prevented with compounds and compositions of the present disclosure.
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Paragraph 00514-00515
(2019/10/29)
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- PHENOTHIAZINE DERIVATIVES AND USES THEREOF
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The present invention provides phenothiazine compounds, processes for their preparation, pharmaceutical compositions comprising the compounds, and the use of the compounds or the compositions in the treatment of various diseases or conditions, for example ribosomal disorders and ribosomopathies, e.g. Diamond Blackfan anemia (DBA).
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Paragraph 00376-00377
(2019/10/29)
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- UNIVERSAL ENZYME RESPONSIVE LINKER FOR ASSEMBLING LIGANDS ON DNA FUNCTIONALIZED NANOMATERIALS
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Described herein is an enzyme-mediated approach to bioconjugation at nanoparticle (NP) surfaces. This process is enabled by a new synthetic linker compatible with the covalent attachment of alkyne modified substrates, including dyes, peptides and nucleic acids. The methods described herein specifically allow for the linkage of molecules to a DNA-functionalized nanoparticle surface. Enzymatic ligation of molecules to the terminal hydroxyl group of DNA using T4 DNA ligase is achieved through incorporation of a single monophosphate on the approaching substrate. In contrast to previous strategies, the linkers disclosed herein are compatible with alkyne modified molecules of a variety of sizes and charges indicating that the ligase minimally requires the monophosphate and the incoming hydroxyl for conjugation to be successful.
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Paragraph 0098; 0099
(2018/10/04)
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- FLUOROHYDROXYPROLINE DERIVATIVES USEFUL IN THE PREPARATION OF PROTEOLYSIS TARGETED CHIMERAS
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There is provided novel small molecule E3 ubiquitin ligase protein binding ligand compounds, and to their utility in PROteolysis Targeted Chimeras (PROTACs), as well as processes for their preparation thereof, and use in medicine. There is particularly provided novel small molecule E3 ubiquitin ligase protein binding inhibitorcompounds based on a fluorohydroxyproline scaffold, to their utility as ligands in synthesizing novel PROTACs, and to synthetic methods therefor.
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Page/Page column 98
(2018/04/14)
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- Photoswitchable Glycolipid Mimetics: Synthesis and Photochromic Properties of Glycoazobenzene Amphiphiles
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Glycolipids as constituents of cell membranes play an important role in cell membrane functioning. To enable the structural modification of membranes on demand, embedding of photosensitive glycolipid mimetics was envisioned and novel amphiphilic glycolipid mimetics comprising a photoswitchable azobenzene unit were synthesized. In this study, the photochromic properties of these glycolipid mimetics were analyzed by means of UV/Vis spectroscopy and reversible photoswitching. The glycolipids were based on a racemic glycerolipid derivative to be comparable in DPPC (dipalmitoylphosphatidylcholine) phospholipid membrane monolayers. Carbohydrate head groups were altered between a β-glucoside and a β-lactosyl unit, as well as acyl chain lengths between C12 and C16, resulting in altered photoswitching. Langmuir isotherms showed that photoswitching of Langmuir films comprising the synthetic photosensitive glycoamphiphiles was successful.
- Reise, Franziska,Warias, Jonas E.,Chatterjee, Kuntal,Krekiehn, Nicolai R.,Magnussen, Olaf,Murphy, Bridget M.,Lindhorst, Thisbe K.
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p. 17497 - 17505
(2018/11/23)
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- EXENATIDE MODIFIER AND USE THEREOF
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Disclosed are an exenatide modifier for connecting the exenatide to a fatty chain with a carboxy in the terminus thereof by means of a hydrophilic connecting arm, and a use thereof in preparing drugs serving as a GLP-1 receptor agonist; a use in preparing drugs for preventing and/or treating diseases and/or symptoms associated with a low GLP-1 receptor activity; a use in preparing drugs for diseases and/or symptoms associated with glycometabolism; a use in preparing drugs for diabetes; a use in preparing drugs for fatty liver disease, and a use in preparing drugs for losing weight.
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Paragraph 0062
(2018/05/24)
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- Triethylene glycol-modified iridium(III) complexes for fluorescence imaging of: Schistosoma japonicum
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Schistosomiasis, an infectious disease caused by the Schistosoma parasitic worm, presents a serious public health issue. To date, investigation of anti-Schistosomiasis drug mechanisms through fluorescence imaging remains challenging due to the lack of appropriate dyes as fluorescent probes. Phosphorescent Ir(iii) complexes have been attracting substantial attention among various classes of fluorophores given their excellent photophysical properties. Herein, four phosphorescent Ir(iii) complexes were synthesized, two of which contained a triethylene glycol (TEG) hydrophilic group. The phosphorescent emission range of the four complexes lay between 500 and 750 nm, and their quantum yields ranged from 0.031 to 0.146. Furthermore, under the experimental concentration conditions, the TEG-modified complexes had low cytotoxicity. Cell fluorescence labeling experiments indicated that the TEG-modified complexes had good membrane permeability. Finally, the TEG-modified complexes showed remarkable labeling effects in adult Schistosoma fluorescence imaging. Thus, TEG-modified Ir(iii) complexes could be used as a new class of bilharzial fluorescent probes.
- Wu, Yongquan,Zeng, Guanjie,Lvyue, Nannan,Wu, Weihua,Jiang, Tianyu,Wu, Rongle,Guo, Wei,Li, Xun,Fan, Xiaolin
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supporting information
p. 4973 - 4980
(2017/07/11)
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- Four styrene double crown ether and beryllium two pyrrole derivative of super-molecular self-assembly (by machine translation)
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The present invention discloses a self-assembling ultra-molecular material, preparation method and its application. The invention to beryllium two pyrrole as the parent substance, its chemical structure has been modified with imine structure beryllium two
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Paragraph 0034; 0042
(2017/07/22)
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- α-Helical peptide vesicles with chiral membranes as enantioselective nanoreactors
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We report peptide vesicles with chiral membranes as enantioselective nanoreactors. The peptide vesicles are able to selectively encapsulate only a single enantiomer from a racemic mixture solution through preferential diffusion across the membranes. Notab
- Chen, Xi,Wang, Yanqiu,Wang, Huaxin,Kim, Yongju,Lee, Myongsoo
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supporting information
p. 10958 - 10961
(2017/10/13)
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- SILICON PHTHALOCYANINE COMPLEX, PREPARATION METHOD AND MEDICINAL APPLICATION THEREOF
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The present invention relates to a silicon phthalocyanine complex, the preparation method and the medicinal application thereof. The present invention particularly relates to a silicon phthalocyanine complex of formula (I), the preparation method thereof and a pharmaceutical composition comprising the same, as well as the use thereof as a photosensitizer, in particular the use in the treatment of cancers, wherein each substituent in formula (I) is the same as defined in the description.
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Paragraph 0106; 0107
(2017/01/26)
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- NITROXIDE CONTAINING AMYLOID BINDING AGENTS FOR IMAGING AND THERAPEUTIC USES
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The present invention provides methods of using nitroxide spin-labeled amyloid beta-binding compounds to image amyloid. The present invention also provides nitroxide spin-labeled amyloid beta-binding compounds
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Paragraph 0148
(2017/03/14)
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- Thermoresponsive dendronized copolymers for protein recognitions based on biotin–avidin interaction
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Thermoresponsive biotinylated dendronized copolymers carrying dendritic oligoethylene glycol (OEG) pendants were prepared via free radical polymerization, and their protein recognitions based on biotin–avidin interaction investigated. Both first (PG1) and second generation (PG2) dendronized copolymers were designed to examine possible thickness effects on the interaction between biotin and avidin. Inherited from the outstanding thermoresponsive properties from OEG dendrons, these biotinylated cylindrical copolymers show characteristic thermoresponsive behavior which provides an envelope to capture avidin through switching temperatures above or below their phase transition temperatures (Tcps). Thus, the recognition of polymer-supported biotin with avidin was investigated with UV/vis spectroscopy and dynamic laser light scattering. In contrast to the case for PG1, the increased thickness for copolymer PG2 hinders partially and inhibits the recognition of biotin moieties with avidin either below or above its Tcp. This demonstrates the significant architecture effects from dendronized polymers on the biotin moieties to shift onto periphery of the collapsed aggregates, which should be a prerequisite for protein recognition. These kinds of novel thermoresponsive copolymers may pave a way for the interesting biological applications in areas such as reversible activity control of enzyme or proteins, and for controlled delivery of drugs or genes.
- Zhou, Chunhua,Abdel-Rahman, Mona A.,Li, Wen,Liu, Kun,Zhang, Afang
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p. 832 - 838
(2017/05/16)
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- ALANINE-BASED MODULATORS OF PROTEOLYSIS AND ASSOCIATED METHODS OF USE
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The description relates to inhibitors of Apoptosis Proteins (TAPs) binding compounds, including Afunctional compounds comprising the same, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present invention. In particular, the description provides compounds, which contain on one end a ligand which binds to the IAP E3 ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. Compounds can be synthesized that exhibit a broad range of pharmacological activities consistent with the degradation/inhibition of targeted polypeptides of nearly any type.
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Paragraph 00390
(2017/02/09)
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- Silicon Phthalocyanines Axially Disubstituted with Erlotinib toward Small-Molecular-Target-Based Photodynamic Therapy
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Small-molecular-target-based photodynamic therapy—a promising targeted anticancer strategy—was developed by conjugating zinc(II) phthalocyanine with a small-molecular-target-based anticancer drug. To prevent self-aggregation and avoid problems of phthalocyanine isomerization, two silicon phthalocyanines di-substituted axially with erlotinib have been synthesized and fully characterized. These conjugates are present in monomeric form in various solvents as well as culture media. Cell-based experiments showed that these conjugates localize in lysosomes and mitochondria, while maintaining high photodynamic activities (IC50 values as low as 8 nm under a light dose of 1.5 J cm?2). With erlotinib as the targeting moiety, two conjugates were found to exhibit high specificity for EGFR-overexpressing cancer cells. Various poly(ethylene glycol) (PEG) linker lengths were shown to have an effect on the photophysical/photochemical properties and on in vitro phototoxicity.
- Chen, Juan-Juan,Huang, Yi-Zhen,Song, Mei-Ru,Zhang, Zhi-Hong,Xue, Jin-Ping
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p. 1504 - 1511
(2017/09/26)
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- Synthesis of structure-defined branched hyaluronan tetrasaccharide glycoclusters
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Hyaluronan is a glycosaminoglycan with a large number of biological activity. Hyaluronan of different molecular weight often shows different biological activity, sometimes even completely opposite, but the mechanism is not clear. Herein, the hyaluronan tetrasaccharide glycoclusters using hyaluronan tetrasaccharide obtained by enzymolysis of natural hyaluronan were firstly synthesized in high yield. The structurally determined and diverse glycoclusters were of wide molecular weight range and might be used for mimicking the biological activity of natural hyaluronan and facilitating the mechanism study.
- Sha, Meng,Yao, Wang,Zhang, Xiao,Li, Zhongjun
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supporting information
p. 2910 - 2914
(2017/07/10)
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- Hydrophilic and Cell-Penetrable Pyrrolidinyl Peptide Nucleic Acid via Post-synthetic Modification with Hydrophilic Side Chains
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Peptide nucleic acid (PNA) is a nucleic acid mimic in which the deoxyribose-phosphate was replaced by a peptide-like backbone. The absence of negative charge in the PNA backbone leads to several unique behaviors including a stronger binding and salt independency of the PNA-DNA duplex stability. However, PNA possesses poor aqueous solubility and cannot directly penetrate cell membranes. These are major obstacles that limit in vivo applications of PNA. In previous strategies, the PNA can be conjugated to macromolecular carriers or modified with positively charged side chains such as guanidinium groups to improve the aqueous solubility and cell permeability. In general, a preformed modified PNA monomer was required. In this study, a new approach for post-synthetic modification of PNA backbone with one or more hydrophilic groups was proposed. The PNA used in this study was the conformationally constrained pyrrolidinyl PNA with prolyl-2-aminocyclopentanecarboxylic acid dipeptide backbone (acpcPNA) that shows several advantages over the conventional PNA. The aldehyde modifiers carrying different linkers (alkylene and oligo(ethylene glycol)) and end groups (-OH, -NH2, and guanidinium) were synthesized and attached to the backbone of modified acpcPNA by reductive alkylation. The hybrids between the modified acpcPNAs and DNA exhibited comparable or superior thermal stability with base-pairing specificity similar to those of unmodified acpcPNA. Moreover, the modified apcPNAs also showed the improvement of aqueous solubility (10-20 folds compared to unmodified PNA) and readily penetrate cell membranes without requiring any special delivery agents. This study not only demonstrates the practicality of the proposed post-synthetic modification approach for PNA modification, which could be readily applied to other systems, but also opens up opportunities for using pyrrolidinyl PNA in various applications such as intracellular RNA sensing, specific gene detection, and antisense and antigene therapy.
- Pansuwan, Haruthai,Ditmangklo, Boonsong,Vilaivan, Chotima,Jiangchareon, Banphot,Pan-In, Porntip,Wanichwecharungruang, Supason,Palaga, Tanapat,Nuanyai, Thanesuan,Suparpprom, Chaturong,Vilaivan, Tirayut
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p. 2284 - 2292
(2017/09/26)
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- A phosphorescence iridium complex synthesis and its used for cercarian fluorescence-labeled
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The invention belongs to the field of photobiology labeling for preventing and treating parasitic diseases, and relates to synthesis of a phosphorescent iridium complex and the purpose of the phosphorescent iridium complex for the fluorescence labeling of
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Paragraph 0039
(2018/01/11)
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- Amphiphilic Molecular Motors for Responsive Aggregation in Water
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The novel concept of amphiphilic molecular motors that self-assemble into responsive supramolecular nanotubes in water is presented. The dynamic function of the molecular motor units inside the supramolecular assemblies was studied using UV-vis absorption
- Van Dijken, Derk Jan,Chen, Jiawen,Stuart, Marc C. A.,Hou, Lili,Feringa, Ben L.
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supporting information
p. 660 - 669
(2016/02/05)
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- Thiophene compound Tetrahydrobenza and (by machine translation)
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The purpose of this invention is to provide with intestinal phosphate transport protein inhibit function (NPT-IIb), hyperphosphatemia as a therapeutic and/or preventive agent for Tetrahydrobenza the effective ingredient of benzothiophene compound or its stereoisomers, geometric isomers, tautomers, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or its prodrug and pharmaceutical composition. (by machine translation)
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Paragraph 0506; 0507; 0508
(2016/10/09)
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- Preparation method of thiophene compound with side chain with alcohol amine group
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The invention discloses a preparation method of a thiophene compound with a side chain with an alcohol amine group. A compound paratoluensulfonyl chloride is used as a raw material and reacts with long-chain glycol under the condition that a triethylamine
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Paragraph 0020; 0021; 0022; 0023; 0024
(2017/01/17)
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