92136-39-5Relevant academic research and scientific papers
PH-controlled aggregation polymorphism of amyloidogenic Aβ (16-22): Insights for obtaining peptide tapes and peptide nanotubes, as function of the N -terminal capping moiety
Elgersma, Ronald C.,Kroon-Batenburg, Loes M.J.,Posthuma, George,Meeldijk, Johannes D.,Rijkers, Dirk T.S.,Liskamp, Rob M.J.
, p. 55 - 65 (2014)
Peptide and protein self-assembly resulting in the formation of amyloidogenic aggregates is generally thought of as a pathological event associated with severe diseases. However, amyloid formation may also provide a basis for advanced bionanomaterials, since amyloid fibrils combine unique material-like properties that make them very useful for design of new types of conducting nanowires, bioactive ligands, and biodegradable coatings as drug-encapsulating materials. The morphology of the supramolecular aggregates determines the properties and application range of these bionanomaterials. An important parameter to control the supramolecular morphology, is the overall charge of the peptide, which is related to the pH of the environment. Herein, we describe the design, synthesis and morphological analysis of a series of N-terminally functionalized Aβ(16-22) peptides (～1/4Lys-Leu-Val-Phe-Phe-Ala-Glu-OH), that underwent a pH-induced polymorphism, ranging from lamellar sheets, helical tapes, peptide nanotubes, and amyloid fibrils as was observed by transmission electron microscopy. Infrared spectroscopy and wide angle X-ray scattering studies showed that peptide self-assembly was driven by β-sheet formation, and that the supramolecular morphology was directed by subtle variations in electrostatic interactions. Finally, a structural model and hierarchy of self-assembly of a peptide nanotube, assembled at pH 1, is proposed.
Two Facile General Methods for the Conjugation of Three Different Molecules
Oh, Keumrok,Shin, Dong Seok,Kim, Hyeong Baik,Sirion, Uthaiwan,Chi, Dae Yoon
, p. 333 - 341 (2021)
In the quest to synthesize compounds that are uniquely optimized for fighting each individual target disease, the importance of developing a new methodology for the bioconjugation of compounds with different functional groups or biological activities cann
Selective Fluoromethyl Couplings of Alkynes via Nickel Catalysis
Li, Huan,Wang, Fang,Zhu, Shengqing,Chu, Lingling
supporting information, (2022/01/20)
We describe here a Ni-catalyzed intermolecular carbo-fluoromethylation of alkynes with aliphatic halides and fluoromethyl halides (BrCF2H and ICH2F) in the presence of zinc, enabling the facile and selective access to a diverse range of biologically valuable CF2H/CH2F-incorporated alkenes with excellent regio- and stereoselectivity. Notably, merging intramolecular radical cyclization with fluoromethyl coupling enables the expedient constructions of CF2H/CH2F-incorporated lactones and lactams with high efficiency and selectivity. Mechanistic studies disclose that this catalytic protocol proceeds via a radical addition to an alkyne followed by selective coupling with the fluoromethyl unit.
From Synthetic Simplified Marine Metabolite Analogues to New Selective Allosteric Inhibitor of Aurora B Kinase
Juillet, Charlotte,Ermolenko, Ludmila,Boyarskaya, Dina,Baratte, Blandine,Josselin, Béatrice,Nedev, Hristo,Bach, Stéphane,Iorga, Bogdan I.,Bignon, Jér?me,Ruchaud, Sandrine,Al-Mourabit, Ali
, p. 1197 - 1219 (2021/02/05)
Significant inhibition of Aurora B was achieved by the synthesis of simplified fragments of benzosceptrins and oroidin belonging to the marine pyrrole-2-aminoimidazoles metabolites isolated from sponges. Evaluation of kinase inhibition enabled the discovery of a synthetically accessible rigid acetylenic structural analogue EL-228 (1), whose structure could be optimized into the potent CJ2-150 (37). Here we present the synthesis of new inhibitors of Aurora B kinase, which is an important target for cancer therapy through mitosis regulation. The biologically oriented synthesis yielded several nanomolar inhibitors. The optimized compound CJ2-150 (37) showed a non-ATP competitive allosteric mode of action in a mixed-type inhibition for Aurora B kinase. Molecular docking identified a probable binding mode in the allosteric site "F"and highlighted the key interactions with the protein. We describe the improvement of the inhibitory potency and specificity of the novel scaffold as well as the characterization of the mechanism of action.
Pillar[5]arene-Based Polycationic Glyco[2]rotaxanes Designed as Pseudomonas aeruginosa Antibiofilm Agents
Coenye, Tom,De Winter, Julien,Diaconu, Andrei,Fransolet, Maude,Gillon, Emilie,Imberty, Anne,Jimmidi, Ravikumar,Michiels, Carine,Mohy El Dine, Tharwat,Vincent, Stéphane P.
supporting information, p. 14728 - 14744 (2021/10/12)
Pseudomonas aeruginosa (P.A.) is a human pathogen belonging to the top priorities for the discovery of new therapeutic solutions. Its propensity to generate biofilms strongly complicates the treatments required to cure P.A. infections. Herein, we describe the synthesis of a series of novel rotaxanes composed of a central galactosylated pillar[5]arene, a tetrafucosylated dendron, and a tetraguanidinium subunit. Besides the high affinity of the final glycorotaxanes for the two P.A. lectins LecA and LecB, potent inhibition levels of biofilm growth were evidenced, showing that their three subunits work synergistically. An antibiofilm assay using a double δlecAδlecB mutant compared to the wild type demonstrated that the antibiofilm activity of the best glycorotaxane is lectin-mediated. Such antibiofilm potency had rarely been reached in the literature. Importantly, none of the final rotaxanes was bactericidal, showing that their antibiofilm activity does not depend on bacteria killing, which is a rare feature for antibiofilm agents.
Discovery of a potent MLL1 and WDR5 protein-protein interaction inhibitor with in vivo antitumor activity
Chen, Weilin,Chen, Xin,Guo, Xiaoke,Jiang, Zhengyu,Li, Dongdong,Long, Guanlu,Wang, Xianghan,You, Qidong
, (2021/07/06)
MLL1-WDR5 interaction is essential for the formation of MLL core complex and its H3K4 methyltransferase activity. Disrupting MLL1-WDR5 interaction has been proposed as a potential therapeutic approach in the treatment of leukemia. A “toolkit” of well-characterized chemical probe will allow exploring animal studies. Based on a specific MLL1-WDR5 PPI inhibitor (DDO-2117), which was previously reported by our group, we conducted a bioisosterism approach by click chemistry to discover novel phenyltriazole scaffold MLL1-WDR5 interaction blockers. Here, our efforts resulted in the best inhibitor 24 (DDO-2093) with high binding affinity (Kd = 11.6 nM) and with improved drug-like properties. Both in vitro and in vivo assays revealed 24 could efficiently block the MLL1-WDR5 interaction. Furthermore, 24 significantly suppressed tumor growth in the MV4-11 xenograft mouse model and showed a favorable safety profile. We propose 24 as a chemical probe that is suitable for in vivo pharmacodynamic and biological studies of MLL1-WDR5 interaction.
Improved Stabilities of Labeling Probes for the Selective Modification of Endogenous Proteins in Living Cells and In Vivo
Lin, Kuan-Yu,Hin Lam, Chak,Lin, Xin-Hui,Hsu, Jung-I,Fan, Syuan-Yun,Gupta, Nitesh K.,Lin, Yu-Chun,Khoon Tee, Boon,Li, Jui-Ping,Chen, Jen-Kun,Tan, Kui-Thong
supporting information, p. 937 - 948 (2021/03/16)
To date, various affinity-based protein labeling probes have been developed and applied in biological research to modify endogenous proteins in cell lysates and on the cell surface. However, the reactive groups on the labeling probes are also the cause of
COMPOUNDS FOR USE IN THE TREATMENT OF LIVER DISEASE
-
Paragraph 00106; 00128, (2021/02/26)
Bile acid derivatives, methods of manufacture thereof, and uses thereof are disclosed herein. The bile acid derivatives have demonstrated potential as therapeutics for treating liver disease.
Design and synthesis of a peptide derivative of ametantrone targeting the major groove of the d(GGCGCC)2 palindromic sequence
Braud, Emmanuelle,De Franco, Michele,Demange, Luc,Ethève-Quelquejeu, Mélanie,Garbay, Christiane,Gresh, Nohad,Ongaro, Alberto,Ribaudo, Giovanni,Zagotto, Giuseppe
, p. 3624 - 3631 (2020/03/17)
In oncology, some DNA intercalating agents have been used in chemotherapy for years to eradicate cancer cells, but these drugs generally suffer from a lack of selectivity for malignant tissues and consequently induce major side-effects. We report herein the design and synthesis of an antitumor intercalating agent ametantrone complemented with two identical peptide arms including a central Lys residue in order to selectively target palindromic sequences of DNA of malignant cells. The peptide arms are linked to the ametantrone core through 1,2,3-triazole. According to our docking prediction, this compound should be double-stranded β-sheet structured, and it has been designed to interact with two guanine residues upstream from a central d(CpG)2 intercalation site on each DNA strand, owing to the H-bonds involving the Lys terminal side chain ammonium group of the peptide arms. This new ametantrone derivative has been obtained thanks to a convergent synthetic pathway, whose key steps were double nucleophilic substitution performed on the ametantrone core, followed by "double-site" 1,3-dipolar cycloaddition affording the 1,4-disubstituted triazole linker almost quantitatively. Preliminary binding assays performed by mass spectrometry proved its accuracy for DNA palindromic sequences. The cytotoxicity of this compound was evaluated on three cancer cell lines and one healthy cell line, and compared to that of mitoxantone, a dihydroxylated analog of ametantrone. Such a peptide derivative was about ten-fold less cytotoxic than mitoxantrone on these cancer cell lines, but about fifty times less cytotoxic on healthy cells. This study could open new avenues towards the design of targeted intercalating agents.
A pH-Switchable Aqueous Organocatalysis with Amphiphilic Secondary Amine–Porphyrin Hybrids
Arlegui, Aitor,Crusats, Joaquim,Cuesta, Victor,Moyano, Albert,Torres, Pol
supporting information, (2020/07/08)
A series of amphiphilic 5-(cyclic-secondary-amine)-10,15,20-tris(4-sulfonatophenyl)porphyrins, designed with the aim of using the amphiphilic porphyrin moiety for the modulation of the aggregation state of the compound by the pH of the medium, have been synthesised, and the relationship between their supramolecular behaviour in acidic aqueous media and their organocatalytic activity in Michael and aldol reactions has been investigated. In particular, we have found that the catalytic activity of the pyrrolidine moiety in an amphiphilic isoindoline–porphyrin hybrid for the aldol reaction of cyclohexanone with 4-nitrobenzaldehyde can be selectively and reversibly switched on and off by adjusting the homogeneity of its solutions through pH variations. The catalysis of the aldol reaction by the secondary amine moiety would otherwise take place regardless of the pH of the medium. We have demonstrated that the aggregation behaviour of these amine–porphyrin hybrids can be also used for the recovery and reutilization of the catalysts.
