127828-22-2Relevant articles and documents
Macrocyclic DNA-mismatch-binding ligands: Structural determinants of selectivity
Granzhan, Anton,Largy, Eric,Saettel, Nicolas,Teulade-Fichou, Marie-Paule
, p. 878 - 889 (2010)
A collection of 15 homodi- meric and 5 heterodimeric macrocyclic bisintercalators was prepared by one- or two-step condensation of aromatic dialdehydes with aliphatic diamines; notably, the heterodimeric scaffolds were synthesized for the first time. The binding of these macrocycles to DNA duplexes containing a mispaired thy- mine residue (TX), as well as to the fully paired control (TA), was investi- gated by thermal denaturation and flu- orescent-intercalator-displacement experiments. The bisnaphthalene derivatives, in particular, the 2, 7-disubstituted ones, have the highest selectivity for the TX mismatches, as these macrocy- cles show no apparent binding to the fully paired DNA. By contrast, other macrocyclic ligands, as well as seven conventional DNA binders, show lesser or no selectivity for the mismatch sites. The study demonstrates that the topology of the ligands plays a crucial role in determining the mismatch-binding affinity and selectivity of the macrocy- clic bisintercalators. 2010 Wiley-VCH Verlag GmbH & Co. KGaA.
Development of novel cyclic peptides as pro-apoptotic agents
Brindisi, Margherita,Maramai, Samuele,Brogi, Simone,Fanigliulo, Emanuela,Butini, Stefania,Guarino, Egeria,Casagni, Alice,Lamponi, Stefania,Bonechi, Claudia,Nathwani, Seema M.,Finetti, Federica,Ragonese, Francesco,Arcidiacono, Paola,Campiglia, Pietro,Valenti, Salvatore,Novellino, Ettore,Spaccapelo, Roberta,Morbidelli, Lucia,Zisterer, Daniela M.,Williams, Clive D.,Donati, Alessandro,Baldari, Cosima,Campiani, Giuseppe,Ulivieri, Cristina,Gemma, Sandra
, p. 301 - 320 (2016)
Our recent finding that paclitaxel behaves as a peptidomimetic of the endogenous protein Nur77 inspired the design of two peptides (PEP1 and PEP2) reproducing the effects of paclitaxel on Bcl-2 and tubulin, proving the peptidomimetic nature of paclitaxel.
Specific fluorescence labeling of target proteins by using a ligand-4-azidophthalimide conjugate
Chiba, Kosuke,Asanuma, Miwako,Ishikawa, Minoru,Hashimoto, Yuichi,Dodo, Kosuke,Sodeoka, Mikiko,Yamaguchi, Takao
, p. 8751 - 8754 (2017)
We herein propose a simple affinity-labeling method using a ligand-4-azidophthalimide (AzPI) conjugate. As a proof of concept, we show that two different ligand-AzPI conjugates enabled highly specific fluorescence labeling of their individual target proteins even in crude cell lysates. This method was also applied to label endogenous target proteins inside living cells.
Facile synthesis and evaluation of C-functionalized benzyl-1-oxa-4,7,10- triazacyclododecane-N,N′,N″-triacetic acid as chelating agent for 111In-labeled polypeptides
Suzuki, Hiroyuki,Kanai, Ayaka,Uehara, Tomoya,Guerra Gomez, Francisco L.,Hanaoka, Hirofumi,Arano, Yasushi
, p. 978 - 984 (2012)
A 12-membered polyazamacrocycle, 1-oxa-4,7,10-triazacyclododecane-N, N′,N″-triacetic acid (ODTA), has been reported to provide an indium chelate of net neutral charge with thermodynamic stability higher than 1,4,7,10-tetraazacyclododecane-N,N′,N″,N?-tetra
Synthesis and evaluation of a pseudocyclic tristhiourea-based anion host
Dahan, Adi,Ashkenazi, Tali,Kuznetsov, Vladimir,Makievski, Svetlana,Drug, Eyal,Fadeev, Ludmila,Bramson, Maayan,Schokoroy, Sari,Rozenshine-Kemelmakher, Emily,Gozin, Michael
, p. 2289 - 2296 (2007)
A novel methodology for the evaluation of receptor arrangement in structurally flexible anion chemosensors was developed and applied to map the binding site of a new pseudocyclic tristhiourea chemosensor (6). The syntheses of 6 and related macrocyclic chemosensor 10 (a model of the folded monomeric structure of 6) are reported. Both chemosensors were evaluated by titration with a variety of structurally different anions in CH3Cl and DMSO, showing a common preference for F-, CH3CO2 -, and H2PO4-. However, within this group of anions, the binding patterns of the chemosensors differed, indicating dissimilarity in the arrangement of the binding sites of 6 and 10.
Design, Synthesis, and Evaluation of VHL-Based EZH2 Degraders to Enhance Therapeutic Activity against Lymphoma
Tu, Yalin,Sun, Yameng,Qiao, Shuang,Luo, Yao,Liu, Panpan,Jiang, Zhong-Xing,Hu, Yumin,Wang, Zifeng,Huang, Peng,Wen, Shijun
, p. 10167 - 10184 (2021/07/26)
Traditional EZH2 inhibitors are developed to suppress the enzymatic methylation activity, and they may have therapeutic limitations due to the nonenzymatic functions of EZH2 in cancer development. Here, we report proteolysis-target chimera (PROTAC)-based EZH2 degraders to target the whole EZH2 in lymphoma. Two series of EZH2 degraders were designed and synthesized to hijack E3 ligase systems containing either von Hippel-Lindau (VHL) or cereblon (CRBN), and some VHL-based compounds were able to mediate EZH2 degradation. Two best degraders, YM181 and YM281, induced robust cell viability inhibition in diffuse large B-cell lymphoma (DLBCL) and other subtypes of lymphomas, outperforming a clinically used EZH2 inhibitor EPZ6438 (tazemetostat) that was only effective against DLBCL. The EZH2 degraders displayed promising antitumor activities in lymphoma xenografts and patient-derived primary lymphoma cells. Our study demonstrates that EZH2 degraders have better therapeutic activity than EZH2 inhibitors, which may provide a potential anticancer strategy to treat lymphoma.
Design, synthesis and biological evaluation of tyrosinase-targeting PROTACs
Cui, Xin,Deng, Yun,Fu, Dingqiang,Li, Guangxun,Qin, Fengming,Tang, Zhuo,Xu, Yan,Yao, Shaohua,Yuan, Yi
supporting information, (2021/10/12)
The human tyrosinase is the most prominent therapeutic target for pigmentary skin disorders. However, the overwhelming majority efforts have been devoted to search mushroom tyrosinase inhibitors, which show poor inhibitory activity on human tyrosinase and certain side effects that cause skin damage in practical application. Herein, a series of degraders that directly targeted human tyrosinase was firstly designed and synthesized based on newly developed PROTAC technology. The best PROTAC TD9 induced human tyrosinase degradation obviously in dose and time-dependent manner, and its mechanism of inducing tyrosinase degradation has also been clearly demonstrated. Besides, encouraging results that low-toxicity PROTAC TD9 was applied to reduce zebrafish melanin synthesis have been obtained, highlighting the potential to treatment of tyrosinase-related disorders. Moreover, this work has innovatively expanded the application scope of PROTAC technology and laid a solid foundation for further development of novel drugs treating pigmentary skin disorders.
LIGAND DRUG CONJUGATES AND MODIFIED BET INHIBITORS
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Page/Page column 9-10, (2021/07/17)
A ligand drug conjugate comprising a) a targeting ligand; b) a cleavable bridge; and a bromodomain and extraterminal (BET) inhibitor is provided. The targeting ligand may comprise a cancer targeting ligand. The BET inhibitor may comprise I-BET762, (+)-JQ1, MS417, OXT015, (2), RVX-208, (3), OXFBD02, OXFBD03, I-BET151, (4), PFI-1, I-BET726, MS436, XD14 or a modified BET inhibitor. Modified BET inhibitors are also provided, including RT48 ((S) -2- (6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-benzo[f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-4-yl)-1-(4-(dimethylamino) piperidin-1-yl) ethan-1-one) and RT53 ((S) -2- (6- (4-chlorophenyl) -8-methoxy-1-methyl-4H-benzo[f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-4-yl) -N-(4- (4- (dimethylamino) piperidin-1-yl) phenyl) acetamide). A pro-drug of a BET inhibitor is also provided. A method of preparing a ligand drug conjugate according to the invention is also provided. The method comprises i) functionalising a BET inhibitor with a tertiary amine to form a modified BET inhibitor according to the invention; ii) bonding the modified BET inhibitor formed in step i) to a cleavable bridge; and iii) bonding the cleavable bridge bound to the modified BET inhibitor formed in step ii) to a targeting ligand. A ligand drug conjugate according to the invention for use as a medicament is also provided.
Evaluation of linker length effects on a BET bromodomain probe
Traquete, Rui,Henderson, Elizabeth,Picaud, Sarah,Cal, Pedro M. S. D.,Sieglitz, Florian,Rodrigues, Tiago,Oliveira, Rudi,Filippakopoulos, Panagis,Bernardes, Gon?alo J. L.
supporting information, p. 10128 - 10131 (2019/08/30)
Fueled by the therapeutic potential of the epigenetic machinery, BET bromodomains have seen high interest as drug targets. Herein, we introduce different linkers to a BET bromodomain benzodiazepine ligand (I-BET762) to gauge its implications in the develo
Thiazole orange – Spermine conjugate: A potent human telomerase inhibitor comparable to BRACO-19
Wang, Siwen,Yang, Dazhou,Singh, Mandeep,Joo, Hyun,Rangel, Vanessa M.,Tran, Aaron,Phan, Erich,Xue, Liang
, p. 20 - 33 (2019/05/06)
In this report, we synthesized a series of TO conjugates containing different amino side chains and investigated their binding to telomeric G-quadruplex DNA (G4) using several biophysical methods including fluorometric titration and thermal denaturation monitored by fluorescence and circular dichroism. The composition of side chains strongly affects the binding of these molecules to G-quadruplex DNA. Incorporation of amino side chains increases the binding affinity of TO toward G4 but has a minimal effect on its selectivity for G4 over duplex DNA. The plausible binding modes are a synergistic effect of end-stacking and groove interactions as indicated by docking studies. Inhibition of human telomerase activity by TO derivatives was determined in vitro by the TRAP assay. Several derivatives can selectively inhibit the activity of telomerase over DNA polymerase at low concentrations. More significantly, TO-spermine conjugate (16) exhibits a remarkable effect on telomerase inhibition in the submicromolar range, which is comparable to the inhibition effect of a well-known G4 ligand, BRACO-19. Our results here provide guidance of utilizing TO derivatives as a viable scaffold to design novel G4 ligands, G4 probes, and potent telomerase inhibitors.