929-75-9Relevant articles and documents
Bivalent HIV-1 fusion inhibitors based on peptidomimetics
Kobayakawa, Takuya,Ebihara, Kento,Tsuji, Kohei,Kawada, Takuma,Fujino, Masayuki,Honda, Yuzuna,Ohashi, Nami,Murakami, Tsutomu,Tamamura, Hirokazu
, (2020/11/07)
Membrane fusion is a valid target for inhibition of HIV-1 replication. A 34-mer fragment peptide (C34), which is contained in the HIV-1 envelope protein gp41, has significant anti-HIV activity. Previously, a dimeric derivative of C34 linked by a disulfide bridge at its C-terminus was found to have more potent anti-HIV activity than the C34 peptide monomer. To date, several peptidomimetic small inhibitors have been reported, but most have lower potency than peptide derivatives related to C34. In the present study we applied this dimerization concept to these peptidomimetic small inhibitors and designed several bivalent peptidomimetic HIV-1 fusion inhibitors. The importance of the length of linkers crosslinking two peptidomimetic compounds was demonstrated and several potent bivalent inhibitors containing tethered peptidomimetics were produced.
Discovery of Macrocyclic Pyrimidines as MerTK-Specific Inhibitors
McIver, Andrew L.,Zhang, Weihe,Liu, Qingyang,Jiang, Xinpeng,Stashko, Michael A.,Nichols, James,Miley, Michael J.,Norris-Drouin, Jacqueline,Machius, Mischa,DeRyckere, Deborah,Wood, Edgar,Graham, Douglas K.,Earp, H. Shelton,Kireev, Dmitri,Frye, Stephen V.,Wang, Xiaodong
, p. 207 - 213 (2017/02/15)
Macrocycles have attracted significant attention in drug discovery recently. In fact, a few de novo designed macrocyclic kinase inhibitors are currently in clinical trials with good potency and selectivity for their intended target. In this study, we successfully engaged a structure-based drug design approach to discover macrocyclic pyrimidines as potent Mer tyrosine kinase (MerTK)-specific inhibitors. An enzyme-linked immunosorbent assay (ELISA) in 384-well format was employed to evaluate the inhibitory activity of macrocycles in a cell-based assay assessing tyrosine phosphorylation of MerTK. Through structure–activity relationship (SAR) studies, analogue 11 [UNC2541; (S)-7-amino-N-(4-fluorobenzyl)-8-oxo-2,9,16-triaza-1(2,4)-pyrimidinacyclohexadecaphane-1-carboxamide] was identified as a potent and MerTK-specific inhibitor that exhibits sub-micromolar inhibitory activity in the cell-based ELISA. In addition, an X-ray structure of MerTK protein in complex with 11 was resolved to show that these macrocycles bind in the MerTK ATP pocket.
Optimization of the Sensitization Process and Stability of Octadentate Eu(III) 1,2-HOPO Complexes
D'Aléo, Anthony,Moore, Evan G.,Xu, Jide,Daumann, Lena J.,Raymond, Kenneth N.
, p. 6807 - 6820 (2015/08/03)
The synthesis of a series of octadentate ligands containing the 1-hydroxypyridin-2-one (1,2-HOPO) group in complex with europium(III) is reported. Within this series, the central bridge connecting two diethylenetriamine units linked to two 1,2-HOPO chromophores at the extremities (5-LIN-1,2-HOPO) is varied from a short ethylene chain (H(2,2)-1,2-HOPO) to a long pentaethylene oxide chain (H(17O5,2)-1,2-HOPO). The thermodynamic stability of the europium complexes has been studied and reveals these complexes may be effective for biological measurements. Extension of the central bridge results in exclusion of the inner-sphere water molecule observed for [Eu(H(2,2)-1,2-HOPO)]- going from a nonacoordinated to an octacoordinated Eu(III) ion. With the longer chain length ligands, the complexes display increased luminescence properties in aqueous medium with an optimum of 20% luminescence quantum yield for the [Eu(H(17O5,2)-1,2-HOPO)]- complex. The luminescence properties for [Eu(H(14O4,2)-1,2-HOPO)]- and [Eu(H(17O5,2)-1,2-HOPO)]- are better than that of the model bis-tetradentate [Eu(5LINMe-1,2-HOPO)2]- complex, suggesting a different geometry around the metal center despite the geometric freedom allowed by the longer central chain in the H(mOn,2) scaffold. These differences are also evidenced by examining the luminescence spectra at room temperature and at 77 K and by calculating the luminescence kinetic parameters of the europium complexes. (Graph Presented).
