- Nanomolar e-selectin antagonists with prolonged half-lives by a fragment-based approach
-
Selectins, a family of C-type lectins, play a key role in inflammatory diseases (e.g., asthma and arthritis). However, the only millimolar affinity of sialyl Lewisx (sLex), which is the common tetrasaccharide epitope of all physiological selectin ligands, has been a major obstacle to the development of selectin antagonists for therapeutic applications. In a fragment-based approach guided by NMR, ligands binding to a second site in close proximity to a sLex mimic were identified. A library of antagonists obtained by connecting the sLex mimic to the best second-site ligand via triazole linkers of different lengths was evaluated by surface plasmon resonance. Detailed analysis of the five most promising candidates revealed antagonists with KD values ranging from 30 to 89 nM. In contrast to carbohydrate-lectin complexes with typical half-lives (t1/2) in the range of one second or even less, these fragment-based selectin antagonists show t1/2 of several minutes. They exhibit a promising starting point for the development of novel anti-inflammatory drugs.
- Egger, Jonas,Weckerle, Celine,Cutting, Brian,Schwardt, Oliver,Rabbani, Said,Lemme, Katrin,Ernst, Beat
-
supporting information
p. 9820 - 9828
(2013/07/26)
-
- E-SELECTIN ANTAGONISTS
-
Compounds, compositions and methods are provided for inhibiting in vitro and in vivo processes mediated by E-selectin binding. More specifically, particular glycomimetic compounds are described, wherein the compounds are E- selectin antagonists.
- -
-
Page/Page column 21
(2012/04/04)
-
- Design and photophysical properties of zinc(II) porphyrin-containing dendrons linked to a central artificial special pair
-
The click chemistry synthesis and photophysical properties, notably photo-induced energy and electron transfers between the central core and the peripheral chromophores of a series of artificial special pair-dendron systems (dendron=G1, G2, G3; Gx=zinc(II) tetra-meso-arylporphyrin-containing polyimides) built upon a central core of dimethylxanthenebis(metal(II) porphyrin) (metal=zinc, copper), are reported. The dendrons act as singlet and triplet energy acceptors or donors, depending on the dendrimeric systems. The presence of the paramagnetic d9 copper(II) in the dendrimers promotes singlet-triplet energy transfer from the zinc(II) tetra-meso-arylporphyrin to the bis(copper(II) porphyrin) unit and slow triplet-triplet energy transfer from the central bis(copper(II) porphyrin) fragment to the peripheral zinc(II) tetra-meso-arylporphyrin. If bis(zinc(II) porphyrin) is the central core, evidence for chain folding is observed; this is unambiguously demonstrated by the presence of triplet-triplet energy transfer in the heterobimetallic systems, a process that can only occur at short distances.
- Bregier, Frederique,Aly, Shawkat M.,Gros, Claude P.,Barbe, Jean-Michel,Rousselin, Yoann,Harvey, Pierre D.
-
experimental part
p. 14643 - 14662
(2012/02/04)
-
- Electron Delocalisation and Stabilisation in Substituted Amino- and Hydroxypropynyl Radicals
-
A series of aminopropynes, RCCCH2NH2 (R = H, Me, t-Bu, Me3Si), RCCCH2N(SiMe3)2, and hydroxypropynes RCCCH2OH (R = H, Me, t-Bu, Me3Si, CF3, and EtO2C), were prepared and the corresponding α-aminopropynyl and α-hydroxypropynyl radicals were examined by e.s.r. spectroscopy.For the first series, the C-N bond rotation barriers were determined from the exchange broadening in the spectra and hence radical stabilization energies were estimated.The spin distribution in these series indicated an extra delocalisation in radicals with captodative substitution.
- MacInnes, Iain,Walton, John C.
-
p. 1077 - 1082
(2007/10/02)
-
- Acetylene derivatives
-
Novel compounds of the following general formula are useful pharmacologic agents and are useful as intermediates for the preparation of pharmacologically useful compounds. STR1 wherein R1 is a straight or branched lower alkyl group having from 1 to 4 carbon atoms, R2 is trialkylmethyl, phenyl, 1-adamantanyl or 2-furyl; R3 is methoxy or ethoxy; and acid addition salts thereof.
- -
-
-