ABSTRACT
A gold(I)-catalyzed cascade reaction for the stereoselective synthesis of sulfur- or selenium-containing indeno[1,2-b]chromene derivatives from o-(alkynyl)styrenes substituted at the triple bond with a thio- or seleno-aryl group is described. The reaction involves a double cyclization process through a proposed key gold-cyclopropyl carbene intermediate that evolves by the intramolecular addition of an aromatic to the cyclopropane ring, affording polycyclic structures. The enantioselective version was studied using gold(I) complexes bearing chiral ligands.
ABSTRACT
Human interleukin-11 (hIL-11) is a pleiotropic cytokine administered to patients with low platelet counts. From a structural point of view hIL-11 belongs to the long-helix cytokine superfamily, which is characterized by a conserved core motif consisting of four α-helices. We have investigated the region of hIL-11 that does not belong to the α-helical bundle motif, and that for the purpose of brevity we have termed "non-core region." The primary sequence of the interleukin was altered at various locations within the non-core region by introducing glycosylation sites. Functional consequences of these modifications were examined in cell-based as well as biophysical assays. Overall, the data indicated that the non-core region modulates the function of hIL-11 in two ways. First, the majority of muteins displayed enhanced cell-stimulatory properties (superagonist behavior) in a glycosylation-dependent manner, suggesting that the non-core region is biologically designed to limit the full potential of hIL-11. Second, specific modification of a predicted mini α-helix led to cytokine inactivation, demonstrating that this putative structural element belongs to site III engaging a second copy of cell-receptor gp130. These findings have unveiled new and unexpected elements modulating the biological activity of hIL-11, which may be exploited to develop more versatile medications based on this important cytokine.
Subject(s)
Interleukin-11/metabolism , Protein Modification, Translational/physiology , Signal Transduction/physiology , Amino Acid Motifs , Animals , Cell Line, Tumor , Cytokine Receptor gp130/chemistry , Cytokine Receptor gp130/genetics , Cytokine Receptor gp130/metabolism , Glycosylation , Humans , Interleukin-11/agonists , Interleukin-11/antagonists & inhibitors , Interleukin-11/chemistry , Interleukin-11/genetics , Mice , Structure-Activity RelationshipABSTRACT
Repertory analysis of homoeopathic cases has always been very time-consuming. For this reason homoeopathic doctors have often had to restrict themselves to searching for the most likely remedies from a total of... (AU)
