ABSTRACT
Chemokines CXCL8 and CXCL1 play a key role in the recruitment of neutrophils at the site of inflammation. CXCL8 binds two membrane receptors, CXCR1 and CXCR2, whereas CXCL1 is a selective agonist for CXCR2. In the past decade, the physiopathological role of CXCL8 and CXCL1 has been investigated. A novel class of small molecular weight allosteric CXCR1 inhibitors was identified, and reparixin, the first drug candidate, is currently under clinical investigation in the prevention of ischemia/reperfusion injury in organ transplantation. Reparixin binding mode to CXCR1 has been studied and used for a computer-assisted design program of dual allosteric CXCR1 and CXCR2 inhibitors. In this paper, the results of modeling-driven SAR studies for the identification of potent dual inhibitors are discussed, and three new compounds (56, 67, and 79) sharing a common triflate moiety have been selected as potential leads with optimized pharmacokinetic characteristics.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Interleukin-8/antagonists & inhibitors , Mesylates/chemical synthesis , Phenylpropionates/chemical synthesis , Propionates/chemical synthesis , Receptors, Interleukin-8A/antagonists & inhibitors , Receptors, Interleukin-8B/antagonists & inhibitors , Allosteric Regulation , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Chemotaxis, Leukocyte , Dinoprostone/biosynthesis , Humans , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/physiology , Macrophages, Peritoneal/drug effects , Macrophages, Peritoneal/metabolism , Mesylates/chemistry , Mesylates/pharmacology , Mice , Models, Molecular , Mutation , Phenylpropionates/chemistry , Phenylpropionates/pharmacology , Propionates/pharmacokinetics , Propionates/pharmacology , Receptors, Interleukin-8A/genetics , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Preclinical imaging modalities represent an essential tool to develop a modern and translational biomedical research. To date, Optical Imaging (OI) and Magnetic Resonance Imaging (MRI) are used principally in separate studies for molecular imaging studies. We decided to combine OI and MRI together through the development of a lentiviral vector to monitor the Wnt pathway response to Lithium Chloride (LiCl) treatment. The construct was stably infected in glioblastoma cells and, after intracranial transplantation in mice, serial MRI and OI imaging sessions were performed to detect human ferritin heavy chain protein (hFTH) and firefly luciferase enzyme (FLuc) respectively. The system allowed also ex vivo analysis using a constitutive fluorescence protein expression. In mice, LiCl administration has shown significantly increment of luminescence signal and a lower signal of T2 values (P<0.05), recorded noninvasively with OI and a 7 Tesla MRI scanner. This study indicates that OI and MRI can be performed in a single in vivo experiment, providing an in vivo proof-of-concept for drug discovery projects in preclinical phase.
Subject(s)
Genes, Reporter/genetics , Molecular Imaging , Animals , Apoferritins/genetics , Apoferritins/metabolism , Brain/metabolism , Cell Line, Tumor , Female , Gene Expression , Humans , Lithium Chloride/pharmacology , Luciferases, Firefly/genetics , Magnetic Resonance Imaging , Mice, Nude , Optical Imaging , Wnt Signaling PathwayABSTRACT
The unusual reactivity of 1-phenyl-1-ethanesulfonic acid in thionyl chloride was investigated. Mechanistic considerations led us to set up a new and efficient synthesis of E-arylethenesulfonamides starting from 1-hydroxy-1-arylalkanes. The easy availability of the starting materials and the straightforward, one-pot procedure make this process an attractive method for the preparation of these compounds currently largely employed in chemical and pharmaceutical fields.