Selective inhibition of the interaction of C1q with immunoglobulins and the classical pathway of complement activation by steroids and triterpenoids sulfates
| Autor: | Vladimir I. Popenko, Anna M. Bichucher, Svetlana Bureeva, Vera Moskaleva, Leonid V. Kozlov, Andrey Symon, Alexey V. Shpak, Alexander Kaplun, Vitaly Shvets, Julian Andia-Pravdivy |
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| Rok vydání: | 2007 |
| Předmět: |
Magnetic Resonance Spectroscopy
medicine.medical_treatment Guinea Pigs Clinical Biochemistry Molecular Conformation Immunoglobulins Pharmaceutical Science In Vitro Techniques Hemolysis Biochemistry Steroid chemistry.chemical_compound Classical complement pathway Betulinic acid Drug Discovery medicine Animals Humans Complement Pathway Classical Molecular Biology Complement C1q Sheep Betulin Pentraxins biology Organic Chemistry Triterpenes Complement system Microscopy Electron chemistry biology.protein Alternative complement pathway Molecular Medicine Indicators and Reagents Steroids |
| Zdroj: | Bioorganic & Medicinal Chemistry. 15:3489-3498 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2007.03.002 |
| Popis: | Since undesirable activation of the complement system through the classical pathway is associated with tissue damage and other pathologic proinflammatory consequences at ischemia/reperfusion injury, autoimmune diseases, and rejection of allo- and xenografts, creation of selective inhibitors of the classical pathway leaving the alternative pathway intact is of great importance. Classical pathway is triggered by binding of its recognizing unit, protein C1q, to a number of targets like antibodies, pentraxins, apoptotic cells, and others. In order to obtain inhibitors blocking the first step of the classical cascade, synthesis of sulfates of steroids (Delta(5)-3beta-hydroxycholenic, Delta(5)-3beta-hydroxyetiocholenic, deoxycholic, and cholic acids) and triterpenoids (betulin, 20,29-dihydro-20,29-dichloromethylenbetulin, betulinic, ursolic, and oleanolic acids) has been performed. Testing of the compounds in classical pathway inhibition assay has displayed derivatives of triterpenoid betulin (betulin disulfate and betulinic acid sulfate) to be the most potent inhibitors. Further studies of the two compounds established that their activity to inhibit the classical pathway had been due to their capability to block the interaction of C1q with antibodies. Betulin disulfate and betulinic acid sulfate have shown weak inhibition of the alternative route of activation, what makes them promising inhibitors for the selective suppression of the classical complement pathway at the earliest possible level as well as perspective agents for blocking the interaction of C1q with its other targets. |
| Databáze: | OpenAIRE |
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