6533b825fe1ef96bd12829ad

RESEARCH PRODUCT

Anti-inflammatory drimane sesquiterpene lactones from an Aspergillus species

Louis P. SandjoSilke FelixTill OpatzGerhard Erkel

subject

ChemokineCell SurvivalClinical BiochemistryPharmaceutical ScienceAntineoplastic AgentsInflammationCXCR3BiochemistryLactonesStructure-Activity RelationshipImmune systemDrug DiscoveryTumor Cells CulturedmedicineHumansCXCL10RNA MessengerReceptorMolecular BiologyCell ProliferationPolycyclic SesquiterpenesDose-Response Relationship DrugbiologyChemistryAnti-Inflammatory Agents Non-SteroidalOrganic ChemistryBiological activityTransfectionMolecular biologyChemokine CXCL10AspergillusBiochemistrybiology.proteinMolecular MedicineDrug Screening Assays Antitumormedicine.symptomSesquiterpenes

description

Abstract IFN-γ inducible protein 10 (IP-10, CXCL10) is a 10 kDa chemokine, which is secreted from various cell types after exposure to pro-inflammatory stimuli. This chemokine is a ligand for the CXCR3 receptor and regulates immune responses by activating and recruiting leukocytes such as T cells, eosinophils, monocytes, and NK cells to sites of inflammation. Altered expression of CXCL10 has been associated with chronic inflammatory and infectious diseases and therefore CXCL10 represents a promising target for the development of new anti-inflammatory drugs. In a search for inhibitors of CXCL10 promoter activity, three structurally related drimane sesquiterpene lactones (compounds 1–3) were isolated from fermentations of an Aspergillus species. Compounds 1 and 2 inhibited the IFN-γ/TNF-α/IL-1β induced CXCL10 promoter activity in transiently transfected human DLD-1 colon carcinoma cells in a dose-dependent manner with IC50 values of 12.4 μM for 1 and 55 μM for 2, whereas 3 was devoid of any biological activity. Moreover, compounds 1 and 2 reduced CXCL10 mRNA levels and synthesis in IFN-γ/TNF-α/IL-1β stimulated DLD-1 cells.

yearjournalcountryeditionlanguage
2014-02-18Bioorganic & Medicinal Chemistry
https://doi.org/10.1016/j.bmc.2014.04.015