Anti-inflammatory drimane sesquiterpene lactones from an Aspergillus species.

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.

• Authors: Silke Felix, Louis P Sandjo, Till Opatz, Gerhard Erkel
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 22 Issue 11 Pg. 2912-8 (Jun 01 2014) ISSN: 1464-3391 [Electronic] England
• PMID: 24792812 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Antineoplastic Agents
• CXCL10 protein, human
• Chemokine CXCL10
• Lactones
• Polycyclic Sesquiterpenes
• RNA, Messenger
• Sesquiterpenes
• drimane

Topics

• Anti-Inflammatory Agents, Non-Steroidal (chemistry, isolation & purification, pharmacology)
• Antineoplastic Agents (chemistry, isolation & purification, pharmacology)
• Aspergillus (chemistry)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Chemokine CXCL10 (antagonists & inhibitors, genetics, immunology)
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Humans
• Lactones (chemistry, isolation & purification, pharmacology)
• Polycyclic Sesquiterpenes
• RNA, Messenger (drug effects, genetics, immunology)
• Sesquiterpenes (chemistry, isolation & purification, pharmacology)
• Structure-Activity Relationship
• Tumor Cells, Cultured