title: Isolation and structures of novel fungal metabolites as chemokine receptor (CCR2) antagonists.
abstract: The chemokine receptor, CCR2, is predominantly expressed on monocytes/macrophages, and on a subset of memory T cells. It binds to several CC type chemokines of the monocyte chemoattractant protein (MCP) family of which MCP-1 exhibits the highest affinity. CCR2/MCP-1 expression/association in monocyte/macrophage/T cells has been associated with inflammatory processes such as rheumatoid arthritis, multiple sclerosis and atherosclerosis. Neutralization of CCR2 with either a peptide or receptor antagonist results in the prevention of joint swelling in rodent models of arthritis. In this paper, bioassay-guided discovery of CCR2 receptor antagonists derived from natural product extracts are reported. These antagonists belong to two main classes exemplified by bisthiodiketopiperazines and cytochalasins. Six compounds, including emestrin, two new emestrin analogs, and chaetomin represent the first group of compounds. These compounds inhibited the binding of MCP-1 to CCR2 (CHO membrane) with IC50 values of 0.8 to 9 microM and exhibited good activity in a whole cell assay using MCP-1 and human monocytes with IC50's ranging from 4-9 microM. Cytochalasins A and B represented the second group and inhibited the binding activity with IC50 values of 5 and 188 microM, respectively. This is the first report of natural product antagonists of the CCR2 receptor.
authors.affiliation: Merck Research Laboratories, Rahway, NJ 07065, USA.
authors.forename: Kithsiri B
authors.initials: KB
authors.lastname: Herath
authors.forename: Hiranthi
authors.initials: H
authors.lastname: Jayasuriya
authors.forename: John G
authors.initials: JG
authors.lastname: Ondeyka
authors.forename: Jon D
authors.initials: JD
authors.lastname: Polishook
authors.forename: Gerald F
authors.initials: GF
authors.lastname: Bills
authors.forename: Anne W
authors.initials: AW
authors.lastname: Dombrowski
authors.forename: Angeles
authors.initials: A
authors.lastname: Cabello
authors.forename: Pasquale P
authors.initials: PP
authors.lastname: Vicario
authors.forename: Hans
authors.initials: H
authors.lastname: Zweerink
authors.forename: Ziqiang
authors.initials: Z
authors.lastname: Guan
authors.forename: Sheo B
authors.initials: SB
authors.lastname: Singh
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D003572:Cytochalasins / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D004220:Disulfides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D005658:Fungi / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D026121:Indole Alkaloids / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D015394:Molecular Structure; D009000:Monocytes / Q000187:drug effects; D010446:Peptide Fragments / Q000378:metabolism; D010879:Piperazines / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C515334:CCR2 protein, human; D018932:Chemokine CCL2; D003572:Cytochalasins; D004220:Disulfides; D026121:Indole Alkaloids; D010446:Peptide Fragments; D010879:Piperazines; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; C106929:monocyte chemoattractant protein 1 (9-76); C001598:chetomin; C067458:emestrin