Discovery of structurally diverse natural product antagonists of chemokine receptor CXCR3

Abstract

The chemokines (CXCL9, CXCL10 and CXCL11) and associated CXCR3 receptor are expressed during the inflammatory process from multiple sclerosis, atherosclerosis or organ transplantation resulting in the recruitment of lymphocytes leading to tissue damage. It is hypothesized that blocking of the ligand/CXCR3 receptor interaction has potential to provide opportunity for development of agents that would block tissue rejection. In this paper, four classes of natural product inhibitors (IC50 ranging 0.1-41 microM) have been described that block the CXCR3 receptor interaction of IP-10 ligand. These include a cyclic thiopeptide (duramycin), polyketide glycosides (roselipins), steroidal glycosides (hypoglausin A and dioscin) and a novel alkyl pyridinium alkaloid that were isolated by bioassay-guided fractionation of the organic extracts derived from actinomycete, fungal, plant and marine sources and discovered using 125I IP-10/CXCR3 binding assay. Duramycin was the most potent with an IC50 of 0.1 microM. Roselipins 2A, 2B and 1A showed IC50 values of 14.6, 23.5, and 41 microM, respectively. Diosgenin glycosides dioscin, hypoglaucin A and kallstroemin D exhibited IC50 values of 2.1, 0.47 and 3 microM, respectively. A novel cyclic 3-alkyl pyridinium salt isolated from a sponge displayed a binding IC50 of 0.67 microM.

Antitumor promoting potential of selected phytochemicals derived from spices

“…However, activation of arachidonic acid by diosgenin in human erythroleukemia TIB-180 cells led to COX-2 overexpression accompanied by apoptosis induction through G 2 /M cell cycle arrest and p53-independent p21 upregulation; a similar COX-2 independent mechanism was observed in K562 erythroleukemia cells (Leger et al, 2004;Liagre et al, 2005). A recent study proves that diosgenin binds to the chemokine receptor CXCR3, which mediates inflammatory responses (Ondeykal et al, 2005). Diosgenin inhibits pAkt expression and Akt kinase activity without affecting PI3 kinase levels, resulting in the inhibition of its downstream targets, NF-kB, Bcl-2, survivin, and XIAP.…”

Fas Ligand Is Responsible for CXCR3 Chemokine Induction in CD4+ T Cell-Dependent Liver Damage

“…In this case, NBI-74330 (40) demonstrates the ability to inhibit receptor activation by all three CXCR3 ligands and this series (T487) of CXCR3 antagonists are currently in phase II clinical trials. In addition to manufactured inhibitors, four other natural CXCR3 antagonists have been reported to be effective in the blockade of CXCR3 action (56). Given the role that CXCR3 ligands play in induction of hepatic damage, prevention of CXCR3 engagement may be beneficial not only for the treatment of the acute/early infection period but also for treatment during the early phases of fibrosis.…”

Towards Small‐Molecule CXCR3 Ligands with Clinical Potential

“…Merck performed a screen ( 125 I-CXCL10) on a library consisting of extracts from microbial, plant, and marine sources. [78] A highly diverse set of hits was picked up, including sugar-derivatised steroid 2 (IC 50 = 470 nm) and dipyridinium salt 3 (IC 50 = 690 nm).…”