Molecular Diversity

, Volume 9, Issue 1, pp 123–129

Discovery of structurally diverse natural product antagonists of chemokine receptor CXCR3


    • Merck Research Laboratories
  • Kithsiri b. Herath
    • Merck Research Laboratories
  • Hiranthi Jayasuriya
    • Merck Research Laboratories
  • Jon D. Polishook
    • Merck Research Laboratories
  • Gerald F. Bills
    • CIBE, Merck Sharp & Dohme de EspanaS. A. Josefa Valcárcel
  • Anne W. Dombrowski
    • Merck Research Laboratories
  • Marina Mojena
    • CIBE, Merck Sharp & Dohme de EspanaS. A. Josefa Valcárcel
  • Gregory Koch
    • Merck Research Laboratories
  • Jerry DiSalvo
    • Merck Research Laboratories
  • Julie DeMartino
    • Merck Research Laboratories
  • Ziqiang Guan
    • Merck Research Laboratories
  • Weerachai Nanakorn
    • The Forest HerbariumRoyal Forest Department
  • Cori M. Morenberg
    • Institute of Economic BotanyThe New York Botanical Garden
  • Michael J. Balick
    • Institute of Economic BotanyThe New York Botanical Garden
  • Dennis W. Stevenson
    • Institute of Economic BotanyThe New York Botanical Garden
  • Marc Slattery
    • Nationa Center for Natural Products ResearchDepartment of Pharmacognosy, School of Pharmacy, The University of Mississippi
  • Robert P. Borris
    • Merck Research Laboratories
  • Sheo B. Singh
    • Merck Research Laboratories
Full-length paper

DOI: 10.1007/s11030-005-1296-8

Cite this article as:
Ondeyka, J.G., Herath, K.b., Jayasuriya, H. et al. Mol Divers (2005) 9: 123. doi:10.1007/s11030-005-1296-8


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 μM) 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 125 I IP-10/CXCR3 binding assay. Duramycin was the most potent with an IC50 of 0.1 μM. Roselipins 2A, 2B and 1A showed IC50 values of 14.6, 23.5, and 41 μM, respectively. Diosgenin glycosides dioscin, hypoglaucin A and kallstroemin D exhibited IC50 values of 2.1, 0.47 and 3 μM, respectively. A novel cyclic 3-alkyl pyridinium salt isolated from a sponge displayed a binding IC50 of 0.67 μ M.


chemokinesCXCL10CXCR3 receptornatural products extract librariestransplantation



high throughput screening


high performance liquid chromatography


column volumes


nuclear magnetic resonance


liquid chromatography/mass spectrometry


high resolution electrospray ionization mass spectrometry


molecular weight


heteronuclear multiple quantum correlation


heteronuclear multiple bond correlation


1H-1H correlation spectroscopy


total correlation spectroscopy


liquid chromatography quadrupole mass spectrometer


electrospray ionization


atmospheric pressure chemical ionization


Fourier transform mass spectrometry


trifluoroacetic acid tR retention time calcd. calculated


high resolution matrix assisted laser desorption ionization time-of-flight mass spectrometry.

Copyright information

© Springer Science + Business Media, Inc. 2005