Molecular Diversity

, Volume 9, Issue 1–3, pp 123–129 | Cite as

Discovery of structurally diverse natural product antagonists of chemokine receptor CXCR3

  • John G. Ondeyka
  • Kithsiri b. Herath
  • Hiranthi Jayasuriya
  • Jon D. Polishook
  • Gerald F. Bills
  • Anne W. Dombrowski
  • Marina Mojena
  • Gregory Koch
  • Jerry DiSalvo
  • Julie DeMartino
  • Ziqiang Guan
  • Weerachai Nanakorn
  • Cori M. Morenberg
  • Michael J. Balick
  • Dennis W. Stevenson
  • Marc Slattery
  • Robert P. Borris
  • Sheo B. Singh
Full-length paper

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 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.

Keywords

chemokines CXCL10 CXCR3 receptor natural products extract libraries transplantation 

Abbreviations

HTS

high throughput screening

HPLC

high performance liquid chromatography

CV

column volumes

NMR

nuclear magnetic resonance

LC/MS

liquid chromatography/mass spectrometry

HRESIMS

high resolution electrospray ionization mass spectrometry

MW

molecular weight

HMQC

heteronuclear multiple quantum correlation

HMBC

heteronuclear multiple bond correlation

COSY

1H-1H correlation spectroscopy

TOCSY

total correlation spectroscopy

LCQ

liquid chromatography quadrupole mass spectrometer

ESI

electrospray ionization

APCI

atmospheric pressure chemical ionization

FTMS

Fourier transform mass spectrometry

TFA

trifluoroacetic acid tR retention time calcd. calculated

HR-MALDITOF-MS

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

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Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  • John G. Ondeyka
    • 1
  • Kithsiri b. Herath
    • 1
  • Hiranthi Jayasuriya
    • 1
  • Jon D. Polishook
    • 1
  • Gerald F. Bills
    • 2
  • Anne W. Dombrowski
    • 1
  • Marina Mojena
    • 2
  • Gregory Koch
    • 1
  • Jerry DiSalvo
    • 1
  • Julie DeMartino
    • 1
  • Ziqiang Guan
    • 1
  • Weerachai Nanakorn
    • 3
  • Cori M. Morenberg
    • 4
  • Michael J. Balick
    • 4
  • Dennis W. Stevenson
    • 4
  • Marc Slattery
    • 5
  • Robert P. Borris
    • 1
  • Sheo B. Singh
    • 1
  1. 1.Merck Research LaboratoriesRahwayUSA
  2. 2.CIBE, Merck Sharp & Dohme de EspanaS. A. Josefa ValcárcelMadridSpain
  3. 3.The Forest HerbariumRoyal Forest DepartmentBangkokThailand
  4. 4.Institute of Economic BotanyThe New York Botanical GardenBronx, NYUSA
  5. 5.Nationa Center for Natural Products ResearchDepartment of Pharmacognosy, School of Pharmacy, The University of MississippiMSUSA

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