Noncyclam tetraamines inhibit CXC chemokine receptor type 4 and target glioma-initiating cells.

Abstract

The three stereoisomers of the noncyclam compound 1 (1(R,R), 1(S,S), and the meso form 1(S,R)) and their corresponding tetrahydrochlorides 11 were prepared from (S)- and (R)-2-methylpiperidine. We have evaluated their inhibitory activity on the CXC chemokine receptor type 4 (CXCR4), toxicity properties, and assessment of their effect on glioma initiating cells (GICs) in comparison with the prototype compound AMD3100. The IC(50) values determined on human recombinant (CHO) cells showed very similar inhibitory activities albeit a lower K(B) for AMD3100, with the 1(R,R) isomer being second in potency. All the compounds showed low cardiac toxicity but, contrary to AMD3100, gave maximum nonlethal doses of around 2.0 mg/kg. The CXCR4 inhibitors had an effect on the state of differentiation of GICs, decreasing the percentage of CD44+ cells in glioblastoma multiform neurospheres in vitro. Moreover, these CXCR4 inhibitors blocked the capacity of cells to initiate orthotopic tumors in immunocompromised mice.

• Authors: Laia Ros-Blanco, Judit Anido, Ramon Bosser, José Esté, Bonaventura Clotet, Ana Kosoy, Luis Ruíz-Ávila, Jordi Teixidó, Joan Seoane, José I Borrell
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 55 Issue 17 Pg. 7560-70 (Sep 13 2012) ISSN: 1520-4804 [Electronic] United States
• PMID: 22909088 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amines
• Antiviral Agents
• Lactams, Macrocyclic
• Receptors, CXCR4

Topics

• Amines (chemistry, pharmacology)
• Animals
• Antiviral Agents (chemistry, pharmacology)
• Brain Neoplasms (metabolism, pathology)
• CHO Cells
• Cricetinae
• Cricetulus
• Flow Cytometry
• Glioma (metabolism, pathology)
• Humans
• Inhibitory Concentration 50
• Lactams, Macrocyclic
• Magnetic Resonance Spectroscopy
• Receptors, CXCR4 (antagonists & inhibitors)
• Spectrometry, Mass, Electrospray Ionization