Noncyclam Tetraamines
Inhibit CXC Chemokine Receptor
Type 4 and Target Glioma-Initiating Cells
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Abstract
The three stereoisomers of the noncyclam compound <b>1</b> (<b>1</b>(<i>R,R</i>), <b>1</b>(<i>S,S</i>), and the <i>meso</i> form <b>1</b>(<i>S,R</i>)) and their corresponding tetrahydrochlorides <b>11</b> were
prepared from (<i>S</i>)- and (<i>R</i>)-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<sub>50</sub> values determined on human recombinant
(CHO) cells showed very similar inhibitory activities albeit a lower <i>K</i><sub>B</sub> for AMD3100, with the <b>1</b>(<i>R,R</i>) 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