Noncyclam Tetraamines Inhibit CXC Chemokine Receptor Type 4 and Target Glioma-Initiating Cells

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 IC₅₀ values determined on human recombinant (CHO) cells showed very similar inhibitory activities albeit a lower <i>K</i>_B 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