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

作者：Ros Blanco Laia; Anido Judit; Bosser Ramon; Este Jose; Clotet Bonaventura; Kosoy Ana; Ruiz Avila Luis; Teixido Jordi; Seoane Joan; Borrell Jose I^*

来源：Journal of Medicinal Chemistry, 2012, 55(17): 7560-7570.

DOI：10.1021/jm300862u

The three stereoisomers of the noncyclam compound 1 (1(R,R), 1(S,S), and the mesa 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 IC50 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.

• 出版日期2012-9-13