TY - JOUR
T1 - Noncyclam tetraamines inhibit CXC chemokine receptor type 4 and target glioma-initiating cells
AU - Ros-Blanco, Laia
AU - Anido, Judit
AU - Bosser, Ramon
AU - Esté, José
AU - Clotet, Bonaventura
AU - Kosoy, Ana
AU - Ruíz-Ávila, Luis
AU - Teixidó, Jordi
AU - Seoane, Joan
AU - Borrell, José I.
PY - 2012/9/13
Y1 - 2012/9/13
N2 - 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 IC50 values determined on human recombinant (CHO) cells showed very similar inhibitory activities albeit a lower KB 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.
AB - 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 IC50 values determined on human recombinant (CHO) cells showed very similar inhibitory activities albeit a lower KB 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.
UR - http://www.scopus.com/inward/record.url?scp=84866320588&partnerID=8YFLogxK
U2 - 10.1021/jm300862u
DO - 10.1021/jm300862u
M3 - Article
C2 - 22909088
AN - SCOPUS:84866320588
SN - 0022-2623
VL - 55
SP - 7560
EP - 7570
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 17
ER -