Noncyclam tetraamines inhibit CXC chemokine receptor type 4 and target glioma-initiating cells.
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.
Grup d'Enginyeria Molecular, Institut Químic de Sarrià, Universitat Ramon Llull, Via Augusta 390, E-08017 Barcelona, Spain.
Laia
L
Ros-Blanco
Judit
J
Anido
Ramon
R
Bosser
José
J
Esté
Bonaventura
B
Clotet
Ana
A
Kosoy
Luis
L
Ruíz-Ávila
Jordi
J
Teixidó
Joan
J
Seoane
José I
JI
Borrell
D000588:Amines / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005434:Flow Cytometry; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D020128:Inhibitory Concentration 50; D047029:Lactams, Macrocyclic; D009682:Magnetic Resonance Spectroscopy; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D021241:Spectrometry, Mass, Electrospray Ionization
D000588:Amines; D000998:Antiviral Agents; D047029:Lactams, Macrocyclic; D019718:Receptors, CXCR4