The Interaction of Mozobil(TM) with Carboxylates

MozobilTM (1,1′-[1,4-phenylenebis(methylene)]bis[1,4,8,11-tetraazacyclotetradecane, 1, also known
as JM3100 and AMD 3100) is a specific antagonist of the chemokine coreceptor CXCR4 and
favours the mobilisation from the bone marrow of stem cells, which can be used for autologous
transplantation. It is believed that the interaction, of both hydrogen bonding and electrostatic
nature, involves a partly protonated form of MozobilTM, LHn
n+ and the COO−
groups of Asp171 and
Asp262 residues protruding from the walls of the pocket of the membrane protein CXCR4. We have
investigated, through potentiometric titrations in 0.1 M NaNO3 at 25 °C, the interaction equilibria
between 1 (L) and linear dicarboxylates A2−. These studies have demonstrated that the main
equilibrium takes place: LH5
5+ + A2− [LH5···A]3+, and that the most stable [LH5···A]3+ complex
forms for A2−
= diphenyl-4,4’-dicarboxylate, whose length matches that of LH5
5+
.
1H NMR titration
experiments have shown that in the 7-10 pH interval LH3
3+, LH2
2+ and LH+
forms establish with
diphenyl-4,4’-dicarboxylate π-π interactions, according to a topological arrangement which
excludes the formation of H-bonds. It is finally suggested that, in the pocket of the CXCR4
membrane proteine, MOZOBILTM operates as a pentammonium cation, which establishes with
carboxylate groups of Asp171 and Asp262 strong interactions of hydrogen bonding and electrostatic
nature.