Acid-base profiling of imatinib (gleevec) and its fragments.
The site-specific basicities of imatinib (Gleevec, a new signal transduction inhibitor drug of chronic myeloid leukemia) and two of its fragment compounds were quantitated in terms of protonation macroconstants, microconstants, and group constants by NMR-pH and pH-potentiometric titrations. Sequential protonation of imatinib follows the N(34), N(11), N(31), N(13) order, in which N(11) and N(31) show commensurable basicity, but negligible intramolecular interaction. Fragment compounds include two "halves" of imatinib, and their moiety-specific basicities confirm the NMR-based protonation sequence of the parent compound. NMR-pH profiles, macro- and/or microscopic protonation schemes, and species-specific distribution diagrams are presented. On the basis of these data, imatinib is shown to be predominantly neutral, monocationic, and tricationic at intestinal, blood, and gastric pH, respectively. The molecular hypotheses on imatinib binding to the Bcr-Abl oncogene fusion protein are interpreted at the site-specific level in view of the moiety basicities of imatinib.
Szakács
Zoltán
Z
Department of Inorganic and Analytical Chemistry, Loránd Eötvös University, Pázmány Péter sétány 1/a, H-1117 Budapest, Hungary.
Béni
Szabolcs
S
Varga
Zoltán
Z
Orfi
László
L
Kéri
György
G
Noszál
Béla
B
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism; D001549:Benzamides; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D000068877:Imatinib Mesylate; D009682:Magnetic Resonance Spectroscopy; D010879:Piperazines / Q000737:chemistry* / Q000378:metabolism; D011199:Potentiometry; D011743:Pyrimidines / Q000737:chemistry* / Q000378:metabolism
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl