Acid-base profiling of imatinib (Gleevec) and its fragments

Zoltán Szakács, Szabolcs Béni, Zoltán Varga, László Örfi, György Kéri, Béla Noszál

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98 Scopus citations


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 N34, N11, N31, N13 order, in which N11 and N31 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.

Original languageEnglish (US)
Pages (from-to)249-255
Number of pages7
JournalJournal of Medicinal Chemistry
Issue number1
StatePublished - Jan 13 2005
Externally publishedYes


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