Synthesis and characterization of amino acid substituted sunitinib analogues for the treatment of AML. Issue 14 (1st August 2018)

• Record Type: Journal Article
• Authors: Nemes, Zoltán; Takács-Novák, Krisztina; Völgyi, Gergely; Valko, Klara; Béni, Szabolcs; Horváth, Zoltán; Szokol, Bálint; Breza, Nóra; Dobos, Judit; Szántai-Kis, Csaba; Illyés, Eszter; Boros, Sándor; Kok, Robbert Jan; Őrfi, László
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 28:Issue 14(2018)
• Page Start: 2391
• Page End: 2398
• Publication Date: 2018-08-01
• Subjects: FLT3-ITD kinase inhibitior -- Acute myeloid leukemia -- Chromatographic Hydrophobicity Index -- Shake-flask partition coefficient determination -- Peptide based targeted delivery; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.06.026
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: 62 amino acid substituted sunitinib analogues were synthesized, inhibiting FLT3-ITD kinase and AML cell line. Physical-chemical properties (solubility, acidity and liphophilicity) were determined for the compounds at pH = 7.4 and 5.5. Compound20a was selected to be conjugated with peptide based delivery systems. Abstract: Acute myeloid leukemia (AML) is the most common type of leukemia in adults. Sunitinib, a multikinase inhibitor, was the first Fms-like tyrosine kinase 3 (FLT3) inhibitor clinically used against AML. Off-target effects are a major concern for multikinase inhibitors. As targeted delivery may reduce such undesired side effects, our goal was to develop novel amino acid substituted derivatives of sunitinib which are potent candidates to be used conjugated with antibodies and peptides. In the current paper we present the synthesis, physicochemical and in vitro characterization of sixty two Fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutant kinase inhibitors, bearing amino acid moieties, fit to be conjugated with peptide-based delivery systems via their carboxyl group. We determined the solubility, p K a, CHI and Log P values of the compounds along with their inhibition potential against FLT3-ITD mutant kinase and on MV4-11 cell line. The ester derivatives of the compounds inhibit the growth of the MV4-11 leukemia cell line at submicromolar concentration.