Synthesis and characterization of amino acid substituted sunitinib analogues for the treatment of AML

Zoltán Nemes; Krisztina Takács-Novák; Gergely Völgyi; Klara Valko; Szabolcs Béni; Zoltán Horváth; Bálint Szokol; Nóra Breza; Judit Dobos; Csaba Szántai-Kis; Eszter Illyés; Sándor Boros; Robbert Jan Kok; László Őrfi

doi:10.1016/j.bmcl.2018.06.026

Synthesis and characterization of amino acid substituted sunitinib analogues for the treatment of AML

Zoltán Nemes, Krisztina Takács-Novák, Gergely Völgyi, Klara Valko, Szabolcs Béni, Zoltán Horváth, Bálint Szokol, Nóra Breza, Judit Dobos, Csaba Szántai-Kis, Eszter Illyés, Sándor Boros, Robbert Jan Kok, László Őrfi

Research output: Contribution to journal › Article › Academic › peer-review

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, pK_a, CHI and LogP 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.

Original language	English
Pages (from-to)	2391-2398
Number of pages	8
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	28
Issue number	14
DOIs	https://doi.org/10.1016/j.bmcl.2018.06.026
Publication status	Published - 1 Aug 2018

Funding

This research was supported by School of PhD. studies of Semmelweis University ; and the Vichem Chemie Ltd . We thank Dr. Gergő Tóth for chiral HPLC separation and spectra. A

Keywords

Acute myeloid leukemia
Chromatographic Hydrophobicity Index
FLT3-ITD kinase inhibitior
Peptide based targeted delivery
Shake-flask partition coefficient determination

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10.1016/j.bmcl.2018.06.026

1-s2.0-S0960894X18305158-mainFinal published version, 496 KBLicence: Taverne

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Nemes, Z., Takács-Novák, K., Völgyi, G., Valko, K., Béni, S., Horváth, Z., Szokol, B., Breza, N., Dobos, J., Szántai-Kis, C., Illyés, E., Boros, S., Kok, R. J., & Őrfi, L. (2018). Synthesis and characterization of amino acid substituted sunitinib analogues for the treatment of AML. Bioorganic and Medicinal Chemistry Letters, 28(14), 2391-2398. https://doi.org/10.1016/j.bmcl.2018.06.026

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title = "Synthesis and characterization of amino acid substituted sunitinib analogues for the treatment of AML",

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, pKa, CHI and LogP 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.",

keywords = "Acute myeloid leukemia, Chromatographic Hydrophobicity Index, FLT3-ITD kinase inhibitior, Peptide based targeted delivery, Shake-flask partition coefficient determination",

author = "Zolt{\'a}n Nemes and Krisztina Tak{\'a}cs-Nov{\'a}k and Gergely V{\"o}lgyi and Klara Valko and Szabolcs B{\'e}ni and Zolt{\'a}n Horv{\'a}th and B{\'a}lint Szokol and N{\'o}ra Breza and Judit Dobos and Csaba Sz{\'a}ntai-Kis and Eszter Illy{\'e}s and S{\'a}ndor Boros and Kok, {Robbert Jan} and L{\'a}szl{\'o} {\H O}rfi",

year = "2018",

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doi = "10.1016/j.bmcl.2018.06.026",

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Nemes, Z, Takács-Novák, K, Völgyi, G, Valko, K, Béni, S, Horváth, Z, Szokol, B, Breza, N, Dobos, J, Szántai-Kis, C, Illyés, E, Boros, S, Kok, RJ & Őrfi, L 2018, 'Synthesis and characterization of amino acid substituted sunitinib analogues for the treatment of AML', Bioorganic and Medicinal Chemistry Letters, vol. 28, no. 14, pp. 2391-2398. https://doi.org/10.1016/j.bmcl.2018.06.026

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T1 - Synthesis and characterization of amino acid substituted sunitinib analogues for the treatment of AML

AU - Nemes, Zoltán

AU - Takács-Novák, Krisztina

AU - Völgyi, Gergely

AU - Valko, Klara

AU - Béni, Szabolcs

AU - Horváth, Zoltán

AU - Szokol, Bálint

AU - Breza, Nóra

AU - Dobos, Judit

AU - Szántai-Kis, Csaba

AU - Illyés, Eszter

AU - Boros, Sándor

AU - Kok, Robbert Jan

AU - Őrfi, László

PY - 2018/8/1

Y1 - 2018/8/1

N2 - 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, pKa, CHI and LogP 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.

AB - 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, pKa, CHI and LogP 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.

KW - Acute myeloid leukemia

KW - Chromatographic Hydrophobicity Index

KW - FLT3-ITD kinase inhibitior

KW - Peptide based targeted delivery

KW - Shake-flask partition coefficient determination

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U2 - 10.1016/j.bmcl.2018.06.026

DO - 10.1016/j.bmcl.2018.06.026

M3 - Article

AN - SCOPUS:85048817708

SN - 0960-894X

VL - 28

SP - 2391

EP - 2398

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 14

ER -

Synthesis and characterization of amino acid substituted sunitinib analogues for the treatment of AML

Abstract

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Keywords

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