In vitro activity of some flavonoid derivatives on human leukemic myeloid cells: evidence for aminopeptidase-N (CD13) inhibition, antiproliferative and cell death properties

Sandrine Bouchet; Marion Piedfer; Santos Susin; Daniel Dauzonne; Brigitte Bauvois; Sandrine Bouchet; Marion Piedfer; Santos Susin; Daniel Dauzonne; Brigitte Bauvois

doi:10.3934/molsci.2016.3.368

AIMS Molecular Science

2016, Volume 3, Issue 3: 368-385. doi: 10.3934/molsci.2016.3.368

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In vitro activity of some flavonoid derivatives on human leukemic myeloid cells: evidence for aminopeptidase-N (CD13) inhibition, antiproliferative and cell death properties

1.
Centre de Recherche des Cordeliers, INSERM UMRS1138, Sorbonne Universités UPMC Paris 06, Université Paris Descartes Sorbonne Paris Cité, F-75006 Paris, France
2.
Assistance Publique des Hôpitaux de Paris, France
3.
Centre de Recherche des Cordeliers, INSERM UMRS872 (2011-2012), Sorbonne Universités UPMC Paris 06, Université Paris Descartes Sorbonne Paris Cité, F-75006 Paris, France
4.
Institut Curie, Departement Recherche, CNRS UMR3666, INSERM U1143, F-75005 Paris, France

Received: 17 May 2016 Accepted: 28 July 2016 Published: 25 January 2016

Leukemia cells from patients with acute myeloid leukemia (AML) display high proliferative capacity and are resistant to death. Membrane-anchored aminopeptidase-N/CD13 is a potential drug target in AML. Clinical research efforts are currently focusing on targeted therapies that induce death in AML cells. We previously developed a non-cytotoxic APN/CD13 inhibitor based on flavone-8-acetic acid scaffold, the 2',3-dinitroflavone-8-acetic acid (1). In this context, among the variously substituted 113 compounds further synthesized and tested for evaluation of their effects on APN/CD13 activity, proliferation and survival in human AML U937 cells, eight flavonoid derivatives emerged: 2',3-dinitro-6-methoxy-flavone-8-acetic acid (2), four compounds (3–6) with the 3-chloro-2,3-dihydro-3-nitro-2-phenyl-4H-1-benzopyran-4-one structure, and three (7–9) with the 3-chloro-3,4-dihydro-4-hydroxy-3-nitro-2-phenyl-2H-1-benzopyran framework. Different structure-activity relationships were observed between APN/CD13 activity and growth/survival processes. We showed that compound 2, but not benzopyran derivatives 3–9, inhibited APN activity (although to a less degree than 1). Both 1 and 2 did not affect AML cell proliferation and survival, indicating that CD13’s APN activity is not required for these processes. In contrast, benzopyran compounds 3–9 inhibited in a concentration-dependent manner the growth of U937 cells by inducing death as evidenced by phosphatidylserine externalization. Cell death was associated with the presence of geminal nitro groupand chlorine at the 3-position of the 2H-1-benzopyran scaffold. The presence of other substituents such as CH₂COOH or CH₂CH=CH₂ groups at the 8-position, NO₂ or I substituents at the 2'- or 3'-position, OCH₃ or OCH₂C₆H₅ groups at the 4'-position did not affect cell death. Importantly, the inhibitory effects evidenced with compounds 7–9 were not due to their potential decomposition into the corresponding (Z)-(2chloro-2-nitroethenyl)benzene and salicylaldehyde. Based on these preliminary data, the 3-chloro,3-nitro-2H-1-benzopyran derivatives could be classified as a new group of compounds with promising antitumor properties; this study therefore provides the opportunity to explore their potential efficiency in AML patients’ cells ex vivo.
- aminopeptidase-N,
- apoptosis,
- benzopyran,
- CD13,
- cell death,
- flavone,
- leukemia,
- metalloproteinase,
- proliferation,
- survival
Citation: Sandrine Bouchet, Marion Piedfer, Santos Susin, Daniel Dauzonne, Brigitte Bauvois. In vitro activity of some flavonoid derivatives on human leukemic myeloid cells: evidence for aminopeptidase-N (CD13) inhibition, antiproliferative and cell death properties[J]. AIMS Molecular Science, 2016, 3(3): 368-385. doi: 10.3934/molsci.2016.3.368

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Abstract

Leukemia cells from patients with acute myeloid leukemia (AML) display high proliferative capacity and are resistant to death. Membrane-anchored aminopeptidase-N/CD13 is a potential drug target in AML. Clinical research efforts are currently focusing on targeted therapies that induce death in AML cells. We previously developed a non-cytotoxic APN/CD13 inhibitor based on flavone-8-acetic acid scaffold, the 2',3-dinitroflavone-8-acetic acid (1). In this context, among the variously substituted 113 compounds further synthesized and tested for evaluation of their effects on APN/CD13 activity, proliferation and survival in human AML U937 cells, eight flavonoid derivatives emerged: 2',3-dinitro-6-methoxy-flavone-8-acetic acid (2), four compounds (3–6) with the 3-chloro-2,3-dihydro-3-nitro-2-phenyl-4H-1-benzopyran-4-one structure, and three (7–9) with the 3-chloro-3,4-dihydro-4-hydroxy-3-nitro-2-phenyl-2H-1-benzopyran framework. Different structure-activity relationships were observed between APN/CD13 activity and growth/survival processes. We showed that compound 2, but not benzopyran derivatives 3–9, inhibited APN activity (although to a less degree than 1). Both 1 and 2 did not affect AML cell proliferation and survival, indicating that CD13’s APN activity is not required for these processes. In contrast, benzopyran compounds 3–9 inhibited in a concentration-dependent manner the growth of U937 cells by inducing death as evidenced by phosphatidylserine externalization. Cell death was associated with the presence of geminal nitro groupand chlorine at the 3-position of the 2H-1-benzopyran scaffold. The presence of other substituents such as CH₂COOH or CH₂CH=CH₂ groups at the 8-position, NO₂ or I substituents at the 2'- or 3'-position, OCH₃ or OCH₂C₆H₅ groups at the 4'-position did not affect cell death. Importantly, the inhibitory effects evidenced with compounds 7–9 were not due to their potential decomposition into the corresponding (Z)-(2chloro-2-nitroethenyl)benzene and salicylaldehyde. Based on these preliminary data, the 3-chloro,3-nitro-2H-1-benzopyran derivatives could be classified as a new group of compounds with promising antitumor properties; this study therefore provides the opportunity to explore their potential efficiency in AML patients’ cells ex vivo.

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