| Summary: | 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<strong>. </strong>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 <strong>(1)</strong>. 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 (<strong>2</strong>), four compounds (<strong>3</strong>–<strong>6</strong>) with the 3-chloro-2,3-dihydro-3-nitro-2-phenyl-4<em>H</em>-1-benzopyran-4-one structure, and three (<strong>7</strong>–<strong>9</strong>) with the 3-chloro-3,4-dihydro-4-hydroxy-3-nitro-2-phenyl-2<em>H</em>-1-benzopyran framework. Different structure-activity relationships were observed between APN/CD13 activity and growth/survival processes. We showed that compound <strong>2</strong>, but not benzopyran derivatives <strong>3</strong>–<strong>9</strong>, inhibited APN activity (although to a less degree than <strong>1)</strong>. Both <strong>1 </strong>and <strong>2 </strong>did not affect AML cell proliferation and survival, indicating that CD13’s APN activity is not required for these processes. In contrast, benzopyran compounds <strong>3</strong>–<strong>9</strong> 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 group<sub> </sub>and chlorine at the 3-position of the 2<em>H</em>-1-benzopyran scaffold. The presence of other substituents such as CH<sub>2</sub>COOH or CH<sub>2</sub>CH=CH<sub>2</sub> groups at the 8-position, NO<sub>2</sub> or I substituents at the 2'- or 3'-position, OCH<sub>3</sub> or OCH<sub>2</sub>C<sub>6</sub>H<sub>5</sub> groups at the 4'-position did not affect cell death. Importantly, the inhibitory effects evidenced with compounds <strong>7</strong>–<strong>9 </strong>were not due to their potential decomposition into the corresponding (<em>Z</em>)-(2chloro-2-nitroethenyl)benzene and salicylaldehyde. Based on these preliminary data, the 3-chloro,3-nitro-2<em>H</em>-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 <em>ex vivo</em>.
|
|---|
