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. 2016 Jan 27:108:39-52.
doi: 10.1016/j.ejmech.2015.11.022. Epub 2015 Nov 27.

Novel iodoacetamido benzoheterocyclic derivatives with potent antileukemic activity are inhibitors of STAT5 phosphorylation

Romeo Romagnoli  1 , Pier Giovanni Baraldi  2 , Filippo Prencipe  2 , Carlota Lopez-Cara  2 , Riccardo Rondanin  2 , Daniele Simoni  2 , Ernest Hamel  3 , Stefania Grimaudo  4 , Rosaria Maria Pipitone  4 , Maria Meli  5 , Manlio Tolomeo  6
Affiliations

Novel iodoacetamido benzoheterocyclic derivatives with potent antileukemic activity are inhibitors of STAT5 phosphorylation

Romeo Romagnoli et al. Eur J Med Chem. .

Abstract

Signal Transducer and Activator of Transcription 5 (STAT5) protein, a component of the STAT family of signaling proteins, is considered to be an attractive therapeutic _target because of its involvement in the progression of acute myeloid leukemia. In an effort to discover potent molecules able to inhibit the phosphorylation-activation of STAT5, twenty-two compounds were synthesized and evaluated on the basis of our knowledge of the activity of 2-(3',4',5'-trimethoxybenzoyl)-3-iodoacetamido-6-methoxy benzo[b]furan derivative 1 as a potent STAT5 inhibitor. Most of these molecules, structurally related to compound 1, were characterized by the presence of a common 3',4',5'-trimethoxybenzoyl moiety at the 2-position of different benzoheterocycles such as benzo[b]furan, benzo[b]thiophene, indole and N-methylindole. Effects on biological activity of the iodoacetamido group and of different moieties (methyl and methoxy) at the C-3 to C-7 positions were examined. In the series of benzo[b]furan derivatives, moving the iodoacetylamino group from the C-4 to the C-5 or C-6 positions did not significantly affect antiproliferative activity. Compounds 4, 15, 20 and 23 blocked STAT5 signals and induced apoptosis of K562 BCR-ABL positive cells. For compound 23, the trimethoxybenzoyl moiety at the 2-position of the benzo[b]furan core was not essential for potent inhibition of STAT5 activation.

Keywords: Apoptosis; BCR/ABL expressing leukemia; In vitro antiproliferative activity; STAT5 inhibitors; Structure-activity relationship.

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Figures

Fig. 1
Fig. 1
Effects of compounds 4–9, 11, 13, 15, 17–20 and 23 on DNA content per cell following exposure of K562 cells for 24 h. a) control; b) 4 (3 μM); c) 5 (2 μM); d) 6 (0.5 μM); e) 7 (0.75 μM); f) 8 (2 μM); g) 9 (2 μM); h) 11 (3 μM); i) 13 (3 μM); j) 15 (2 μM); k) 17 (2 μM); l) 18 (2 μM); m) 19 (3 μM); n) 20 (1 μM); o) 23 (5 μM).
Fig. 2
Fig. 2
Effects of compounds 4–9, 11, 13, 15, 17–20 and 23 on pSTAT5 expression in K562 cells. Intracellular levels of phosphorylated STAT5 were evaluated by flow cytometry after a 24 h exposure of cells to each compound as described in Materials and Methods. Thin line: cells stained with an isotype monoclonal antibody; dotted line: cells stained with an anti-pSTAT5 monoclonal antibody; thick line: cells stained with an anti-pSTAT5 monoclonal antibody after a 24 h exposure to each compound. a) 4 (3 μM); b) 5 (2 μM); c) 6 (0.5 μM); d) 7 (0.75 μM); e) 8 (2 μM); f) 9 (2 μM); g) 11 (3 μM); h) 13 (3 μM); i) 15 (2 μM); j) 17 (2 μM); k) 18 (2 μM); l) 19 (3 μM); m) 20 (1 μM); n) 23 (5 μM).fied).
Chart 1
Chart 1
Structure of reference compound 1 and new iodoacetamido 2-aroyl benzoheterocyclic derivatives 2–23 (R = H, if not specified).
Scheme 1
Scheme 1
Reagents and conditions. a: BrCH2COBr, Py, CH2Cl2, rt, 1 h; b: NaI, CH3CON(CH3)2, rt, 18 h.
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