Discovery of derivatives of 6(7)-amino-3-phenylquinoxaline-2-carbonitrile 1,4-dioxides: novel, hypoxia-selective HIF-1α inhibitors with strong antiestrogenic potency

Synthesis of 7-amino-6-halogeno-3-phenylquinoxaline-2-carbonitrile 1,4-dioxides: a way forward for targeting hypoxia and drug resistance of cancer cells

“…Additionally, the 7-aminoderivatives of 6halogenoquinoxaline-2-carbonitrile 1,4-dioxide showed higher apoptotic potency for both leukemia cell lines (K562; K562/4) than the previously obtained series of their regioisomeric analogues (3,4). 10 In striking contrast to the previously obtained regioisomers 3 and 4a (Fig. 1), compound 14a had similar IC 50 values against all tested cell lines compared to its 6-substituted analogue 4b (Fig.…”

“…1) and its structure are of fundamental importance for antiproliferative potency and hypoxic selectivity of these derivatives. 10,11 Thus, derivative 3 with the piperazine residue in position 7 was noticeably more potent against MCF7 and MDA-MB-231 under normoxic (10 times) and hypoxic conditions (20 times) than its regioisomer 4a (for R ¼ H, Fig. 1).…”

“…1 and Tables 1 and 2). 10 Nevertheless, the location of the substituents also plays an important role in the cytotoxic properties. Overall, comparison of the cytotoxicity of the obtained derivatives 13a-g with the previously obtained regioisomeric analogues 10 showed that compounds 13a-g containing an amino group at position 7 of the quinoxaline core were 2-5 times more cytotoxic than their isomers.…”

“…Thus, in search for new knowledge regarding the possibility of chemical modication of the quinoxaline scaffold and for further exploration of the structureactivity relationships for quinoxaline-2-carbonitrile 1,4-dioxides, a novel water-soluble derivative with residues of cyclic diamines was obtained. 10 Lead compound 4b (for R ¼ F, Fig. 1) suppressed HIF-1a expression and demonstrated a strong anti-estrogenic effect.…”

“…1) suppressed HIF-1a expression and demonstrated a strong anti-estrogenic effect. 10 The position of the pharmacophore group in the heterocyclic core of 3-phenylquinoxaline-2-carbonitrile 1,4-dioxides (e.g., compounds 3-4, Fig. 1) and its structure are of fundamental importance for antiproliferative potency and hypoxic selectivity of these derivatives.…”