New quinoxaline 1,4-di-N-oxides. Part 1: Hypoxia-selective cytotoxins and anticancer agents derived from quinoxaline 1,4-di-N-oxides

Hypoxic cells which are common feature of solid tumors are resistant to both anticancer drugs and radiation therapy. Thus, the identification of drugs with the selective toxicity toward hypoxic cells is an important target in anticancer chemotherapy. Tirapazamine has been shown to be an efficient and selective cytotoxin after bioreductive activation in hypoxic cells which is thought to be due to the presence of the 1,4-di-N-oxide. A new series of quinoxaline 1,4-di-N-oxides and fused quinoxaline di-N-oxides were synthesized and evaluated for hypoxic–cytotoxic activity on EAC cell line. Compound 10a was the most potent cytotoxin IC50 0.9 μg/mL, potency 75 μg/mL, and was approximately 15 times more selective cytotoxin (HCR > 111) than 3-aminoquinoxaline-2-carbonitrile which has been used as a standard (HCR > 7.5). Compounds 4 and 3a,b were more selective than the standard. In addition, antitumor activity against Hepg2 (liver) and U251 (brain) human cell lines was evaluated, compounds 9c and 8a were the most active against Hepg2 with IC50 values 1.9 and 2.9 μg/mL, respectively, however, all the tested compounds were nontoxic against U251 cell line.

A new series of quinoxaline 1,4-di-N-oxides (B) and fused quinoxaline di-N-oxide (C) were synthesized and evaluated for antitumor activity against liver carcinoma (Hepg2) and brain tumor (U251), human cell lines. Compounds 9c and 8a demonstrated potent antitumor activity against Hepg2 with IC50 1.9 and 2.9 μg/mL, respectively, accompanied by lack of toxicity against U251. The hypoxic–cytotoxic activity was also evaluated for selected compounds. Compound 10a was the most potent cytotoxin IC50 0.9 μg/mL, potency 75 μg/mL, and was 15 times more selective toward hypoxic cells (HCR > 111) than the standard (A) (HCR > 7.5). Enaminone 4, enamine derivatives 3a,b were more selective (HCR >10, >8.7, 9.4, respectively) than the standard in hypoxia.Figure optionsDownload as PowerPoint slide