Azobenzene derivatives show anti-cancer activity against pancreatic cancer cells only under nutrient starvation conditions via G₀/G₁ cell cycle arrest

Pancreatic cancer is one of the most aggressive cancers with a poor prognosis. Previous studies suggested that nutrient-deprived conditions may play a critical role in pancreatic cancer cell survival and resistance to chemotherapy. We describe a novel series of azobenzene derivatives including (E)-1-(4-methyl-3-((2-methyl-5-(naphthalen-1-yl)phenyl)diazenyl)phenyl)naphthalen-2-ol (9) with efficacy and selectivity in nutrient-deprived conditions. Although anticancer drug 5-fluorouracil (5-FU) was ineffective under nutrient-deprived conditions, five of our designed compounds, 9 and four other related compounds 11–14, showed anticancer activity with IC₅₀ values ranging from 1.5 to 9.6 μM. Interestingly, only 9 showed no cytotoxicity in normal conditions. This selectivity profile of 9 is clearly opposite to that of 5-FU. Furthermore, cell cycle analysis showed that, in contrast to S phase arrest induced by 5-FU, 9 caused G₀/G₁ phase arrest, which might block cancer cell growth by arresting them in quiescence. Therefore, it could be a novel and promising candidate for effective pancreatic cancer treatment under nutrient-deprived conditions.