In Silico and In Vitro Perspectives on the Potential Anticancer Activity and Toxicity of Anticancer Drug Modified with Carbohydrates Containing Novel Triazole Compounds

Abstract 5‐Fluorouracil (5‐FU) is one of the first‐line chemotherapeutic agents used in systemic therapy of solid tumors. However, several challenges restrict the use of 5‐FU such as serious side effects and short plasma half‐life. Because carbohydrates and 1,2,3‐triazoles have various biological activities, they have been extensively used in medicine to obtain more effective anticancer drugs in recent years. The aim of this study is to modify 5‐FU with carbohydrates containing 1,2,3‐triazole compounds to reduce its toxic effect, and to reveal the anticancer properties of the obtained 5‐FU derivatives. These derivatives (5‐FU‐I, 5‐FU‐II, and 5‐FU‐III) revealed dose‐dependent cytotoxic effects on CaCo‐2, PANC‐1, and A549 cancer cells. It was determined that cytotoxic effects of the 5‐FUs change dependent on used carbohydrate types, cell lines, and administered doses. These derivatives showed apoptotic and necrotic cell deaths which used to destroy the cancer cells. 5‐FUs showed no genotoxic effect in the bacterial reverse mutasyon assay. They demonstrated strong antiangiogenic properties in the HET‐CAM test. In silico study results demonstrated that carbohydrate modification can increase half‐life and clearance, also decrease side effects of 5‐FU. In silico data supported the in vitro findings and results demonstrated 5‐FU derivatives were better drug candidates. Our results reveal that 5‐FUs derivatives modified carbohydrates containing 1,2,3‐triazole compounds have potential in cancer therapy.