Design and synthesis of TPP⁺-Mitomycin C conjugate with reduced toxicity

Mitomycin C (MMC) is a class of alkylating anticancer drug, which non-specifically interacts with nuclear DNA and cross-links guanine and cytosine of DNA, thereby affecting DNA replication and synthesis. However, toxic effects largely impeded MMC's clinical applications. In this study, triphenylphosphine groups (TPP⁺) were attached to MMC via the active aziridine amine with the aim to reduce its toxicity. MTT assay suggested that 5 possessed a good anticancer activity (IC₅₀ = 1.09 μM, A549) with negligible effects on human normal cells (IC₅₀ > 20 μM, L02 and HUVEC), while MMC exhibited IC₅₀ values of less than 2.5 μM on the tested human normal cells. Dose range-finding experiments suggested that 5 had little effect on the body weight and tissues in mouse at a dose of 20 mg/kg, indicating significantly reduced toxicity as compared to MMC (LD₅₀ < 2.5 mg/kg). Collectively, these data suggested that TPP⁺ group could be an effective vector to reduce toxicity of MMC.