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 (IC = 1.09 μM, A549) with negligible effects on human normal cells (IC > 20 μM, L02 and HUVEC), while MMC exhibited IC 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 (LD < 2.5 mg/kg). Collectively, these data suggested that TPP group could be an effective vector to reduce toxicity of MMC.