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

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 mu M, A549) with negligible effects on human normal cells (IC50 > 20 mu M, L02 and HUVEC), while MMC exhibited IC50 values of less than 2.5 mu M 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.

Automated summary

In this study, the toxic effects of mitomycin C (MMC), an anticancer drug, were reduced by attaching triphenylphosphine groups (TPP+) to it. The resulting compound, 5, showed good anticancer activity and negligible toxicity to human normal cells. In mice, 5 had little effect on body weight and tissues, indicating reduced toxicity compared to MMC. These findings suggest that TPP+ can effectively reduce the toxicity of MMC.