Design and synthesis of TPP+-Mitomycin C conjugate with reduced toxicity. (1st December 2022)

• Record Type: Journal Article
• Authors: Huang, Ding; Zhang, Maojie; Zhang, Haiyan; Cui, Zhiying; Luo, Dong; Li, Tao; Li, Xuemin; He, Yun; Zhang, Shao-Lin
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 77(2022)
• Publication Date: 2022-12-01
• Subjects: Anticancer -- Triphenylphosphonium cation -- Mitomycin C; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2022.129036
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: A TPP + group was firstly attached to MMC with the aim to reduce its toxicity. Compound 5 possessed a good anticancer activity (IC50 = 1.09 μM, A549) with negligible effect on human normal cells (IC50 > 20 μM, L02 and HUVEC) Compound 5 had little effect on the body weight and tissues in mouse at a dose of 20 mg/kg. Abstract: 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.