Many DNA cross-linking agents are used as anticancer agents. However the major concern for anticancer chemotherapeutic agents is their side-effects due to lack of specificity towards cancer cells. The development of anticancer prodrugs that are activated by unique features inside cancer cells is an attractive approach to achieve therapeutic activity and selectivity. Due to their fast growth and redox imbalance, most cancer cells have increased levels of reactive oxygen species (ROS) in comparison to their normal counterpart, such as superoxide, H2O2, and the hydroxyl radical. We exploit this distinctive feature of cancer cells to develop drugs that target tumors while cause less damage to surrounding healthy cells. In particular, we use boron chemistry for developing H2O2-activated prodrugs. A series of boron-based DNA cross-linking agents have been discovered to be activated by H2O2 that is considered as one of the most common ROS in cancer cells. These agents are not active by themselves but can selectively react with H2O2 to release quinone methides or nitrogen mustards which are capable of alkylating or cross-linking DNA. In vitro cytotoxicity assays showed that these agents were not toxic towards normal cells but greatly inhibited cancer cell growth. The efficacy and selectivity were further investigated in normal mice and Xenograft breast cancer models. The details of the chemistry and implications will be discussed.

Hydrogen peroxide activated DNA cross-linking agents and their biomedical application

254th National Meeting (2017)

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