Hydrogen peroxide inducible DNA cross-linking agents: targeted anticancer prodrugs.
The major concern for anticancer chemotherapeutic agents is the host toxicity. The development of anticancer prodrugs targeting the unique biochemical alterations in cancer cells is an attractive approach to achieve therapeutic activity and selectivity. We designed and synthesized a new type of nitrogen mustard prodrug that can be activated by high level of reactive oxygen species (ROS) found in cancer cells to release the active chemotherapy agent. The activation mechanism was determined by NMR analysis. The activity and selectivity of these prodrugs toward ROS was determined by measuring DNA interstrand cross-links and/or DNA alkylations. These compounds showed 60-90% inhibition toward various cancer cells, while normal lymphocytes were not affected. To the best of our knowledge, this is the first example of H(2)O(2)-activated anticancer prodrugs.
Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, 3210 North Cramer Street, Milwaukee, Wisconsin 53211, USA.
Yunyan
Y
Kuang
Kumudha
K
Balakrishnan
Varsha
V
Gandhi
Xiaohua
X
Peng
D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D007364:Intercalating Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008466:Mechlorethamine / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
D018906:Antineoplastic Agents, Alkylating; D007364:Intercalating Agents; D011355:Prodrugs; D017382:Reactive Oxygen Species; D008466:Mechlorethamine; D004247:DNA; D006861:Hydrogen Peroxide