Novel Cytotoxic Agents Targeted to Cancer Cells
Presentation
Overview
Overview
Description
DNA alkylation by small molecules is a strategy that has been commonly used to destroy unwanted cells, and DNA-alkylating drugs play an important role in cancer chemotherapy. However most of these drugs have little specificity, either for cancer cells, or for particular DNA sequences, and their selective destruction of cancer cells depends upon the rapid proliferation of cancer cells compared to normal cells. The potency of these drugs is usually severely diminished due to their widespread uptake by normal cells, and due to non-specific DNA-alkylation, leading to the formation of multiple kinds of DNA lesions, not all of which result in cytotoxic consequences. In addition, the lack of targeting ability of these drugs results in unwanted side-effects (for example, hair loss, gastric irritation, etc.). More significantly, the indiscriminate DNA-damage caused by these compounds can sometimes lead to mutations in normal cells which are believed to be responsible for cases of secondary cancer, typically leukemia, following chemotherapy with DNA-alkylating drugs. This talk will describe a strategy that combines both cell-targeting ability, and DNA-sequence specific alkylation, for producing cytotoxic, non-mutagenic N3-methyladenine (3-MeA) DNA adducts in estrogen receptor positive cells, such as breast cancer cells. The design and synthesis of a compound based on this strategy, and the results of the in vitro testing of this compound will be discussed.
