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Research Interests - The Lee Group
This summary is designed to give a broad overview of the cancer research program in the Lee group, conducted by Dr. Moses Lee, Dr. Sameer Chavda and Dr. Balaji Babu and their students. It highlights three on-going projects, two of which are centered on DNA sequence recognition, and the third is focused on anti-angiogenesis.
The first project concerns gaining fundamental insight into the molecular recognition of DNA sequences by polyamides, which are analogs of a naturally occurring product called distamycin. These polyamide compounds preferentially bind as anti-parallel stacked dimers in the minor groove and they exhibit exquisite sequence specificity. These agents have a broad range of applications, including the modulation of gene expression in molecular genetics, the development of DNA-based medicines, and the design of novel DNA-based biosensors.
The second project involves the design, synthesis, as well as the biochemical and biological evaluation of compounds that are analogs of duocarmycins. Duocarmycins are extremely cytotoxic natural products that possess powerful DNA minor groove alkylating properties. Since their discovery numerous structure-activity relationship studies have been conducted and four analogs were selected for clinical evaluation. Due to toxicity of these compounds to the bone marrow, their clinical usefulness is severely compromised. We have designed and synthesized a new class of duocarmycin analogs, and found them to strongly inhibit the growth of cancer cells in culture, but displayed minimal toxicity. Furthermore, one duocarmycin analog from out laboratory exhibits potent anticancer activity against human tumor xenografs grown in skid mice, and it is undergoing further preclinical evaluations.
Boger, D. L.; Johnson, D. S. Angew. Chem., Int. Ed. Engl.
In the third area, my group has embarked on a project to design novel heterocyclic analogs of combretastatin A4, (CA4), a natural product isolated from an African willow tree, Combretum caffrum. CA4 possesses potent anti-angiogenic and anticancer activity, but due to its poor water solubility it was not clinically investigated. Our laboratory has synthesized numerous analogs of CA4, and studied their structure and biological activity relationships. Our studies provided evidence that the critical criterion for these compounds to be cytotoxic is their twisted conformation.