| Popis: |
Chemotherapy for cancer always has many off-target effects that damage healthy cells. Many chemotherapeutic drugs can affect the function of normal cells in the heart, kidneys or nervous system cause another health problem. Reactive Oxygen Species (ROS) are molecules produced in cell metabolism. ROS are important for proliferation, differentiation, senescence, apoptosis, and chemoresistance of cancer cells. Compared to normal cells, it has been found that ROS concentration is elevated in lots of cancers. These differences between cancer and normal cells are the basis for the development of new chemotherapy agents that selectively target the cancer cell but not impair the function of normal cells. Based on these observations, we made several ROS activated compounds and found a lead compound, MA14, which has an IC50 of 2 µm against AML cancer cells. I hypothesized that the high selectivity of MA14 is due to its unique oxidation mechanism in the presence of H2O2. Herein, the oxidation mechanism of MA14 was investigated using MS and NMR spectroscopy. In the presence of ROS, MA14 goes through oxidative-cyclizing to form two isomers. These isomers could be further oxidized to non-toxic products. I also synthesized several molecules to study the relationship between structure and activity. It is shown that the a-carbon of the side chain is essential for cytotoxicity. The size of the cyclic amine has a moderate influence on activity. I took advantage of the finding that the phenol group to the MA14 could be modified. In particular, I designed and synthesized several compounds based on the MA14 structure that released substituted phenols in the presence of ROS. It is shown that the oxidation mechanism is influenced by the electron density of the phenol. Further, we found that these compounds could selectively target AML cells while the normal cell can be surviving. To further develop the concept, we designed and synthesized prodrugs, termed self-cyclizing reagents, which react with cellular oxidative equivalents and eject a PI3K inhibitor. We show that the self-cycling reagent reduces affinity to PI3KA, is slow to intracellularly oxidation, ejects the inhibitor Pi103 in cells, and is resistant to liver microsomes. Modest activity is shown in untreated acute myeloid leukemia cells due to changes in antioxidant proteins. Interestingly, co-treatment with doxorubicin or cytosine arabinoside led to strong anti-cell synergism with a ~90-fold enhancement in IC50 value specifically for Kasumi-1 AML but not cord blood cells. Besides, in collaboration with Dr. Nira Ben-Jonathan, we identified an inhibitor that binds to PRLR and blocked PRL-induced cell growth by HTC. We further characterize and synthesis the one SIM-6 for cell and animal studies. The biology data show that the SIM-6 could selectively kill different types of breast cancer cell and the normal cell could survive. Importantly, SIM-6 could effectively reduce the tumor volume on breast cancer animal models, especially for PRL-positive mouse which indicated that the SIM-6 is a leading compound for breast-cancer therapy. |
