The objective of this research is to discover new compounds active against tumors that are resistant to existing anticancer agents. These new compounds will have polycyclic aromatic nuclei designed for strong intercalative binding with DNA,l and side chains with basic amino groups that can confer water solubility upon salt formation. The amine pKa will be controlled to permit both good DNA binding and cell penetration. Computer modeling and measurement or calculation of physical properties will aid the design of these compounds. They will be synthesized by efficient routes based on established types of carbocyclic or heterocyclic chemistry. New compounds will be screened initially in a panel of human tumor cells using the micro culture tetrazolium assay. Tumor cell lines will include two that show multiple drug resistance and express the P-glycoprotein drug efflux pump. The best compounds will be tested against P388 leukemia and multidrug resistant P388 leukemia in mice. Cardiotoxicity will be evaluated in cultured rat myoctes. DNA alkaline election assays will assess topoisomerase II mediated DNA damage including single and double stranded breaks and DNA-protein cross links. Correlations between cytotoxicity and each specific type of DNA damage will be made. From the information obtained above, a comprehensive data base for SAR using antitumor potency, molecular DNA damage, and cardiotoxicity as descriminates will be constructed. It will provide the basis for the design of subsequent analogues. Furthermore, it might provide a better understanding of some of the factors involved in drug resistance by tumor cells and how they can be overcome.
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| Sami, S M; Dorr, R T; Solyom, A M et al. (1995) Amino-substituted 2-[2'-(dimethylamino)ethyl]-1,2-dihydro-3H- dibenz[de,h]isoquinoline-1,3-diones. Synthesis, antitumor activity, and quantitative structure--activity relationship. J Med Chem 38:983-93 |
| Sami, S M; Dorr, R T; Alberts, D S et al. (1993) 2-substituted 1,2-dihydro-3H-dibenz[de,h]isoquinoline-1,3-diones. A new class of antitumor agent. J Med Chem 36:765-70 |
| Dorr, R T; Shipp, N G; Lee, K M (1991) Comparison of cytotoxicity in heart cells and tumor cells exposed to DNA intercalating agents in vitro. Anticancer Drugs 2:27-33 |
