The goal of this research is to discover new components of low cardiotoxicity which are active against breast cancer and other resistant tumors. They will have polycyclic aromatic nuclei designed for intercalative binding with DNA, and side chains with basic groups which, upon protonation, confer water solubility and enhanced DNA binding. New analogue design and synthesis will utilize an extensive data base, aided by QSAR, molecular modeling, and sequence selectivity. New types of analogues will be emphasized, including those with alkylating groups which can supplement intercalation with covalent bonding. New netropsin- related compounds may have sequence selectivity in DNA binding. Those with pyrrole rings should show AT selectivity, whereas those with imidazole rings (lexitropsins) should show GC selectivity. Preliminary screening will be performed in a panel of tumor cells including human melanoma, ovarian, breast, and lung, plus sensitive and MDR mouse leukemia. Cardiotoxicity will be measured in fetal rat myocytes. Compounds with the best antitumor and cardiotoxicity profiles will be advanced to studies in mice, including acute toxicity, leukopenia, and activity against P388 leukemia and B16 melanoma. They also will be submitted to the NCI for broad screening. The best compounds will be tested in SCID mice against MCF-7 human breast cancer and other human tumors sensitive in our cell culture assays or selective in the NCI panel. Mode of action studies will include assessment of DNA damage using the alkaline elution assay. Single and double strand breaks and DNA-protein cross links will be determined and correlated with cytotoxicity and cardiotoxicity. Inhibition of topoisomerases I and II will be measured and correlated with antitumor activity and alkaline elution results. The metabolism of our best analogue (EL-53) will be studied further. Drug design studies will involve molecular modeling and QSAR. Experiments which can identify preferred DNA binding sequences and major or minor groove preference will support the modeling studies. Sequence selectivity will be determined by footprinting experiments using cleavage reagents and gel electrophoresis, and groove preference will be determined by comparative deltaTm values on DNAs rich in AT or GC pairs, or glycosylated in the major groove. QSAR studies will examine correlations of antitumor activity with physical properties of compounds and mechanisms of DNA damage. These studies will be important in further optimizing the antitumor activity of subsequent analogues.
| Sami, S M; Dorr, R T; Alberts, D S et al. (2000) Analogues of amonafide and azonafide with novel ring systems. J Med Chem 43:3067-73 |
| Sami, S M; Dorr, R T; Solyom, A M et al. (1996) 6- and 7-substituted 2-[2'-(dimethylamino)ethyl]-1,2-dihydro-3H-dibenz[de,h] isoquinoline-1,3-diones: synthesis, nucleophilic displacements, antitumor activity, and quantitative structure-activity relationships. J Med Chem 39:1609-18 |
| Sami, S M; Dorr, R T; Alberts, D S et al. (1996) 2-[2'-(Dimethylamino)ethyl]-1,2-dihydro- 3H-dibenz[de,h]isoquinoline-1,3-diones with substituents at positions 4, 8, 9, 10, and 11. Synthesis, antitumor activity, and quantitative structure-activity relationships. J Med Chem 39:4978-87 |
