Cytotoxicity and sequence specificity of C- and N-terminus conjugates of N-methylpyrrole polyamides with seco-cyclopropaneindoline
Toth, J. L.; Henry, J. A.; Taherbhai, Z. T.; Staples, T.; Summerville, K.; Handl, H. L.; Hudson, S. J.; Kiakos, K.; Hartley, J. A.; Lee, M. Cytotoxicity and sequence specificity of C- and N-terminus conjugates of N-methylpyrrole polyamides with seco-cyclopropaneindoline. Med. Chem. Res. 2003, 12, 87-93.
The cytotoxicity and covalent DNA sequence specificity of three novel conjugates of polyamides and seco-cyclopropaneindoline (or seco-CI), a minimum alkylating pharmacophore of CC-1065 are reported. Compounds 1 and 2 consist of a seco-Cl group attached to the C-terminus of either one or two N-methylpyrrole units, respectively. In compound 3, the seco-Cl group is attached to the N-terminus of a one pyrrole-containing analog of distamycin. Following a one-hour exposure of human chronic myeloid leukemia K562 cells, compounds 1 and 2 gave a similar level of cytotoxicity (IC(50) 1-2 rectangleM). Compound 3 was considerably less active (IC(50) >30 rectangleM), despite the fact that it and compound 1 contain one-pyrrole unit each. Using Taq polymerase stop assay, the sequence specificity of the target compounds was determined. Like CC- 1065 and the duocarmycins, compounds 1 and 2 retained the preferential alkylation for the 5'-AAAA(865)A-3' sequence. Compound 3 was less sequence discriminating and showed a preference for alkylation at a 5'-TTTTA(843)-3' sequence over the 5'AAAA(865)A-3' site.
Medicinal Chemistry Research