SEQUENCE-SPECIFIC DNA ALKYLATION OF NOVEL TALLIMUSTINE DERIVATIVES

Three different groups of analogs of the sequence-specific minor groov e alkylator tallimustine (2) have been synthesized and investigated. W ithin group I, the dibromo nitrogen mustard (3) and the half-mustard ( 4) are more cytotoxic (IC50 = 0.6 and 40 ng/ml respectively) than tall imustine (IC50 = 50.3 ng/ml) against L1210 cells with high reactivity against the region 5'-TTTTGA. The diol derivative (6) and the difluoro nitrogen mustard (5) were not cytotoxic against L1210 cells and did n ot show any detectable DNA alkylation. The two compounds modified in t he propionamidine terminus (7 and 8, group II), showed lower cytotoxic potency (IC50 = 130 and 94 ng/ml respectively) against L1210 cells th an tallimustine (IC50 = 50.3 ng/ml) and a loss of in vitro sequence sp ecificity for DNA alkylation. Considering the compounds in which the p yrrole rings were replaced by one (9) or two (10) pyrazole rings, comp ound 9 was not significantly cytotoxic against L1210 cell line and was apparently unable to produce alkylation on the DNA fragments tested, while compound 10 showed decreased cytotoxicity (IC50 = 114 ng/ml) and no modification in the pattern and intensity of DNA alkylation. The d ata obtained in this work suggest that it is possible to increase tall imustine potency by modifying the nitrogen mustard moiety. Moreover, t he sequence specificity of DNA alkylation appears to be affected by th e modification of the propionamidino moiety but not by the isosteric m odification of the pyrrole rings. The correlation between cytotoxicity and alkylation pattern suggests that tallimustine exerts its cytotoxi city through DNA sequence-specific alkylation of the adenine located i n the sequence 5'-TTTTGA.