Sequence-specific DNA alkylation of novel tallimustine derivatives.
Three different groups of analogs of the sequence-specific minor groove alkylator tallimustine (2) have been synthesized and investigated. Within group I, the dibromo nitrogen mustard (3) and the half-mustard (4) are more cytotoxic (IC50 = 0.6 and 40 ng/ml respectively) than tallimustine (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 not show any detectable DNA alkylation. The two compounds modified in the propionamidine terminus (7 and 8, group II), showed lower cytotoxic potency (IC50 = 130 and 94 ng/ml respectively) against L1210 cells than tallimustine (IC50 = 50.3 ng/ml) and a loss of in vitro sequence specificity for DNA alkylation. Considering the compounds in which the pyrrole rings were replaced by one (9) or two (10) pyrazole rings, compound 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 data obtained in this work suggest that it is possible to increase tallimustine potency by modifying the nitrogen mustard moiety. Moreover, the sequence specificity of DNA alkylation appears to be affected by the modification of the propionamidino moiety but not by the isosteric modification of the pyrrole rings. The correlation between cytotoxicity and alkylation pattern suggests that tallimustine exerts its cytotoxicity through DNA sequence-specific alkylation of the adenine located in the sequence 5'-TTTTGA.
Marchini
S
S
Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Cozzi
P
P
Beria
I
I
Geroni
C
C
Capolongo
L
L
D'Incalci
M
M
Broggini
M
M
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry*; D001345:Autoradiography; D004247:DNA / Q000737:chemistry*; D018983:DNA Footprinting; D004214:Distamycins / Q000737:chemistry*; D004587:Electrophoresis, Agar Gel; D006801:Humans; D007939:Leukemia L1210 / Q000473:pathology; D009588:Nitrogen Mustard Compounds / Q000737:chemistry*; D014407:Tumor Cells, Cultured
D018906:Antineoplastic Agents, Alkylating; D004214:Distamycins; D009588:Nitrogen Mustard Compounds; C066900:tallimustine; D004247:DNA