Structure-activity relationship of a series of C-terminus modified aminoalkyl, diaminoalkyl- and anilino-containing analogues of the benzoic acid mustard distamycin derivative tallimustine: Synthesis, DNA binding and cytotoxicity studies
Brooks, N.; Hartley, J. A.; Simpson, J. E.; Wright, S. R.; Woo, S.; Centioni, S.; Fontaine, M. D.; McIntyre, T. E.; Lee, M. Structure-activity relationship of a series of C-terminus modified aminoalkyl, diaminoalkyl- and anilino-containing analogues of the benzoic acid mustard distamycin derivative tallimustine: Synthesis, DNA binding and cytotoxicity studies. Bioorg. Med. Chem. 1997, 5, 1497-1507.
As part of our investigations into the design of more cytotoxic analogues of the experimental anticancer drug tallimustine, 1, C-terminus modified aminoalkyl-, 2c, diaminoalkyl-, 3, and anilino-containing, 4, derivatives have been synthesized. Compounds 2-c differ by 2, 3, or 4 methylene units in the C-terminus, respectively. Results from an ethidium displacement study on poly(dA-dT), poly(dG-dC), calf thymus DNA and T4 coliphage DNA showed that compounds 2-4 interact in the minor groove of the polynucleotides with a preference for poly(dA-dT) over poly(dG-dC). Compound 4 bound more weakly to the DNAs than 2-c and 3. Using a CD dilution assay compounds 2-c and 3 were demonstrated to bind irreversibly to calf thymus DNA. The sequence selectivity by which compounds 2-4 alkylate DNA was demonstrated using a Taq polymerase stop assay. All the compounds alkylated preferentially at the 3-€²-purine residue in a 5²-TTTTGPu-3² sequence (Pu = A or G). This observed sequence specificity is similar to that of tallimustine and a related compound 5. At an equimolar concentration the aminoalkyl compounds 2c (2b > 2a > 2c), and diaminoalkyl compound 3 were more efficient at alkylating these sequences than the anilino compound 4. Following a one hour exposure of human chronic myeloid leukemia K562 cells, compounds 2b and 3 have lower IC50 values (1.64 Î¼M and 3.03 Î¼M, respectively) than tallimustine (5 Î¼M) and similar values to a related compound 5 (2.2 Î¼M). The order of cytotoxicity for all the compounds is 2b > 5 > 3 > 2a > 1 > 2c = 4. These results indicate that the cytotoxicities of these compounds are related to their relative ability to alkylate the consensus DNA binding sequence.
Bioorganic & Medicinal Chemistry