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.
As part of our investigations into the design of more cytotoxic analogues of the experimental anticancer drug tallimustine, 1, C-terminus modified aminoalkyl-, 2a-c, diaminoalkyl-, 3, and anilino-containing, 4, derivatives have been synthesized. Compounds 2a-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 2a-c and 3. Using a CD dilution assay compounds 2a-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'-purine residue in a 5'-TTTTGPu-3' 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 2a-c (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 microM and 3.03 microM, respectively) than tallimustine (5 microM) and similar values to a related compound 5 (2.2 microM). 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.
Brooks
N
N
Department of Oncology, UCL Medical School, London, U.K.
Hartley
J A
JA
Simpson
J E
JE
Wright
S R
SR
Woo
S
S
Centioni
S
S
Fontaine
M D
MD
McIntyre
T E
TE
Lee
M
M
D000478:Alkylation; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D004247:DNA / Q000187:drug effects*; D004214:Distamycins / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D009588:Nitrogen Mustard Compounds / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D004214:Distamycins; D009588:Nitrogen Mustard Compounds; C066900:tallimustine; D004247:DNA