Sequence Specificity, Reactivity, and Antitumor Activity of DNA-Alkylating Pyrrole-Imidazole Diamides Original Research Article

Three conjugates of imidazole (Im)-pyrrole (Py) diamide and a DNA-alkylating moiety derived from the antibiotic duocarmycin A were synthesized, and their sequence specificity, reactivity, and antitumor activity comparatively examined. Sequencing gel analysis indicated that ImPyDu (1) alkylates DNA at the 3′ end of AT-rich sequences at micromolar concentration. ImPyDu86 (2) reacts with DNA at AT-rich sites together with dialkylation sites at micromolar concentration. ImPyLDu86 (3) efficiently alkylates dialkylation sites at nanomolar concentration. Average values of log IC50 against a 39 cancer cell line panel of 1–3 were −4.59, −5.95, and −8.25, respectively. The differential growth inhibition pattern of 1–3 varied with relatively low correlation coefficients. Array-based gene expression monitoring was performed for 3 in a human lung cancer cell line. Substantial downregulation of expression was seen for genes involved in DNA damage response, transcription, and signal transduction.