Sequence-Specific Alkylating Agent as A Novel Type of Antitumor Agent

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By the completion of the human genome project, many diseases including cancer, hereditary and viral diseases can be understood by the DNA sequence level. Control of the specific gene expression will provide ultimate gene therapy. Minor groove binding polyamides containing N-methylpyrrole and N-methylimidazole amino acids exhibit promising performance based on the recognition of nucleic acid sequences. We recently demonstrated that a hybrid between segment A of duocarmycin A (Du) and a Py-Im hairpin polyamide, selectively alkylates one of the matched sequences within a 450-bp DNA fragment. During this project various types of sequence-specific DNA binding agents have developed and used for the regulation of gene expression. The highly efficient DNA alkylation facilitated by the incorporation of L allowed us to develop a new type of sequence-specific DNA interstrand crosslinking agent that cross-links double strands only in the presence of ImImPy, at the 9-bp sequence 5'-PyGGC(T/A)GCCPu- … More 3'. In developing an efficient sequence-specific alkylating hairpin polyamide, the choice of alkylating moiety and its location in the minor groove was found to be very important. For instance, comparative study of DNA alkylation by four different alkylating Py-Im hairpin polyamides clearly demonstrated that the composition of the vinyl linker dramatically affects the DNA alkylating reactivity. Furthermore, a new combination of Im and the vinyl linker effectively acted to target G-C base pairs in the sequence-specific recognition by DNA alkylating reagents. These synthetic compounds alkylated predetermined DNA sequences to inhibit transcription, and some of them possessed significantly different potency for certain cancer cell lines in the screening panel assay. The effective DNA alkylating agent developed in the present investigation provides a promising approach for developing new types of biological agents to control gene transcription. We are currently investigating whether DNA alkylating hairpin polyamides targeting coding regions inhibit polymerase elongation during transcription. One of the future directions of rational design of molecular medicine in the post genome era has been proposed. Less