Anticancer activities of alkylating pyrrole-imidazole polyamides with specific sequence recognition.
In recent years, many diseases including cancer and hereditary and viral diseases have been understood at the DNA sequence level. Direct control of the expression level of a specific gene would provide a promising approach for knowledge-based therapy. N-methylpyrrole and N-methylimidazole polyamides are a new type of small compound that precisely bind to the minor groove of the DNA duplex in a sequence-specific fashion and recruit alkylating agents to the target sequence. We designed and synthesized a series of sequence-specific alkylating Py-Im polyamide conjugates that selectively alkylate predetermined DNA sequences. We have shown that sequence-specific alkylating agents possess gene-silencing activities when they alkylate coding regions of template strands and show promising potency against human cancer cell lines and xenografts possessing human cancer cells. In this study, we focus on recent progress in alkylating Py-Im polyamides with regard to sequence specificity and biological activities, and the future direction of the rational molecular design of genetic switches in the post-genome era is described.
Shinohara
Ken-Ichi
K
aDepartment of Chemistry, Graduate School of Science bInstitute for Integrated Cell-Materials Science (iCeMS) Kyoto University, Yoshida-ushinomiyacho, Sakyo, Kyoto, Japan.
Bando
Toshikazu
T
Sugiyama
Hiroshi
H
D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D001483:Base Sequence / Q000187:drug effects*; D045744:Cell Line, Tumor; D020868:Gene Silencing; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D009757:Nylons / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D018906:Antineoplastic Agents, Alkylating; D007093:Imidazoles; D009757:Nylons; D011758:Pyrroles; C096654:N-methylpyrrole; C018100:1-methylimidazole