Molecular design of sequence specific DNA alkylating agents

M Minoshima, T Bando, K Shinohara… - Nucleic Acids …, 2009 - academic.oup.com
M Minoshima, T Bando, K Shinohara, H Sugiyama
Nucleic Acids Symposium Series, 2009academic.oup.com
Sequence-specific DNA alkylating agents have great interest for novel approach to cancer
chemotherapy. We designed the conjugates between pyrrole (Py)-imidazole (Im)
polyamides and DNA alkylating chlorambucil moiety possessing at different positions. The
sequence-specific DNA alkylation by conjugates was investigated by using high-resolution
denaturing polyacrylamide gel electrophoresis (PAGE). The results showed that polyamide
chlorambucil conjugates alkylate DNA at flanking adenines in recognition sequences of Py …
Abstract
Sequence-specific DNA alkylating agents have great interest for novel approach to cancer chemotherapy. We designed the conjugates between pyrrole (Py)-imidazole (Im) polyamides and DNA alkylating chlorambucil moiety possessing at different positions. The sequence-specific DNA alkylation by conjugates was investigated by using high-resolution denaturing polyacrylamide gel electrophoresis (PAGE). The results showed that polyamide chlorambucil conjugates alkylate DNA at flanking adenines in recognition sequences of Py-Im polyamides, however, the reactivities and alkylation sites were influenced by the positions of conjugation. In addition, we synthesized conjugate between Py-Im polyamide and another alkylating agent, 1-(chloromethyl)-5-hydroxy-1,2-dihydro-3H-benz[e]indole (seco-CBI). DNA alkylation reactivies by both alkylating polyamides were almost comparable. In contrast, cytotoxicities against cell lines differed greatly. These comparative studies would promote development of appropriate sequence-specific DNA alkylating polyamides against specific cancer cells.
Oxford University Press