Molecular design of sequence specific DNA alkylating agents.
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.
Minoshima
Masafumi
M
Graduate School of Science, Kyoto University, Kitashirakawa-oiwakecho, Kyoto 606-8502, Japan. mino@kuchem.kyoto-u.ac.jp
Bando
Toshikazu
T
Shinohara
Ken-ichi
K
Sugiyama
Hiroshi
H
D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry* / Q000494:pharmacology; D001483:Base Sequence; D002470:Cell Survival / Q000187:drug effects; D002699:Chlorambucil / Q000737:chemistry*; D004247:DNA / Q000737:chemistry; D006801:Humans; D007093:Imidazoles / Q000737:chemistry; D020014:K562 Cells; D009757:Nylons / Q000737:chemistry* / Q000494:pharmacology; D011758:Pyrroles / Q000737:chemistry
D018906:Antineoplastic Agents, Alkylating; D007093:Imidazoles; D009757:Nylons; D011758:Pyrroles; D002699:Chlorambucil; D004247:DNA