Alkylation of a human telomere sequence by heterotrimeric chlorambucil PI polyamide conjugates.

Gengo Kashiwazaki, Toshikazu Bando, Ken-ichi Shinohara, Masafumi Minoshima, Hana Kumamoto, Shigeki Nishijima, Hiroshi Sugiyama, Gengo Kashiwazaki, Toshikazu Bando, Ken-ichi Shinohara, Masafumi Minoshima, Hana Kumamoto, Shigeki Nishijima, Hiroshi Sugiyama, Gengo Kashiwazaki, Toshikazu Bando, Ken-ichi Shinohara, Masafumi Minoshima, Hana Kumamoto, Shigeki Nishijima, Hiroshi Sugiyama

Index: Bioorg. Med. Chem. 18 , 2887-2893, (2010)

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Abstract

We designed and synthesized human telomere alkylating N-methylpyrrole-N-methylimidazole (PI) polyamide conjugates (1-6). The C-type conjugates 1-3 possessed a chlorambucil moiety at the C terminus, whereas the N-type conjugates 4-6 had one of these moieties at the N terminus. The DNA alkylating activity of these conjugates was evaluated by high-resolution denaturing polyacrylamide gel electrophoresis using a 220bp DNA fragment containing the human telomere repeat sequence 5'-(GGGTTA)(4)-3'/5'-(TAACCC)(4)-3'. C-type conjugates are designed to alkylate the G-rich-strand-containing 5'-GGGTTA-3' and N-type conjugates were designed to alkylate the complementary C-rich strand-containing 5'-TAACCC-3' sequence. The difference between conjugates 1-3 and 4-6 lies in the linker region between the polyamide moiety and chlorambucil. Conjugates 1 and 4 efficiently alkylated the 5'-GGTTAGGGTTA-3' and 5'-CCCTAACCCTAA-3' sequences, respectively, by recognizing 11bp in the presence of distamycin A (Dist), in a heterotrimeric manner: one long alkylating polyamide conjugate (1-6) and two short partners (Dist).Copyright 2010 Elsevier Ltd. All rights reserved.