Requirement of β-alanine components in sequence-specific DNA alkylation by pyrrole–imidazole conjugates with seven-base pair recognition

• Published in: Bioorganic & medicinal chemistry Vol. 16; no. 5; pp. 2286 - 2291
• Main Authors: Bando, Toshikazu, Minoshima, Masafumi, Kashiwazaki, Gengo, Shinohara, Ken-ichi, Sasaki, Shunta, Fujimoto, Jun, Ohtsuki, Akimichi, Murakami, Masataka, Nakazono, Satomi, Sugiyama, Hiroshi
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.03.2008; Elsevier Science
• Subjects: Alanine - chemistry; Alkylation; Antineoplastic agents; Antitumor agent; Base Pairing; Base Sequence; Biological and medical sciences; DNA - chemistry; DNA - genetics; DNA alkylation; General aspects; Imidazoles - chemistry; Medical sciences; Pharmacology. Drug treatments; Pyrroles - chemistry; Pyrrole–imidazole; Sequence-specificity; Temperature; β-Alanine; Sequence-specificity; DNA alkylation; Pyrrole–imidazole; Antitumor agent; β-Alanine; Antineoplastic agent; Sequence specificity; Nylon; Oligopeptides; Peptides; Nucleotide sequence; Oligomer; Base pairing; In vitro; Alkylation; α-Aminoacid; Alkylating agent; Structure activity relation; DNA; Solid phase; Pyrrole-imidazole; Conjugated compound; Chemical synthesis
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2007.11.064

To investigate the effect of incorporation of β-alanine in alkylating N-methylpyrrole (Py)– N-methylimidazole (Im) polyamide, seco-CBI conjugates 2– 8 were synthesized by an Fmoc solid-phase method and subsequent coupling with an alkylating moiety. DNA-alkylating activities of conjugates 2– 8 were evaluated by high-resolution denaturing gel electrophoresis with 202-base pair (bp) DNA fragments. Alkylation by conjugates 2 and 3, which have antiparallel pairings of β-alanine (β) opposite β (β/β) and Py/β, occurred mainly at the adenine (A) of the matching sequences, 5′-AGCTCC A-3′ (site 1) and 5′-AGCACC A-3′ (site 3). However, conjugate 4, with β/Py, did not show any DNA-alkylating activities. Similarly, conjugate 5, which possessed a Py/Py pair, weakly alkylated the matching sites at micromolar concentrations. Conjugates 6 and 7, which possessed β/β and Py/β pairs, respectively, alkylated at the A of the matching sequences, 5′-ACTACC A-3′ (site 2) and 5′-ACAACC A-3′ (site 4). In contrast, conjugated 8, with a Py/Py pair, showed lower activity and less alkylated DNA at sites 2 and 4 with mismatched alkylation at site 1 at a higher concentration than that of 6 and 7. These results demonstrate that incorporation of β-alanine is required for the sequence-specific alkylation by seco-CBI Py–Im conjugates with a seven-base pair sequence.