Synthesis and Biological Properties of Highly Sequence-Specific-Alkylating N-Methylpyrrole鈥?i>N-Methylimidazole Polyamide Conjugates

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• 作者：Gengo Kashiwazaki ; Toshikazu Bando ; Tomofumi Yoshidome ; Seiji Masui ; Toshiki Takagaki ; Kaori Hashiya ; Ganesh N. Pandian ; Junichi Yasuoka ; Kazunari Akiyoshi ; Hiroshi Sugiyama
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：March 8, 2012
• 年：2012
• 卷：55
• 期：5
• 页码：2057-2066
• 全文大小：559K
• 年卷期：v.55,no.5(March 8, 2012)
• ISSN：1520-4804

文摘

Four new alkylating N-methylpyrrole-N-methylimidazole (PI) polyamide conjugates (1鈥?b>4) with seven-base-pair (bp) recognition ability were synthesized. Evaluation of their DNA-alkylating activity clearly showed accurate alkylation at match site(s). The cytotoxicities of conjugates 1鈥?b>4 were determined against six human cancer cell lines, and the effect of these conjugates on the expression levels of the whole human genome in A549 cells were also investigated. A few genes among the top 20 genes were commonly downregulated by each conjugate, which reflects their sequence specificity. Conversely, many of the top 10 genes were commonly upregulated, which may have been caused by alkylation damage to DNA. Moreover, the antitumor activities of the PI polyamide conjugates 2 and 3 were investigated using nude mice transplanted with DU145 or A549. The intravenous administration of each liposomal conjugate in water yielded tumor-suppressing effects specifically toward DU145 cells and not A549 cells, which was pertinent to cytotoxicity.