Synthesis and biological properties of highly sequence-specific-alkylating N-methylpyrrole-N-methylimidazole  polyamide conjugates.
Four new alkylating N-methylpyrrole-N-methylimidazole (PI) polyamide conjugates (1-4) 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 1-4 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.
Department of Chemistry, Graduate School of Science, Kyoto University, Kitashirakawa-oiwakecho, Sakyo-ku, Kyoto 606-8502, Japan.
Gengo
G
Kashiwazaki
Toshikazu
T
Bando
Tomofumi
T
Yoshidome
Seiji
S
Masui
Toshiki
T
Takagaki
Kaori
K
Hashiya
Ganesh N
GN
Pandian
Junichi
J
Yasuoka
Kazunari
K
Akiyoshi
Hiroshi
H
Sugiyama
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D004591:Electrophoresis, Polyacrylamide Gel; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015894:Genome, Human; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008081:Liposomes; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009757:Nylons / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
D018906:Antineoplastic Agents, Alkylating; D007093:Imidazoles; D007211:Indoles; D008081:Liposomes; D009757:Nylons; D011758:Pyrroles; D004247:DNA; C427203:calf thymus DNA