Sequence specificity, reactivity, and antitumor activity of DNA-alkylating pyrrole-imidazole diamides.
Three conjugates of imidazole (Im)-pyrrole (Py) diamide and a DNA-alkylating moiety derived from the antibiotic duocarmycin A were synthesized, and their sequence specificity, reactivity, and antitumor activity comparatively examined. Sequencing gel analysis indicated that ImPyDu (1) alkylates DNA at the 3' end of AT-rich sequences at micromolar concentration. ImPyDu86 (2) reacts with DNA at AT-rich sites together with dialkylation sites at micromolar concentration. ImPyLDu86 (3) efficiently alkylates dialkylation sites at nanomolar concentration. Average values of log IC(50) against a 39 cancer cell line panel of 1-3 were -4.59, -5.95, and -8.25, respectively. The differential growth inhibition pattern of 1-3 varied with relatively low correlation coefficients. Array-based gene expression monitoring was performed for 3 in a human lung cancer cell line. Substantial downregulation of expression was seen for genes involved in DNA damage response, transcription, and signal transduction.
Bando
Toshikazu
T
Division of Biofuctional Molecules, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Surugadai, Kanda, Chiyoda-Ku, 101-0062, Tokyo, Japan.
Iida
Hirokazu
H
Tao
Zhi Fu
ZF
Narita
Akihiko
A
Fukuda
Noboru
N
Yamori
Takao
T
Sugiyama
Hiroshi
H
D000478:Alkylation; D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry / Q000494:pharmacology*; D001483:Base Sequence; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism*; D003958:Diamide / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D000080890:Duocarmycins; D020869:Gene Expression Profiling; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D007211:Indoles / Q000737:chemistry; D020128:Inhibitory Concentration 50; D008969:Molecular Sequence Data; D015394:Molecular Structure; D020411:Oligonucleotide Array Sequence Analysis; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology; D011760:Pyrrolidinones / Q000737:chemistry
D018906:Antineoplastic Agents, Alkylating; D000080890:Duocarmycins; D007093:Imidazoles; D007211:Indoles; D011758:Pyrroles; D011760:Pyrrolidinones; D003958:Diamide; D004247:DNA; C058289:duocarmycin A