Antitumor activity of sequence-specific alkylating agents: pyrolle-imidazole CBI conjugates with indole linker.
DNA-targeting agents, including cisplatin, bleomycin and mitomycin C, are used routinely in cancer treatments. However, these drugs are extremely toxic, attacking normal cells and causing severe side effects. One important question to consider in designing anticancer agents is whether the introduction of sequence selectivity to DNA-targeting agents can improve their efficacy as anticancer agents. In the present study, the growth inhibition activities of an indole-seco 1,2,9,9a-tetrahydrocyclopropa[1,2-c]benz[1,2-e]indol-4-one (CBI) (1) and five conjugates with hairpin pyrrole-imidazole polyamides (2-6), which have different sequence specificities for DNA alkylation, were compared using 10 different cell lines. The average values of -log GI50 (50% growth inhibition concentration) for compounds 1-6 against the 10 cell lines were 8.33, 8.56, 8.29, 8.04, 8.23 and 8.83, showing that all of these compounds strongly inhibit cell growth. Interestingly, each alkylating agent caused significantly different growth inhibition patterns with each cell line. In particular, the correlation coefficients between the -log GI50 of compound 1 and its conjugates 2-6 showed extremely low values (R<0). These results suggest that differences in the sequence specificity of DNA alkylation lead to marked differences in biological activity. Comparison of the correlation coefficients between compounds 6 and 7, with the same sequence specificity as 6, and MS-247, with sequence specificity different from 6, when used against a panel of 37 human cancer cell lines further confirmed the above hypothesis.
Department of Chemistry, Graduate School of Science, Kyoto University, Kitashirakawa-Oiwakecho, Sakyo, Kyoto 606-8502, Japan.
Ken-ichi
K
Shinohara
Toshikazu
T
Bando
Shunta
S
Sasaki
Yogo
Y
Sakakibara
Masafumi
M
Minoshima
Hiroshi
H
Sugiyama
D000225:Adenine / Q000737:chemistry; D000478:Alkylation / Q000187:drug effects; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D001483:Base Sequence; D045744:Cell Line, Tumor; D003521:Cyclopropanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry*; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy*; D009690:Nucleic Acid Conformation; D009757:Nylons / Q000737:chemistry; D016133:Polymerase Chain Reaction; D011758:Pyrroles / Q000737:chemistry*; D013941:Thymine / Q000737:chemistry
C506823:1,2,9,9a-tetrahydrocyclopropa(1,2-c)benz(1,2-e)indol-4-one; D018906:Antineoplastic Agents, Alkylating; D003521:Cyclopropanes; D007093:Imidazoles; D007211:Indoles; D009757:Nylons; D011758:Pyrroles; C029899:imidazole; C030374:indole; D000225:Adenine; D013941:Thymine