| Budget Amount *help |
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2005: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2004: ¥2,600,000 (Direct Cost: ¥2,600,000)
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| Research Abstract |
1.Synthesis
(1)Synthesis of Novel DNA-Binding Molecules Using Indole-Alkalod Nucleus as Molecular-Recognizing Device :
About thirty kinds of new β-carboline derivatives and ellipticine analogs were synthesized in high yield by multi step reactions in this study. The N-methyl-N-nitrosourea moiety was linked to the β-carboline or ellipticine nucleus as an intercalator. The linker between these two structures consists of amide, ether, or amine. The length of the linker was 2 - 7 atoms, and the linker was connected to the 3- or 9-atom of β-carboline and the 2- or 5-atom of ellipticine. Finally, Binding mode of these compounds to DNA was determined by linear dichroism or fluorescence anisotropy of dye-DNA firm, which is oriented by the chain alignment.
(2)Synthesis of Novel DNA-Binding Molecules Using 1,6-Naphthyridine Nucleus as Molecular-Recognizing Device :
The precursors of the 1,6-naphthyridine-methylnitrosoureas were synthesized from 7-fluoro-1,6-naphthyridine derivatives in high yields. In addition, quinolones, quinolines, pyrimidine, and 1,3,8-triazanaphthalenes were newly synthesized in high yields by efficient methods. Especially, synthesis of pyrimidines by four-component coupling reaction is completely new method, and bears watching.
2.Evaluation of Antineoplastic Acitivity
Antineoplastic activity of the compounds mentioned above was evaluated on the cell lines, Sarcoma 180, HeLa S-3, and L1210 to give high activity (IC_<50><1μM).
3.Alkylation of DNA with DNA-Targeting Antineoplastic Drug
DNA-methylation behavior of β-carboline- or ellipticine-N-methyl-N-nitrosourea was compared with that of N-methyl-N-nitrosourea itself. The reaction gave N^3-methyladenine and N^7-methylguanine as major products. In the former two hybrid compounds, the formation of N^3-methyladenine was increased. As a result, minor groove selectivity was enhanced (5-100 times of N-methyl-N-nitrosourea).
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