42 ブレオマイシンの制癌機構解明への合成的研究 : 軸配位子および連結部位の役割(口頭発表の部)

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Antitumor antibiotics bleomycins (BLMs) induce G-C and G-T specific DNA cleavage owing to the functions of the following structural units; i) pyrimidine moiety to activate dioxygen by ironcomplexation, ii) disaccharide moiety to stabilize the iron-oxygen complex and facilitate membrane transport, iii) bithiazole region to interact with guanine base, and iv) linker moiety to combine each part of BLM at an appropriate distance and in a suitable orientation. Synthetic models for the metal-binding site of BLM with 4-methoxypyridine (PYML-6) and 4-dimethylaminopyridine (PYML-8) show dioxygen activation up to 97% and 125% of BLM, respectively. β-Methylstyrene is oxidized with the Fe(II)-O_2, Fe(III)-H_2O_2, or Fe(III)-PhIO complex systems of PYML-8 to give a set of products including optically active epoxide. The product composition suggests different active species generated from each complex system. Structure-function study on the 2,3-diaminopropionamide region, the fifth ligand moiety, was carried out by use of synthetic models based on PYML-6. Model compounds whose axial lignd moiety is replaced by 3-aminopropionic acid or 2,3-diaminopropionic acid (PYML-9, PYML-10) show pH-dependent oxygen activating power, i.e., 〜40% at physiological pH and 〜85% at alkaline pH. This accounts for the mechanism of the inactivation of BLM by an enzyme, BLM hydrolase, which hydrolyzes the carbamoyl group of 2,3-diaminopropionamide moiety to a carboxyl group. Model ligands having an axial imidazole ring instead of an amino group (PYML-13, PYML-14) show different property as metal complex although they can activate molecular oxygen relatively efficiently. These results demonstrate the significance of coordination of the axial amino group for efficient oxygen activation. The concerted mechanism of DNA cleavage by BLM, especially the role of the linker moiety, is studied by synthetic models, PYML(6)-(4R-APA)-distamycin, PYML(6)-(AHM)-distamycin, and PYML(6)-(4S-APA)-distamycin, in which the oxygen-activating PYML-6 moiety and the A,T-binding distamycin moiety are connected through (R)-4-aminopentanoic acid, (2S,3S,4R)-4-amino-3-hydroxy-2-methylpentanoic acid, and (S)-4-aminopentanoic acid, respectively. Efficiency and base sequence specificity in the DNA cleavage by PYML(6)-(AHM)-distamycin are virtually identical to those of PYML(6)-(4R-APA)-distamycin, indicating no influence of the removal of the 2-methyl and 3-hydroxyl groups of the linker amino acid. On the other hand, PYML(6)-(4S-APA)-distamycin shows markedly decreased DNA cleavage activity compared with PYML(6)-(4R-APA)-distamycin, suggesting that the efficiency of DNA cleavage largely depends on the stereochemistry of the linker moiety.
天然有機化合物討論会の論文
1991-09-07

42 ブレオマイシンの制癌機構解明への合成的研究 : 軸配位子および連結部位の役割(口頭発表の部)

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