26 グリコペプチド系抗生物質バンコマイシンの糖部分の修飾(口頭発表の部)
スポンサーリンク
概要
- 論文の詳細を見る
Glycopeptide antibiotics represented as vancomycin (1) are final defense against bacterial infection. The mechanism of this class of antibiotics inhibits gram positive bacterial cell wall biosynthesis due to bind the key peptide fragment, L-Lys-D-Ala-D-Ala with five hydrogen bonding. However recently some enterococci showed resistance against vancomycin by changing the terminal D-Ala to D-Lac and the activity was significantly decreased by approximately 3000 times by luck of one hydrogen bonding. Recent X-ray crystal structure of vancomycin showed asymmetric dimmer and the glucose-C6 hydroxyl group of one monomer faced to the binding pocket. Therefore we focused this position and hypothesized to build additional hydrogen bonding or hydrophobic effect by introducing several functional group to improve activity. First, two amines and one carboxyl group were needed to be protect with aloc and allyl groups. The protected vancomycin was treated with 2-mesitylenesulfonyl chloride and pyridine at 4℃ to give glucose C6 sulfonated intermediate selectively and displaced with KI then deprotected aloc and allyl groups with Pd catalyst. This key intermediate (3) was displaced with several nucleophiles to give glucose-C6 modified vancomycins. The best analogues were 2-thio-6-azathymine (5) which is more active against susceptible strains and 5-thio-4-amino-3-hydrazino-1, 2, 4-triazole (6, Purpald^[○!R]) which showed specific activity against resistant strains of 46 derivatives. However activities of these glucose-C6 modified vancomycin analogues against vancomycin resistant Enterococci were not enough. Introduction of N-4-(4-chlorophenyl)benzyl group on vancosamine amine greatly improved their activities. N-4-(4-chlorophenyl)benzyl glucose-C6-iminotriphenylphosphine analogue (11) was most active. Furthermore Time-Kill Studies showed modification of glucose-C6 and vancosamine amine exhibited bactericidal activity. The mode of action of these glucose-C6 modified analogues was not clear. Their binding affinity against Ac_2-t-Lys-D-Ala-D-Ala and Ac_2-L-Lys-D-Ala-D-Lac are almost identical with parent vancomycin. This imply there was the other mode of action. ES I mass spectra of them suggested their interesting physical characters. Pseudoaglycon tetramer ion peak was observed on the ESI mass spectrum of 5 which was most active against all vancomycin susceptible strains. No dimer or tetramer peak was observed in the mass spectrum of 6. It is possible that aggregation in the solution might take part in improving activity. Further study is currently in progress in our laboratory.
- 天然有機化合物討論会の論文
- 1998-08-31
著者
関連論文
- 13 細胞毒性ステロイドアルカロイドRitterazine類の構造-活性相関(口頭発表の部)
- 26 グリコペプチド系抗生物質バンコマイシンの糖部分の修飾(口頭発表の部)
- 11 伊豆半島産群体ホヤRitterella tokiokaの強力な細胞毒性を有する新規ステロイドアルカロイドRitterazine類の構造と活性(口頭発表の部)