Development of new antifungal and anti-HIV agents based on the mannose binding quinone glycoside

点击翻译按钮获取中文摘要

In order to improve the pharmacokinetics of antifungal antibiotic pradimicins, synthesis of new derivatives that have higher water solubility and lower self aggregation property was investigated in this study. After examining several derivatives, it was found that the new derivatives designated PRM-DCA have desired properties. PRM-DCA was obtained by the oxidative cleavage of 1,2-diols in the xylose moiety and the following oxidation of aldehyde to carboxylic acid. Thus, the new derivatives possess two carboxylic acid functionalities in their sugar part. Pradimicin A, N,N-dimethylpradimicin C, and BMY-28864 were subjected to the oxidative conversion and the PRM-DCA derivatives were obtained in 60-75% isolation yield. The solubility of the PRM-DCA in PBS solution was enhanced in comparison with the parent compounds : ca. 30 times in case of pradimicin A, and ca. 2 times in case of N,N-dimethylpradimicin C and BMY-28864. The affinity of PRM-DCA derivatives to D-mannose was decreased 20 times compared to the parent compounds. The aggregation of PRM-DCA derivatives with mannan was less than 5% of the parent compounds in case of pradimicin A and N,N-dimethylpradimicin C, and less than 30% in case of BMY-28864. As described above, it was shown that the new derivatives PRM-DCA were prepared in one-pot reaction from the natural products and had high water solubility and low aggregation property. The PRM-DCA derivatives showed antifungal activity against Candida albicans, Cryprococcus neoformans, and Asperigillus fumigatus although the potency was same or weaker than the parent compounds. On the other hand, the new derivatives did not exhibit acvitity against HIV and influenza virus although the parent compounds exhibit good activity against such virus. In addition, PRM-DCA derivatives were shown to be useful as a starting material to synthesize the prodrugs and the drug-conjugates by using the carboxyli acid residues.