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

为了改善抗真菌抗生素普拉米星的药代动力学，本研究合成了具有较高水溶性和较低自聚集性的新型衍生物。在研究了几种衍生物后，发现命名为PRM-DCA的新衍生物具有所需的性质。PRM-DCA通过木糖部分中的1，2-二醇的氧化裂解和随后的醛氧化成羧酸而获得。因此，新的衍生物在其糖部分具有两个羧酸官能团。将普拉米星A、N，N-二甲基普拉米星C和BMY-28864进行氧化转化，以60-75%的分离产率获得PRM-DCA衍生物。与母体化合物相比，PRM-DCA在PBS溶液中的溶解度增强：约100%。普拉米星A的情况下为30倍，约为20倍。对于N，N-二甲基普拉米星C和BMY-28864，2次。PRM-DCA衍生物对D-甘露糖的亲和力比母体化合物降低了20倍。PRM-DCA衍生物与甘露聚糖的聚集在普拉米星A和N，N-二甲基普拉米星C的情况下小于母体化合物的5%，在BMY-28864的情况下小于30%。如上所述，表明新衍生物PRM-DCA是由天然产物在一锅反应中制备的，并且具有高水溶性和低聚集性质。PRM-DCA衍生物对白色念珠菌、新生隐球菌和烟曲霉具有一定的抗真菌活性，但活性与母体化合物相当或较弱。另一方面，新的衍生物没有表现出抗HIV和流感病毒的活性，尽管母体化合物表现出抗这些病毒的良好活性。此外，PRM-DCA衍生物显示出可用作通过使用羧酸残基合成前药和药物缀合物的起始材料。

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.