Search and development for new compounds to overcome drug resistance from natural sources

寻找和开发新化合物以克服天然来源的耐药性

基本信息

批准号：
07307022
负责人：
KOBAYASHI Jun'ichi
金额：
$ 14.46万
依托单位：
HOKKAIDO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1997
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07307022/
关键词：
natural products multidrug-resistance P-glycoprotein antitumor tubulin mechanism of MDR MDR modifier MRSA

项目摘要

In this research project, we have investigated on search and development for new compounds to overcome drug resisiance from natural sources.1) From the Japanese yew Taxus cuspidata and the Chinese yew Taxus chinensis, new taxoids and related diterpenoids were isolated and the structures elucidated on the basis of spectroscopic data and chemical means. Some taxoids increased accumulation. of vincristine in multidrug-resistant cells and inhibited binding of azidopine to P-glycoprotein. Taxuspine C enhanced the chemotherapeufic effect of anticancer agent in vivo.2) A structure-activity relationship study RA-related cyclic peptides revealed that RA-VII showed the most potent antitumor activity. RA-VII is under a clinical phase I trial.3) Total synthesis of curacin A,a novel antimitotic agent isolated from a Caribbean cyanobacterium, and studies on the structure-activity relationships of ustiloxin D,antimitotic-cyclic peptidc produced by the rice plant pathogen, were carried out.4) Some new bioactive compounds which reversed multidrug resistance were isolated from actinomycetes and plants.5) MS-209 is a novel quinoline compound which can overcome multidrug resistance both in vitro and in vivo and is being evaluated in a clinical phase II study. We found that MDR reversal activity of PSC833, an analogue of cyclosporin A,was potentiated by MRK-16.6) Ribosylation by mycobacterial strains as a new mechanism of rifampin inactivation was found and these inactivated metabolites were isolated and the structures were determined.7) Seco-aglucovancomycins were synthesized by means of TTN oxidation as a key step. We found that interaction between bacterial cell wall model and these seco-aglucovancomycins consisted of hydrogen bondings and molecular shape fittings. Total synthesis of hapalosin, a cyclic peptide possessing multidrug resistance reversing activities was accomplished.

在该研究项目中，我们已经研究了新化合物的搜索和开发，以克服自然来源的药物解决方案。1）从日本紫杉的出租车cuspidata和中国紫菜撒西尼西斯，新的税类和相关的二甲类类苯二甲酸酯，并阐明了结构。光谱数据和化学方法的基础。一些类符号增加了积累。多药耐药细胞中的长辛克碱，并抑制叠氮化胺与P-糖蛋白的结合。出租车C增强了体内抗癌剂的化学疗法作用。2）结构活性关系研究与RA相关的循环肽表明，RA-VII显示出最有效的抗肿瘤活性。 RA-VII是在临床I期试验下。3）素素A（从加勒比蓝细菌中分离出的新型抗魔法剂）的总合成，以及对紫氧蛋白D的结构活性关系的研究，由水稻生产的抗氧化剂peptidC产生4）一些从放线菌和植物中分离出逆转多药耐药性的一些新的生物活性化合物。5）MS-209是一种新型的奎诺林化合物，可以在体外和体内都可以克服多种耐药性，并且正在体内评估，并且正在评估。临床II期研究。我们发现，PSC833（Cyclosporin A的类似物）的MDR逆转活性被MRK-16.6）通过分枝杆菌菌株增强了核糖基化，因为发现了利福平灭活的新机制，并确定了这些灭活的代谢物，并确定了结构。7）SECO.7）7）7） - 阿古瓜霉素通过TTN氧化作为关键步骤合成。我们发现细菌细胞壁模型与这些seco氨基糖霉素之间的相互作用由氢键和分子形状配件组成。 HAPALOSIN的总合成，即具有多药抗性逆转活动的环状肽。