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

在本研究项目中，我们研究了从天然来源寻找和开发克服耐药性的新化合物。1)从日本红豆杉（Taxus cuspidata）和中国红豆杉（Taxus chinensis）中分离出新的类群及其相关的二萜类化合物，并通过光谱和化学手段对其结构进行了鉴定。部分类型体积累增加。多药耐药细胞中的长春新碱，并抑制叠氮多平与p -糖蛋白的结合。Taxuspine C在体内增强了抗癌药物的化疗效果。2)对RA-VII相关环肽的构效关系研究表明RA-VII具有最强的抗肿瘤活性。RA-VII正在临床I期试验中。3)研究了从加勒比海一株蓝藻中分离的新型抗有丝分裂剂curacin A的全合成，以及该水稻植物病原菌产生的抗有丝分裂环肽ustiloxin D的构效关系。4)从放线菌和植物中分离到一些新的逆转多药耐药的生物活性化合物。5) MS-209是一种体外和体内均可克服多重耐药的新型喹啉化合物，正在进行临床II期研究。我们发现环孢素A类似物PSC833的耐多药逆转活性被分枝杆菌的MRK-16.6核糖基化增强，同时发现了利福平失活的新机制，并对这些失活代谢物进行了分离和结构测定。7)以TTN氧化为关键步骤合成了seco -aglucovancomycin。我们发现细菌细胞壁模型与这些次农业万古霉素之间的相互作用包括氢键和分子形状的配合。完成了具有逆转多药耐药活性的环肽hapalosin的全合成。

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.