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

本研究从天然植物中寻找和开发新的化合物以克服耐药性。1）从日本红豆杉（Taxus cuspidata）和中国红豆杉（Taxus chinensis）中分离得到新的紫杉烷类化合物和相关的二萜类化合物，并根据光谱数据和化学方法鉴定了其结构。一些紫杉烷增加积累。长春新碱在多药耐药细胞中的作用，并抑制叠氮平与P-糖蛋白的结合。2）RA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正在进行I期临床试验。3）从加勒比蓝细菌中分离的新型抗有丝分裂剂curacin A的全合成，以及由水稻植物病原体产生的抗有丝分裂-环肽ustiloxin D的构效关系研究，4）从放线菌和植物中分离到了一些新的具有逆转多药耐药性的活性化合物。5）MS-209是一种新型喹啉类化合物，可克服体内外多药耐药性，正在进行临床II期研究评估。我们发现MRK-16可增强环孢素A类似物PSC 833的MDR逆转活性。6）发现分枝杆菌菌株的核糖基化作用是利福平失活的新机制，并对失活代谢产物进行了分离和结构测定。我们发现这些开环葡萄糖万古霉素与细菌细胞壁模型之间的相互作用包括氢键和分子形状拟合。本论文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.