|其他摘要||Opportunistic fungal infection, mainly resulting from Candida, Cryptococcus, and Aspergillus, are life-threatening in immunocompromised patients with cancer, AIDS, diabetes, or organ transplant, etc. The current antifungal armamentarium include five major drug classes, polyenes, azoles, allylamines, echinocandins and flucytosine. Representatives from the five classes are amphotericin B (AMB), fluconazole (FLU), terbinafine, caspofungin, and flucytosine, respectively. However, these synthesized antifungal drugs suffers one or more major shortcomings. For example, significant dose-limiting toxicities to kidney for AMB, rapid development of resistance for the azole drugs, limitation of the use to dermatophytoses for terbinafine, and lack of effectiveness in cryptococcosis for caspofungin. This has highlighted the need to discover new antifungal agents from natural products, preferably with new modes of action.
C-27 steroidal saponins are an important class of natural products which used widely as starting materials for the synthesis of steroidal hormones. Previous researches on steroidal saponins from Liliales plant display significant antifungal activity. To search for new antifungal agents, the phytochemical studies on Smilacina atropurpurea (Franch) Wang et Tang, Polygonatum prattii Baker, Yucca elephantipes Regel and Dioscorea nipponica Makino were carried out which led to the isolation of forty-two constituents including nineteen new steroidal glycosides. Of them, seven polyhydroxylated in A-ring and seven cis-fused A/B ring uncommon steroidal compounds were involved (Chapters 1-4).
To meet the need of pharmacy, the preparation methods and quality control of freeze-dried powder containing water-soluble steroidal saponins from D. nipponica were established on the bases of phytochemical studies. The current standard of "Chuan-Shan-Long Injection" was also revised through chemical fingerprint research (Chapter 4).
Fifty-one steroidal sapogenins and saponins obtained from this thesis and other four plants: Agave americana L., Polianthes tuberosa L., Polygonatum zanlanscianense Pamp., and Dioscorea parviflora Ting., were tested for their antifungal activity against the opportunistic pathogens Candida albicans, C. glabrata, C. krusei, Cryptococcus neoformans and Aspergillus fumigatus. The results showed that four tigogenin saponins exhibited significant activity against C. neoformans and A. fumigatus, comparable to the positive control amphotericin B with low cytotoxicity to mammalian cells which could be used widely for development and application. The analytic results of structure-activity relationships (SAR) of the tested steroids presented that both the oxidated level of the aglycone and the characteristic of sugar moiety worked significantly on antifungal activity (Chapter 5).
C-27 steroidal saponins, as important secondary metabolites, are abundant in genus Polygonatum. We comprehensively analyzed the chemical diversity of steroidal glycosides in Polygonatum plants and through which the evolution rules of these compounds have discussed based on the oxidated level of aglycone and the properties of sugar moiety. The relativity between steroidal saponins and systematic taxonomy was also discussed in this thesis together with the morphologic characteristic, chromosome and karyotype analysis, etc. And the study provided chemical information and proofs for the systematic evolution of Polygonatum species (Chapter 6).
In addition, the progress and the development tendency on research of antifungal drugs were reviewed in the thesis (Chapter 7).
These researches in this paper led to the publication of two SCI articles [totle IF (2005), 6.553], five papers prepared and two patents appled.|