Studies On The Relationship Between Fine Stereostructure And Biological Activity Of Taxane Diterpenoids

Paclitaxel is a new type of diterpenoids isolated from Taxus brevifolia by Wani et al. in 1971, which has novel mechanism of anticancer action.There have been many merits in the fields of phytochemistry, chemical synthesis, tissue culture and pharmacology of taxane diterpenoids during the past 20 years, but there are still some important problems that need further study on these compounds, such as resources shortage, poor solubility in water and cross drug-resistance. During the period of this dissertation work, I determined 62 new crystal structures(including 11 taxane diterpenoids), analyzed precise stereostructures of taxane diterpenoids in solid state, studied the regularity of taxoids' structures in crystal state and free state, found out the quantitative index of the groups related to biological activity, and studied the interaction between the receptor and taxol and its analogs on the basis of the crystal structure of αβ-tubulin reported by Eva Nogales et al. in 1998. All of the results provided basic data for further design of new drugs acting on tubulin.Eleven single crystals of taxane diterpenoids were obtained by solution diffusion method at low temperature, and their crystal structures were determined by X-ray diffraction method. The molecules include two 6/12 skeleton compounds(taxachitriene B and 2,20-diacetyl-5-deacetyl taxachitriene B), which were the first-reported crystal structures of this type of taxane diterpenoids, four compounds with 6/8/6 skeleton and C₄-C₂₀ double bond(taxinine A, 5-decinnamoyl taxinine J, 7-deacetyl taxinine J and taxinine), two compounds with 6/8/6/4 skeleton (13,14-dehydro-7-triethylsilyl-13-trimethylsilyl baccatin III and 10-deacetyl-7-epitaxol), two compounds with 5/7/6 skeleton and C₄ saturated substituent(taxuchin B, the first taxane diterpenoid having a chlorine atom, and taxayuntin G), and a 5/7/6/4 skeleton compound(taxayuntin B).Analysis of the structures of 27 taxane diterpenoids in crystal and free states gave the regularity of their structures:(1)the skeleton of taxane diterpenoids is conservative. The molecular skeletons of the compounds having the same skeleton but with different substituents are similar. The substituents at C₂ and C₉ are conservative. The substituents at these two atoms have similar direction in different compounds having the same skeleton. (2)The skeletons of taxane diterpenoids are bow-shaped. The size of the bow was described by the distance between atom C₅ and atom C₁₃, which was affected by the substituent at C₄. The distance in taxane...