Taxoids From Twigs And Needles Of Taxus Chinensis And Modifications On Core Structures Of Paclitaxel Analogs

Paclitaxel(=Taxol^R), an anitumor agent isolated from bark of Pacific yew Taxus breviforlia originally, has been considered one of the most effective drug for the treatment of metastatic ovary and breast cancers. To avoid destroying limited natural resource, regenerate twigs and needles of Taxus plants has been developed as alternative materials for extracting its precursor, 10-deacetylbaccatinⅢ, which will be used in semisynthesis of pharmaceutical product of paclitaxel. Finding new taxoids in Taxus plants to develop effective paclitaxel analogs is undoubtedly an interesting idea. Structure modifications on known taxoids, especially paclitaxel-related compounds, can also find new approach to developed new generation of palcitaxel analogs.1. Taxoids from twigs and needles of Taxus chinensisTaxus chinensis, a Taxus species indigenous to China, drew our attention to investigate the taxoids in this plant. On the basis of pharmacological screening results that several portions of the ethanolic extract of this plant exhibit anticancer activity towards three cancer cell lines, we then extracted, isolated and structurally elucidated 14 taxoids, including a group of new bicyclic taxoids (taxachitrienes) with different skeleton from other taxoids hitherto reported.From twigs and needles of this plant obtained four new 6/12 ring-fused bicyclic taxoids, namely taxachitriene A, taxachitriene B, 20-deacetyltaxachitriene A and 5-deacetyltaxachitriene B, together with a abeo(15→1) taxane taxuchin B, the only example of chlorine-containing taxoid to date, and a normal 6/8/6 ring-fused taxoid 5-acetyltaxinine M. Known taxoids consist of taxol, 10-deacetyltaxol, 10-deacetyl-cephalomannine, 10-deacetylbaccatinⅢ, 1β-hydroxy-7,9-dideacetylbaccatin I, taxacin, taxinine M and taxagifine.Structure of taxachitriene A was determined by spcetroscopic methods and chemical reactions, including deduction of its relative configuration and dominant conformation by difference NOE. X-ray diffraction experiment of crystallizable compound taxachitriene B was performed to ensure the correct structure determination. Besides, spectral characteristics for taxachitrienes were summed up. The discovery of taxachitrienes strongly supported the hypothesis for biogenesis pathway of taxane diterpenoids.2. Modifications on core structure of paclitaxel analogsA known taxoid 7-epi-10-deacetylpaclitaxel was used as starting material for the core modification aiming at C-10, C-14, C-2 and C-7 of paclitaxel analogs. Fifty target compounds and intermediates, in which 42 are new compounds, were synthesized, and several compounds were pharmacologically evaluated. In the meantime to synthesize these compounds, chemical reactivities of taxoids were also explored. The most important results are depicted as follows.(1) Nucleophilic reactivities of 10β-OH and 7α-OH were compared. As a result, a facile access to semisynthetic 7-epi-paclitaxel was proposed.(2) 10-Oxo rearranged products were obtained when 10β-OH were trifluorosulfonated in 7α-OH free substrates. It was found that the formation of 10-oxo products can be attributed to the assisstance of 7α-OH, a new example for neighbouring group participation in the reaction of taxoids. The 4-deacetyl products formed when reducing△^10,11,△^12,18 compounds can also be explained by anchimeric assisstance.(3) Thorough studies on 7-epimerization of paclitaxel and related taxoids under basic conditions led to the conclusion that 13α-OH may play an important role in controlling ratio of 7-epimer mixtures.(4) Bromine atom was introduced into C-14 position of taxoids through enol silyl ethers. It is the first time to report the synthesis of bromine-containing taxoids, and both C-13 and C-14 substituted paclitaxel analogs besides naturally occuring taxoid 1413-OH-10-deacetylbaccatinⅢ.(5) Azido group was successfully introduced into C-2 position oftaxoid. It is for the first time to synthesize nitrogen-containing taxoid at C-2. The unusual 2α-azido substituted pattern through 2α-methansulfonate may be attributed to the 1, 2(β)-epoxide intermediate.In conclusion, "Taxoids from twigs and needles of Taxus chinensis and modifications on core structure of paclitaxel analogs" provide some useful information on natural occurrence, chemical reactivities of taxoids and development of new paclitaxel analogs.