Taxane diterpenoids

10-deacetyl baccatin III-10-0-acetyl transferase. The double dashed arrows indicate multiple reactions including uncharacterized steps. The dashed box represents a bypass of paclitaxel biosynthetic pathway. 

Although cell suspension cultures (DDC cells) have been used in the industry to produce paclitaxel, the variability in product accumulation is still a key challenge to the regular commercial use [2]. In parallel to the examples shown in Section 8.3.1, CMCs were isolated from Taxus cuspidate to produce paclitaxel [68]. The CMCs demonstrated great advantages over the DDCs and overcame 

In addition, hairy root culture was attempted by two groups for paclitaxel production. One of the hairy root lines, established using seedlings of T. cuspidate (Korean yew), accumulated 52.5 mg 1 paclitaxel after 2 weeks in a 20-1 bioreactor operating under MeJA induction [73]. The other hairy root culture generated from the plantlets of TaxusX media (a hybrid species between T. cuspidate and T. baccata) accumulated 210 pgg DW paclitaxel following MeJA induction [74]. 

Hosts Engineering strategies Role in the paclitaxel pathway Expression system Main observations 

Native hosts Overexpression of DBAT with MeJA elicitation [75] Pathway enzyme T. mairei cell suspension Increase in baccatin III and paclitaxel 

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Novel polycyclic heterocyclic systems including the isoxazoline ring were described. Thus, oximes 191 and 193 in the presence of sodium hypochlorite afforded heterocycles 192 or 194, respectively (equations 83 and 84). Intramolecular cycloaddition of nitrile oxide was used in the synthesis of the A-ring fragments of la,25-dihydrovitamin D3 and taxane diterpenoids, sulphur-containing isoxazoles, fluoro-substituted aminocyclopentanols and aminocyclopentitols . New gem- and vic-disubstituted effects in such cyclization reactions have been reviewed by Jung. ... 

Taxus species are well known due to the antitumor and anticancer activities of their taxane diterpenoids, which have attracted many researchers to them [5,7,8]. In Taxus species (Taxaceae), lignans have been shown to occur in different parts of the tree, extending from the needles to the roots [5,8]. 

R618 J.-Y. Zhou, W.-M. Chen and Q.-C. Fang, The C-NMR Features of Natural Taxane Diterpenoid Compounds , Zhiwu Xuebao, 2000,42,1... 

JO. Kingston DGI, Molinero AA, Rimoldi JM (1993) The Taxane Diterpenoids. In Herz W, Kirby GW, Moore RE, Steglich W, Tamm C (ed) Progress in the Chemistry of Organic Natural Products. Springer-Verlag, New York, p 1... 

In some cases, product distribution is influenced by the solvent used. As observed in efforts toward the synthesis of taxane diterpenoids, intermediate 48 when left standing in methanol for three days was completely converted to 49. On the other hand, in the aprotic solvent CDCI3, 48 was present in an 88 12 ratio with 49. These results are rationalized as follows. The strain of the bridgehead double bond in 48 causes 49 to be favored thermodynamically. In the presence of MeOH, where intermolecular hydrogen bonding is predominant, spirocycle 49 is... 

Jaziri M, Diallo BM, Vanhaelen MH, Vanhaelen-Fastre RJ, Zhiri A, Been AG, Homes J (1991) Enzyme-linked immunosorbent assay for the detection and the semi-quantitative determinatimi of taxane diterpenoids related to taxol in Taxus sp. and tissue cultures. J Pharm Belg 46 93—99... 

Taxol is differentiated from most other taxane diterpenoids by its ester side chain at C-13 and by its oxetane ring D. It can be viewed as the N-benzoyl-p-phenylisoserine ester of baccatin 111. The conventional planar representation of taxol can be misleading since its structure is best described as inverted cup shape as shown in Fig. 101.2. 

The physiological activity of extracts from yew species has been known for millennia. In 1856, Lucas (358) isolated a mixture of alkaloids, which he called taxine and, 100 years later, Graf (359) showed this to be a mixture of at least seven compounds. Over 250 taxane diterpenoids are now known. Paclitaxel (312) was isolated from Taxus brevifolia (the Pacific Yew) in 1967 [360, 361] and its structure determined by X-ray crystallography in 1971 (362). The discovery of its anticancer properties led to a huge amount of research into its extraction, synthesis, production, and application. Bristol-Myers Squibb trademarked the name Taxol for paclitaxel and they, other pharmaceutical companies and academic researchers have invested much into the study of pacUtaxel and the search for active analogues and prodrugs. Some of the more significant materials in this series are shown in Fig. 8.59. 

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