10-Deacetyl baccatin III

Starting from needles of Taxus baccata (1 g 10-deacetyl baccatin III obtained from 1000 g dried needles). 

Gueritte-Voegelein, R, S nilh, V., David, B., Guenard, D., Potier, P. (1986) Chemical Studies of 10-Deacetyl Baccatin III. Hemisynthesis ofTaxol Derivatives. Tetrahedron, 42, 4451-4460. 

Systems with different selectivity were nsed for the separation of 10-deacetyl-baccatin III (10 DAB 111) from yew extracts [69]. A silica column with stepwise gradient elution with aqneous methanolic mobile phases can be nsed for separation of the taxoid fraction from nonpolar materials, partial separation of the taxoid fraction into a polar one (containing 10-DAB 111), and for a medinm polarity taxoid fraction (containing paclitaxel and cephalomannine). Most polar material (tannins... 

Larotaxel (XRP-9881, RPR 109881A) 59 (Sanofi-Aventis) is undergoing Phase III trials in patients with advanced pancreatic cancer who had been previously treated with gemcitabine, as well as in combination with cisplatin to treat locally advanced/metastatic urothelial tract or bladder cancer.124 A Phase III trial for the treatment of advanced breast cancer has been completed. Larotaxel 59129>130 js a semi-synthetic derivative of 10-deacetyl baccatin III with a docetaxel-like side chain that has a low affinity for the P-glycoprotein drug efflux pump, an efflux mechanism that diminishes the effectiveness of the marketed drugs paclitaxel 60 and docetaxel. Importantly, this low affinity should enable larotaxel 59 to be effective in tumours resistant to paclitaxel 60... 

Under oxidizing conditions (Jones reagent), taxol is converted to the 7-keto derivatives 20a and 20b (43) (see Scheme 3). Under these same conditions (2,11,28), the free 13-hydroxyl group of baccatin III (13b) and 10-deacetyl baccatin III (13a) is oxidized to form 13-oxobaccatin III (21b) and the deacetyl derivative (21a), respectively. Treatment of compound 20c, derived from the oxidation product 20a after protection of its 2 -hydroxyl group, with base leads to rearrangement products such as D-seco taxane 22. 

Initially, researchers focused on the separation of paclitaxel from cephalomannine, a paclitaxel analogue that shares the C-13 ester side-chain and, therefore, exhibits cytotoxic activity. Cephalomannine was found to elute close to paclitaxel and caused interferences for determination and purification purposes. Lately, the main taxane targets are baccatin III and 10-deacetyl-baccatin III (10-DAB III). Both compounds lack the C-13 side-chain (Fig. 1) thus, they do not show antitumour activity. Both baccatins, especially 10-DAB III, serve as synthons for the synthesis of paclitaxel or analogues. 7-Epi-paclitaxel differs from paclitaxel only in the stereochemistry of the hydroxy group in the C-7 position. 7-Epi-paclitaxel, a product of paclitaxel epimerization, shows cytotoxic activity and difficulty in separation from paclitaxel. The deacetyl derivatives of paclitaxel, 7-epi-paclitaxel, baccatin III, and cephalomannine, are also quite often the... 

Comparison of these values with the ones calculated from peaks eluting at similar retention times in the analysis of extracts could be a fast way to verify the identity and to check the peak purity. Analysis of the semipurified taxine mixture by gradient HPLC-DAD revealed the presence of seven taxanes with 10-deacetyl baccatin III (10-DAB III) among them. All the nine expected taxines were positively identified (Table 1). 

Fig. 4. Anticancer drugs paclitaxel and docetaxel. Both compounds can be obtained by chemical structure modification of baccatin III or 10-deacetyl baccatin III...

Paclitaxel and docetaxel are taxane plant alkaloids with antimitotic activity (see Table 124-12). Paclitaxel was isolated from the bark of the Pacific yew tree, Taxus brevifolia, but is now produced semisyntheti-cally from the needles of the European yew, Taxus baccata. Docetaxel is a semisynthetic taxoid extracted from 10-deacetyl baccatin III, a noncytotoxic precursor found in the renewable needle biomass of yew plants. ... 

Early production of 1 kg of paclitaxel required extraction from about 13 000 kg of the Pacific yew tree bark. This process was refined, and paclitaxel is now produced by a semi-synthetic route. The starting material, 10-deacetyl baccatin III (10-DAB) is obtained from the needles of Taxus baccata (European yews) or T. wallichiana (Himalayan yews). The yield is around 1000 kg of needles to produce 1 kg of 10-DAB. 

Protease or lipase enzymes were useful for the regioselective aminoacylation of lobucavir. Lipase was also used for resolution of a synthon for the paclitaxel side chain. The paclitaxel side-chain ester was also prepared by reduction of a keto ester precursor. Enzymatic reduction of ketones to chiral alcohols is another reaction that has been widely applicable. C14-deacylase, ClO-deacety-lase, and C7-xylosidase were identified from microorganisms isolated from soil samples and were useful for converting complex mixtures of taxanes found in yew extracts primarily to 10-deacetyl baccatin III, a precursor for the semisynthesis of paclitaxel and analogs. 

For centuries, plants have been a unique source of therapeutically significant alkaloids and they continue to be excellent sources of drugs. Furthermore, alkaloids of natural origin serve as a model for the semisynthesis or the synthesis of derivatives which have improved pharmacokinetic properties, a higher efficacy and/or less toxicity. One of the most recent examples is the isolation of the anticancer agent, called taxol, from the stem bark Of the Pacific yew tree Taxus brevifolia in 1971 by Wani and co-workers [1] and the development, a few years later, of docetaxel, a semisynthetic derivative obtained from 10-deacetyl-baccatin III [2]. 

The synthesis of oral taxane 40 also reqnired 4,10-dideacetyl baccatin 43 (Fignre 16.11C) as starting material for the chemical synthesis of the C-4 methyl-carbonate derivative of 10-deacetyl baccatin III 44. A microbial process was developed for deacetylation of 10-deacetylbaccatin III 35 to 4,10-dideacetylbaccatin III 43 nsing a Rhodococcus sp. SC 162949 isolated from soil using culture enrichment techniqnes [69]. Chemically, 43 is converted to 44, a C-4 methylcarbonate derivative 10 deactylbacattin III. 

Pacific yew (Taxus brevifolia) bark, the original source for this drug [92], has been supplemented with other yew sources such as bark, needles, and roots of T. media x Hicksii, T canadensis, and T. cuspidata. Semisynthesis of paclitaxel maybe accomphshed using baccatin HI or 10-deacetyl baccatin III from T. baccata, but full laboratory synthesis is too expensive for commercial uses. 

Small amounts of paclitaxel were also isolated from Turkish Tombul hazelnut tree leaf (0.05 J.g/g extract) and hard shell (0.08(tg/g extract). In addition to paclitaxel, 10 deacetyl baccatin III and cephalomannine (leaf and hard shell) and baccatin III (green leafy cover) were found in the extracts (Table 13.10). Taxanes were not detected in the extracts of hazelnut kernel and hazelnut skin from Turkish Tombul cultivar. 

Oxidation at the 7-position was reported in the previous review 10) to yield the unstable 7-oxotaxol, which underwent facile oxetane ringopening on treatment with mild base (765). Oxidation of 10-deacetyl-baccatin III under Swem conditions gave the unstable 7-oxo derivative, which underwent ring opening under the reaction conditions to give the enone 4.1.2.13 (767, 168). The Dess-Martin reagent was less selective, giving a 7,13-dioxo product 42). 

The synthesis of taxol and taxol analogs from baccatin III and its precursor 10-deacetyl baccatin III was described in section 8 above, and this approach constitutes the current commercial synthesis of taxol and docetaxel. The concept of converting other taxoid precursors into taxol or bioactive taxol analogs continues to intrigue chemists, however, and several groups have investigated such conversions. 

Holton RA, Zhang Z, Clarke PA, HN, Procter DJ (1998) Selective Protection of the C(7) and C(10) Hydroxyl Groups in 10-Deacetyl Baccatin III. Tetrahedron Lett 39 2883... 

Damen EWP, Braamer L, Scheeren HW (1998) Direct Conversion of 10-Deacetyl-baccatin III into Baccatin III as a Useful Synthetic Tool for a High Yield Paclitaxel Semisynthesis. Herba Pol 44 238... 

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