10-Deacetyl paclitaxel

A C-11,12 double-bond rearranged product 24 was observed when 2, 7-Yarovenko reagent (Et2NCF2CHFCl), which can be then transformed into 2 -Troc-10-deoxy paclitaxel (25) by catalytic hydrogenation, along with the formation of a small amount of 12-fluorinated 26. All taxoids, after deprotection, showed reduced cytotoxicity seven to eight times. 

Datta et al. synthesized 10-epi and 9a-OH paclitaxel analogs by iterative oxidation-reduction transformations, furnishing 39-41. lO-Epi pachtaxel 39a and 10-deacetyl paclitaxel 39b are slightly more active than pachtaxel in both cytotoxicity and tubuhn binding assays, whereas their 9(R) counterparts 40 are comparable... 

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... 

A particular application of membrane bioreactors, patented in 2005 [20], concerns the production of an antitumor substance (paclitaxel). Since a full synthesis of paclitaxel is not possible due to its low yield, a semisynthesis of 10-deacetyl-baccatin... 

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... 

Generally, C-10 deacetylation or deoxygenation made an insignificantly negative and positive contribution to the cytotoxicity against sensitive tumor cells, respectively, by comparison with paclitaxel. 

Acylation of free hydroxyl at C-7 in paclitaxel usually led to the reduction and even loss of cytotoxicity of the derivatives, when steric hindrance of the acyl groups increases. Bhat et al. have used a parallel solution phase synthetic method to construct a 26-membered library of C-7 esters, and concluded that modification at C-7 were detrimental to cytotoxicity against the MCF-7 cell line. Only a few exceptions, including 10-deacetyl-lO-propionyl-7-chloroacetyl... 

Previous results have shown that lO-deacetyl-7-acyl paclitaxels or docetaxels... 

Low activity or inactivity of azetidine D-ring 94a and 94b, very poor activity of 4-carbonate-thia-paclitaxel 95 in tubulin polymerization and inactivity in cytotoxicity tests, together with inactivity of 4-deacetyl-selena-paclitaxel 96 in both... 

Chen, S.-H. First syntheses of C-4 methyl ether paclitaxel analogues and the unexpected reactivity of 4-deacetyl-4-methyl ether baccatin III. Tetrahedron Lett., 1996, 37 3935. 

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... 

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. 

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. 

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