Taxoids derived from

Ojima I, Slater JC, Kuduk SD, Takeuchi CS, Gimi RH, Sun CM, Park YH, Pera P, Veith JM, Bemacki RJ. (1997) Syntheses and structure-activity relationships of taxoids derived from 14 betahydroxy-lO-deacetylbaccatin III. 

P-Hydroxy-10-deacetylbaccatin III (75, 14P-OH-DAB) was first isolated from the needles of the Himalayan yew tree (Taxus wallichiana Zucc.) and its structure was determined by X-ray crystallographic analysis in 1992.93 Because of an extra hydroxyl group at the C-14 position, 14P-OH-DAB (75) has much higher water solubility than DAB (3), the key precursor of paclitaxel and docetaxel. We envisaged that new taxoids derived from 75 would improve water solubility and bioavailability, and also reduce hydrophobicity-related drug resistance. These improved... 

Table 12. Cytotoxicity of Taxoids and Pseuc/o-Taxoids Derived from 14P-OH-DAB (IC50, nM)a...

In parallel to the development of the second-generation taxoids from DAB (3) (Section III.C), we have investigated the effects of the C-3 and C-10 modifications on the anticancer activities of taxoids derived from 14-OH-DAB (75).43... 

Huang, G. Y Guo, J. Y Liang, X. T. Studies on structure modificaton and structure-activity relationship of new taxoids derived from sinenxan A. Acta Pharm. Sin., 1998, 33 576-586. 

Ojima I, Park YH, Sun C-M, Fenoglio I, Appendino G, Pera P, Bemacki RJ (1994) Structure-Activity Relationships of New Taxoids Derived from 14/ -Hydroxy-10-deacetylbaccatin III. J Med Chem 37 1408... 

Most research has focused on the development of paclitaxel analogs or prodrugs with enhanced specificity MDR reversal and orally effective taxoids have also been developed recently. Meanwhile, scientists have gained insights into the mechanism of action of taxoids at molecular level, that is, binding sites on tubulin and dynamics of tubulin polymerization. It is worth pointing out that the SAR results derived from traditional medicinal chemistry have shown the essential... 

A true taxoid dimer was prepared by Cheng and coworkers by Diels-Alder cyclization of taxinine B and taxacin I derivatives. Thus oxidation of 20-hydroxy-4,5-ene-7-oxotaxinine derived from natural taxinine B... 

Payre C, Mourabit AA, Merckle L, Ahond A, Poupat C, Potier P (2000) Semisynthesis of D-ring-modified Taxoids Thietane Derivatives from Taxine B. Tetrahedron Lett 41 4891... 

Combeau C, Commercon A, Mioskowski C, Rousseau B, Aubert F, Goeldner M (1994) Predominant Labeling of j3- over a-Tubulin from Porcine Brain by a Photo-activatable Taxoid Derivative. Biochemistry 33 6676... 

Paclitaxel (Taxol) 57, a natural terpenoid product derived from the bark of the Pacific yew Taxus brevifolia [83-85], and its hemisynthetic analog docetaxel (Taxotere) 58, are two recently discovered promising antitumor agents. At this moment, very few data have been published about the microbial metabolism of taxoid compounds only site-specific hydrolyses of acyl side chains at C-13 or C-10 by extracellular and intracellular esterases of Nocardioides albus SC 13911 and N. lutea SC 13912, respectively, have been reported [86]. On the other hand, Hu et al. [87-89] recently described some fungal biotransformations of related more abundant natural taxane diterpenes extracted from Chinese yews or their cell cultures, in order to obtain new active substances or precursors for hemisyn-thesis of paclitaxel analogs. 

The problem was overcome with the use of mildly fixed microtubules [10] in which the paclitaxel binding site is unaltered, while protected from cold and dilution depolymerisation and a paclitaxel molecule bound to a fluorescent probe (either fluorescein or difluorofluorescein) [8], The fluorescent derivatives of paclitaxel were then tested to check that they compete with taxoids for the same site, with the same 1 1 stoichiometry producing the same celular effects as paclitaxel and docetaxel, thus it can be assumed that they bind for the same site [9], Using these stabilized microtubules, it is possible to determine precisely the binding constant of the fluorescent taxoid which was found to be of the order of 108 M at 25°C. 

A series of 14p-hydroxy and 14p-acyloxy taxoids 34 with lOp, 5a, 2a-acetoxy, or hydroxy substitutions without C-13 oxygenations and oxetane D ring have been isolated from the cell culture of T. yunnanensis. Attachment of the A-benzoylphe-nyhsoserine side chain to C-14, and incorporation of the 4(20), 5-oxetane ring and change of 2-acetate did not improve their activity. The fact that all derivatives are far less active than paclitaxel prompted the authors to suggest that C-14 isoserine isomers did not bind to tubulin properly. 

Systematic studies on the selection of the best mobile phases to assure the best micropreparative separation of analyzed taxoids, especially of 10-DAB III, as well as its less polar derivatives baccatin III, paclitaxel, and cephalomannine obtained from the extracts of fresh and dried needles and stems of Taxus baccata L. by Glowniak and Mroczek have been undertaken [2]. The TLC investigation on silica gel included solvent systems with one and two polar modifiers, multicomponent mobile phases, as well as some multiple development techniques and gradient elution. As polar modifiers, methanol, acetone, dioxane, ethyl acetate and ethylmethylketone, as well as their mixtures, have been reinvestigated, but dichloromethane, chloroform, benzene, toluene, heptane, and their mixtures were used as solvents. 

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