Taxane derivatives

Roche M, Kyriakou H, Seiden M. (2006) Drug evaluation Tesetaxel — an oral semisynthetic taxane derivative. Curr Opin Invest Drugs 7 1092-1099. 

Taraboletti G, Gatto C, Riva A, et al. Anti-Angiogenic and Anti-Metastatic Activity of IDN 5390, a New C-Seco Taxane Derivative. Proceedings of the AACR, Vol. 42, March 2001. abstract 3162. 

Docetaxel is a semisynthetic taxane derived from the European yew tree. Its mechanism of action, metabolism, and elimination are identical to those of paclitaxel. It is approved for use as second-line therapy in advanced breast cancer and non-small cell lung cancer, and it also has major activity in head and neck cancer, small cell lung cancer, gastric cancer, advanced platinum-refractory ovarian cancer, and bladder cancer. Its major toxicities are listed in Table 54-4. 

Fig. (6). Structures of Taxol and taxane derivatives characterized from various Taxus species. It belongs to a group of compounds with a four-membered oxetane ring and an ester side-chain, both of which are essential for anticancer activity. Taxol was isolated...

Taxol is derived from GGPP via cyclization reactions, employing the same mechanistic principles as in mono- and sesquiterpenes. Baccatin III (2), another taxane derivative, has been found (up to 0.2%) in the bark. A number of other taxane derivatives were isolated and characterized as 10 - deacetyltaxol, 10 - deacetylbaccatin III (3), cephalomannine (4) and 10 - deacetylcephalomannine (5) while some of them have been microbiologically transformed into taxol, Fig. (6). 

The baccatins III (116), IV (117), VI (118), and VII (119) and the 1-des-hydroxy-derivative of baccatin IV have been shown122 to be taxane derivatives with an oxetan ring. 

Holton, R. A. Chai, K.-B. Cl acyloxy and hydrido taxane derivatives and pharmaceutical compositions containing them. U.S. patent 6,462,208, October 8, 2002. 

Takeda, Y. Yoshino, T. Uoto, K. Terasawa, H. Soga, T. A new method for synthesis of 7-deoxytaxane analogues by hydrogenation of A -taxane derivatives. Chem. Pharm. Bull, 2002, 50 1398-1400. 

In addition to the compounds described by Suffness and Cordell in their 1985 review, the principal structures of which will be mentioned here, many new taxane-type substances have been discovered in extracts of yew since 1968. Each of these compounds may be classed as a particular type of taxane derivative characterized either by substitutions on certain carbon atoms (C-1, C-7, C-13) or by a particular functionality at C-20 (exo methylene, epoxide, oxetane, or direct linkage to C-2). 

Adsorption of the ketone on montmorillonite clay enhances the axial attack of NaBH reduction to >99% for 4-t-butylcyclohexanone 3.26 and 78% for 3,3,5-trimethylcyclohexanone 3.29 [SRI], Other hindered substituted borohydrides also give higher levels of equatorial attack [CYl]. From the numerous studies to date, it appears that torsional and steric factors are very often predominant, as illustrated by the reduction of eight-membered cyclic taxane derivatives [SH7]. An interesting solvent effect in the reduction of a sugar derivative has been recently shown. The reduction of a substituted rigid six-membered ketone with DIBAH in CH2CI2 or... 

Sodium Azide/Ammonium Cerium(IV) Nitrate. Silyl enol ethers give a-azido ketones on treament with sodium azide and anhydrous ammonium cerium(IV) nitrate in anhydrous acetonitrile (see Eq. 97).297 325 33i With a glycal, the 2-azido-1-hydroxy nitrate derivative is formed.332 Low yields due to hydrolysis of the silyl enol ether may be improved by use of the triisopropylsilyl (TIPS) derivatives,331 although with a sterically encumbered taxane-derived enol ether the TMS derivative gives higher yields than the TIPS derivative.325 The mechanism is believed to involve addition of an azide radical to the double bond. 

The Taxane Diterpenes.— The taxane skeleton represents an alternative mode of cyclisation of the macrocyclic diterpene hydrocarbon. Seven new taxane derivatives have been isolatedfrom Taxus baccata and characterised on the basis of spectroscopic and other data. Their structures are summarised in the following formulae (136a—g). In addition, the structure of baccatin-III (137), one of a group of complex esters isolated from the same source, has been com-pleted. The application of the olefin Octant rule to the taxane A double bond leads to the absolute configuration of these diterpenes. 

Fenoglio, L, Nano, G.M., Vander Velde, D.G., and Appendino, G., Chemistry and occurrence of taxane derivatives. XXV. Synthesis of azetidine-type taxanes. Tetrahedron Lett. 37 (18), 3203, 1996. Hoshino, H., Shimizu, N., Shimada, N., Takita, T., and Takeuchi, T., Inhibition of infectivity of human immunodeficiency virus by oxetanocin, J. Antibiot. 40 (7), 1077, 1987. 

Normal taxane derivatives isolated from different Taxus species. 

Appendino G, Fenoglio I, Cravotto G, Varese M (1994) The Chemistry and Occurrence of Taxane Derivatives. Xin. The Oxidation of 10-Deacetylbaccatin IB. Gazz Chim Ital 124 253... 

Mongelli N, Biasoli G, Menichincheri M, Fusar Bassini D, Ciomei M (1995) Taxane Derivatives with Antitumor Activity. PCT Int Appl WO 95 25,728 (Chem Abstr 124 56359)... 

Appendino G, Varese M, Gariboldi P, Gabetta B (1994) The Chemistry (15) and Occurrence of Taxane Derivatives. XV. A New Rearrangement of Oxetane-Type Taxoids. Tetrahedron Lett 35 2217... 

Torregiani E, Barboni L, Rafaiani G, Lambertucci C, Appendino G (1996) The Chemistry and Occurrence of Taxane Derivatives. XXVI. A Reactivity Study on 11(15- 1) Abeotaxanes. Gazz Chim Ital 126 809... 

Mayhew E, Franklin JC, Bhatia S, Harmon PA, Janoff AS (1996) Preparation of Hydrophobic Taxane Derivatives for Treatment of Cancer and Pharmaceutical Compositions Containing Them. PCT Int Appl WO 96 21,658 (Chem Abstr 125 196057)... 

DeMattei JA, Leanna MR, Li W, Nichols PJ, Rasmussen MW, Morton HE (2001) An Efficient Synthesis of the Taxane-Derived Anticancer Agent ABT-271. J Org Chem... 

Rearranged taxane deriv., T40.9 3P-Hydroxy-5a-norcholanic acid, T48.7 C23H45N3O... 

On the basis of these data, epothilones A, B and some congeners have been widely pursued as lead structures for the development of a new generation of non-taxane-derived microtubule stabilizers for cancer treatment [5]. Five representatives of this class are currently undergoing clinical evaluation in humans. This outcome confirms the view that natural products provide a vast pool of potential lead structures for drug discovery. In a very general sense, the strategy that resulted in 12-aza-epothilones could be viewed as the synthesis-based equivalent to the discovery of a new natural product with a specific biological activity. 

Miller RW 1980 A brief survey of Taxus alkaloids and other taxane derivatives. (Review). J Nat Prod 43 425-437... 

Due to the poor solubility of Paclitaxel, various groups have developed taxane analogs with greater aqueous solubility. Taxane 9 (Figure 11.2) is a water soluble taxane derivative which when given orally was as effective as i.v. Paditaxd in five tumor models [40]. The chiral intermediate (3P-cis)-3-acetyloxy-4-(l,l-dimethylethyl)-2-azetidinone, (J )-IO was prepared for the semisynthesis of... 

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