Modifications of Taxol

Modifications of taxol by manipulation of specific functional groups on the entire system can be performed by treatment with the appropriate reagents. 

10-Deoxytaxol 2.67 is prepared from taxol 241 in four steps. Dehydration of the alcohol group at C-10 requires protection of the hydroxy functions at C-2 and C-7, which is accomplished with Troc-Cl, affording the corresponding 2,2,2-trichloroethyl carbonate 266 [193]. 

Oxidation of taxol 241 with Jones reagent yields 7-oxotaxol, 2, 7-dioxotaxol, or 2 -oxo-7-acetyl taxol. In order to selectively obtain 7-oxotaxol 269, it is necessary to block the C-2 hydroxy function of 241, which is accomplished using the Troc group, introduced with Troc-Cl, to afford 2 -O-Troc-taxol 268 [194]. 

Deprotection and further selective N-debenzoylation of 272 to afford 270 are accomplished by treatment vith magnesium methoxide in methanol [195]. 

The design and synthesis by solid-phase methods of a combinatorial chemistry library of C-7 acyl, C-10 acyl, and C-7,10 diacyl analogues of paclitaxel taxol) has been described [196]. In this connection, a patent application on Methods and useful intermediates for paclitaxel [taxol] synthesis from C-7,10 di-Cbz 10-deace-tylbaccatin III is vorthy of mention [197]. 

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Kapoor VK and Mahindroo (1997) Recent advances in structure modifications of taxol (paclitaxel). Ind J Chem 36B, 639-652. 

Structural modification of taxol at the C-2 position has been fruitful in that several analogs with improved activity as compared with taxol have been discovered. 

Use has been made of the bond cleavage processes initiated by an adjacent carbonyl function for the modification of steroidial ketols such as 18 [97], Reduction in ethanol eliminates the hydroxyl function and in the same reaction, the carbonyl function is reduced to a secondary alcohol. In compound 19 where there are several groups to act as electrophores, carbon-oxygen bond cleavage is initiated from the most easily reduced dienone function [98], Cleavage of the carbon-oxygen bond in an a-acetoxycarbonyl function is achievable in good yields from multifunctional compounds such as the sesquiterpene taxol [99]. 

There has been intense interest in recent years in selective modification of functionality in baccatin III, 1, the basic diterpenoid core of paclitaxel (Taxol ) which is now established as a clinically active antitumour drug. Given the complexity of 1, rearrangements are common even under mild conditions and attempts to carry out apparently simple transformations are frequently frustrated, as shown by the following example. The 13p-chloro derivative 2 was prepared and fully characterised, then treated with sodium azide in aqueous DMF at 60°C in the expectation that the 13 a azide would be obtained. The product, however, was shown to be the ring cleaved compound 3 (71% yield). 

Paclitaxel (Taxol) is a diterpenoid compound that contains a complex taxane ring as its nucleus (Figure 62.1). The side chain linked to the taxane ring at carbon 13 is essential for its antitumor activity. Modification of the side chain has led to identification of a more potent analogue, docetaxel (Taxotere), which has clinical activity against breast and ovarian cancers. Originally purified as the parent molecule from yew bark, paclitaxel can now be obtained for commercial purposes by semisynthesis from 10-desacetylbaccatin, a precursor found in yew leaves. It also has been successfully synthesized from simple off-the-shelf reagents in a complex series of reactions. 

Better known as taxol, paclitaxel (pak lih tax el) is the first member of the taxane family used in cancer chemotherapy. A semi-synthetic paclitaxel is now available through chemical modification of a precursor found in the needles of yew species. 

STRUCTURE MODIFICATIONS AND THEIR INFLUENCES ON ANTITUMOR AND OTHER RELATED ACTIVITIES OF TAXOL AND ITS ANALOGS... 

The study of natural products, or Nature s Combinatorial Library , has had a long history as a source of drugs, and plants have historically been at the forefront of natural product drug discovery. In the anticancer area, for example, vinblastine and vincristine, etoposide, paclitaxel (Taxol), docetaxel, topotecan, and irinotecan, among others, are all plant-derived natural products or modified versions of plant compounds, while antimalarial therapy would be much poorer without quinine and artemisinin and the drugs derived from these plant products. This chapter provides an overview of the major medicinal agents that are themselves natural products isolated from plants or are chemical modifications of such lead compounds. It covers the therapeutic areas of cancer, HIV, malaria, cardiovascular, and central nervous system (CNS) diseases. Natural plant products have also made contributions in areas such as immunomodulatory and antibiotic activities," and the reader is referred to the cited reviews for information on these areas. 

In the chemistry area virtually every position on the ring and on the side chain of taxol has been subjected to structural modifications and ring contractions and ring expansions have also been employed in attempts to generate improved analogues. This work has been described in several reviews and the interested reader is referred to these for more information. 

Rice, A., et al. Chemical modification of paclitaxel (Taxol) reduces P-glycoprotein interactions and increases permeation across the blood—brain barrier in vitro and in situ. J. Med. Chem. 2005, 48, 832-838. 

Modifications at the C-9 position of taxol were initially facilitated by the isolation of 9-dihydrobaccatin (3.2.1) from T. canadensis, the Canadian yew (97). The availability of this compound was then used to advantage by Klein, who converted it into 9-dihydrotaxol. Protection of 3.2.1 as its 7,9-acetonide 3.2.2, selective deacetylation at C-13 to give 3.2.3, addition of the side chain to give 3.2.4, and deprotection gave the (9i )-dihydrotaxol 3.2.5 98). 

Extensive studies have been made of the effect of structural modifications to ring B on the activity of taxol. Most of the work has focussed on analogs at C-2, C-9, and C-10, although some 1-deoxy analogs have also been investigated. 

Studies of the chemistry of the phenylisoserine side chain of taxol continue to be made, reflecting the importance of this structural unit for the synthesis of taxol from baccatin III and the potential of preparing improved analogs of taxol by modification of the side chain. Synthetic... 

Kant J (1995) The Chemistry of the Taxol Side Chain Synthesis Modifications and Conformational Studies. In Farina V (ed) The Chemistry and Pharmacology of Taxol and its Derivatives. Elsevier Science B V, Amsterdam, p 255... 

Modification of Natural Compounds. Because of their high selectivity and the mild conditions in which they operate, enzymes are especially suited for the modification of natural molecules, which are often highly functionalized and labile. It can be used to increase the lipophilicity of polar molecules by grafting of fatty acids (65). Oppositely, the water solubility of paclitaxel (Taxol) could be increased up to 1600-fold by performing the enzyme-catalyzed reactions indicated in Figure 13 (66). It is interesting to note that thermolysin, a protease, was not known to catalyze this kind of esterification. 

Taxol consists of several rings including a four-membered ring, a six-membered ring, and an eight-membered ring and peripheral functionalities. Modification of the taxol skeleton and elucidation of its structure-activity have led to the following features ... 

From an additional study, modification or removal of the sugar moiety also has a substantial influence on the cytotoxic potency of eleutherobin and its cross-resistance in Taxol-resistant cells [14]. These structure/activity profiles should be usable for future design of more potent eleutherobin derivatives. 

Except for a few results concerning type A and B taxanes in which either esterification or saponification was used to confirm structures by comparison with known compounds, studies of opening of the epoxide rings (36), or determination of the structure of autoxidation products (55), most of the published chemistry has been effected on baccatin Ill-type compounds (13b). Thus, two synthetic approaches for structural modifications have been described in the literature using, in one case, taxol itself as starting material or, instead, 10-deacetylbaccatin III (13a), extracted from leaves (easily collected without causing damage to the tree). 

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