Taxol derivatives

Ethanolamine, IPA, reflux, 21 h, >50% yield. These conditions did not affect the C-10 acetate or the C-13 side chain of a taxol derivative. ... 

Gao Y, Kuang Y, Guo ZE, Guo Z, Krauss IJ, Xu B (2009) Enzyme-instructed self-assembly confers nanofibers and a supramolecular hydrogel of taxol derivative. J Am Chem Soc 131 13576-13577... 

Interesting conversions of thietane taxol derivatives have also been studied and discussed <1999JOC2694, 2001JOC5058, 2000TL4891> and may be considered as transformations of the thietane ring substituents. The protected derivative 57 has undergone benzylation and subsequently has been reduced to give compound 58,... 

Oxirane taxol derivatives have also been found to be convenient starting materials for the synthesis of taxols fused with a thietane ring. The oxirane-derived taxine B derivatives 118 and 119 have undergone reaction with potassium thioacetate in dimethylformamide (DMF) at 60°C <2000TL4891, 2001JOC5058>, leading to the formation of thietane-derived taxine B derivatives 57 and 121. In the case of the bromine derivative 118, the thietane-taxol 57 was not the exclusive product and the 1,2-dithiolane derivative 120 occurred as the major product (Equations 35 and 36). 

Several valued terpene alkaloids [86] from Taxaceae bear / -Phe 8 or a-hydroxy-/ -Phe (phenylisoserine) side-chains at C13 and C5. Often these aromatic //-amino acids are N-methylated, as exemplified by a-hydroxylated Wintersteirfs acid, found to be a side-chain of taxine A 42 (Scheme 1.5.7). The N-benzoylphenylisoserine ester moiety of paclitaxel (taxol) has been found to be essential for its crucial mi-crotubuli-stabilizing activity. Accordingly synthetic taxol derivatives [97] that have already reached the market (e.g. non-natural docetaxel (40, taxotere)) or are still undergoing clinical/preclinical trials, e.g. non-natural BAY 59-8862/IDN5109 41... 

Esterification.1 This reagent in combination with a catalytic amount of 4-dimethylaminopyridine (DMAP) is very effective for esterification of carboxylic acids with alcohols or thiols at room temperatures. However, reaction of aromatic and hindered acids requires several days at room temperature. French chemists report that only this method is useful for esterification of the protected baccatin III derivative (2) with (2R,3S)-N-benzoyl-0-(l-ethoxyethyl)-3-phenylisoserine (3) to provide the protected taxol derivative (4). A reaction conducted at 73° for 100 hours with 6 equiv. of 1 and 2 equiv. of DMAP produced 4 in 80% yield. Natural taxol, a cancer chemotherapeutic agent, is obtained by removal of the protective groups at C2 and C7 of 4. 

Similarly, benzylidene acetals can be oxidatively cleaved with /er/-butyl hydroperoxide in the presence of catalytic amounts of copper(II)124 or palla-dium(ll)l2iu26 to give a benzoate ester and a free hydroxyl group but the regioselectivity of the reaction is usually poor. Recent efforts to optimise the efficacy of Taxol derivatives for the treatment of solid tumours included an oxidative cleavage of a benzylidene acetal [Scheme 373].127... 

A larger 600-member bergenin-based library using acylations, oxidations, halo-genations, and glycosylations and a 24-member 3,6-dihydroxytropane library have been prepared by the same group (313) a library of acylated taxol derivatives was also reported (314). A survey of theoretical applications for combinatorial biocatalysis has recently appeared (315). 

Souto, A. A. Acuna, U. Andreu, J. M. Barasoain, I. Abal, M. Amat-Guerri, E. New fluorescent water-soluble taxol derivatives. Angew. Chem. Ini. Ed. Engl., 1995, 34 2710-2712. 

Greenwald, R. B. Rendri, A. Bolikal, D. Gilbert, C. W. Highly water soluble taxol derivatives 2 -polyethyleneglycol esters as potential prodrugs. Bioorg. Med. Chem. Lett., 1994, 4 2465-2470. 

Despite the existence of a large number of taxol derivatives, only taxol itself has given rise at present to significant pharmacological and biological studies. However, some work employing the mixture taxol—cephalomannine 115) (more easily extracted from the bark of T. baccata than taxol itself) as well as derivatives having a xylose residue attached to the taxane skeleton may be cited 116). 

Also there is Taxol, derived from the bark of the Pacific yew, an evergreen tree or shrub, notably of the Pacific Northwest. (Yew wood was once favored by the Indians for bows and other purposes.) If successful, its relative scarcity vs. demand indicates that chemistry will have to come to the rescue, especially the specialty known as organic synthesis. 

Greenwald, R.B., Pendri, A. and Bohkal, D., Highly water solnble taxol derivatives 7-polyethylene glycol carbamates and carbonates. Journal of Organic Chemistry, 60(2), 331, 1995. 

Most studies of structure activity relationships (SAR) rely on degradations of baccatin and semisynthesis. [1, 3, 4] First insights into the SAR of taxol derivatives have been summerized in a recent article on C ring aryl derivatives, [4] and more can be expected in the near future as patented information becomes released. Total synthesis, especially in preparing the way for the synthesis of derivatives, will be of great importance to elucidate the relationship between structure, microtubuli stabilization and anticancer activity more thoroughly. This impact of total syn-... 

Clinical use of Taxol included many solid tumours with best results in ovarian and breast cancers. Extraction of Taxol (paclitaxel) from the yew bark is quite difficult three trees were needed for 1 gram of drug (one cycle of chemotherapy). This difficulty has encouraged the pursuit of semisynthetic production. The strategy included immediately increasing the amount of Taxol derived from... 

In the cases of thrombin inhibitors and taxol derivatives, hydrophobic clustering may help stabilize the bioactive conformations. However, many factors over and above pure hydrophobic interactions can stabilize the aqueous conformation. In contrast, many receptor antagonists that bind to a variety of receptor systems are constructed from templates that should resist hydrophobic collapse. The... 

Various ether derivatives of taxol have also been prepared. Simple C-7 silyl ethers have poor in vitro cytotoxicity (148 but other ether derivatives sometimes have improved activity. Thus treatment of 2 -protected taxol derivatives with chloromethyl methyl ether followed by deprotection yields the acetal derivative 4.1.1.19 (757), while treatment of baccatin III with dimethyl sulfide in the presence of benzoyl peroxide followed by coupling with side chain gives thiomethyl derivatives such as 4.1.1.20 (158). This latter compound has been selected for development by Bristol-Myers Squibb, and is currently in clinical trials (759). Other ethers such as the amino acid derivative 4.1.1.21 have also been prepared by treatment of 4.1.1.20 with chloroacetic acid, N-iodosuccinimide, and silver triflate followed by N-methylpiperazine (158). 

The [ I]-labeled taxol derivative 11.1.5 was prepared by reacting the stannane 11.1.4 with sodium [ I]-iodide (384). 

The 2-(m-aminobenzoyl)taxol derivative 11.3.8 gave interesting results, since it was found that its absorption and emission spectra, and specifically the difference between them, were solvent dependent. Using this information it was possible to ascertain that the fluorophore binding site on the microtubule is in an environment of intermediate polarity, and it was also shown that tubulin has two binding sites for taxol, one high affinity site and one low affinity site (397). 

Fluorescent taxol derivatives with the fluorophore at the C-10 position have also been studied. The two analogs A15.2.1 and A15.2.2 were prepared and evaluated. Both derivatives retained good activity as promoters of microtubule assembly, and the spectroscopic data for bound ligands were consistent with the presence of a charged amino acid in close proximity to the fluorophore (556). 

Samaranayake G, Magri NF, Jitrangsri C, Kingston DGI (1991) Modified Taxols. 5. Reaction of Taxol with Electrophilic Reagents, and Preparation of a Rearranged Taxol Derivative with Tubulin Assembly Activity. J Org Chem 56 5114... 

Py S, Pan J-W, Khuong-Huu F (1994) Cleavage Reactions of 10-Deacetylbaccatin III. Retrosynthetic Approach to the Total Synthesis of Taxol Derivatives. Tetrahedron 50 6881... 

Chaudhary AG, Rimoldi JM, Kingston DGI (1993) Modified Taxols. 10. Preparation of 7-Deoxytaxol, a Highly Bioactive Taxol Derivative, and Interconversions of Taxol and 7-epi-Taxol. J Org Chem 58 3798... 

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