Taxol biological activity

Oxetanes are present in several biologically active natural compounds as, for example, the taxol ring skeleton. An interesting method used to obtain this particular ring is the thermal [2 -i- 2] cycloaddition reaction. Longchar and co-workers reported a novel [2-1-2] cycloaddition of /1-formil enamides 5, often used in other cycloaddition and condensation processes, with acetylenic dienophiles 6 under microwave irradiation (in a domestic oven) to afford ox-etenes 7 in 80% yields [29]. This reaction was directed towards the synthesis of D-ring annelated heterosteroids (Scheme 2). 

Entry 4 involves nitrogen participation and formation of an iminium ion that is reduced by NaBH4. The reaction in Entry 5 creates an 11-methylenebicyclo[4.3.1]undecen-3-one structure found in a biologically active natural product. Note that this fragmentation creates a bridgehead double bond. Entry 6 involves construction of a portion of the taxol structure. The reaction in Entry 7 is stereospecific, leading to the E-double bond. 

Epothilones A, B and E (4,5 and 6) (Fig. 2) are representative members of a new class of bacterially derived natural products which exhibit potent biological activity. Isolated by Hofle and coworkers [6] from a soil sample collected near the Zambesi river, the compounds have provided a great deal of excitement in the scientific community due to their potent cytotoxicity against a number of multiple drug-resistant tumor cell lines and because of the mechanism by which they exert this effect. Like Taxol [7], the epothilones promote the combination of a- and 3-tubulin subunits and stabilize the resulting microtubule structures. This mode of action inhibits the cell division process and is, therefore, an attractive strategy for cancer chemotherapy [7,8]. 

Synthetic taxol was found to be identical in all respects with natural taxol, including spectroscopic characteristics (IR, NMR, MS, optical rotation) and biological activity (microtubule stabilisation and cytotoxicity against Molt-4 leukaemia cells). 

Polyamino acids are easy to prepare by nucleophUe-initiated polymerisation of amino acid JV-carboxyanhydrides. Polymers such as poly-(L)-leucine act as robust catalysts for the epoxi-dation of a wide range of electron-poor alkenes, such as y-substituted a,Ji-unsaturated ketones. The optically active epoxides so formed may be transformed into heterocyclic compounds, polyhydroxylated materials and biologically active compounds such as dUtiazem and taxol side chain. 

Some research groups have derivatized biological active and very important natural products (Scheme 3.30) like Indolactam V (207) [297], Sarcodictyin (208) [298] Taxol (209) [299] and Vancomycin (210) [123]. For example, the soHd-phase synthesis of Indolactam derivatives (213) with three points of diversity has been reported by Waldmann et al. in 1999 (Scheme 3.31) [297]. 

Magri, N. F. and D. G I. Kingston. 1988. Moded taxols. 4. Synthesis and biological activity of taxols mod in the side chainJ. Nat. Prod.51 298-306. 

Mellado, W F., N. F. Magri, D. G I. Kingston, R. Garcia-Arenas, G.A. Orr, andS. B. Horwitz. 1984. Preparation and biological activity of taxol acetateBiochem. Biophys. Res. Commd04 329-336. 

This reaction is particularly suitable for the preparation of the Wieland-Miescher ketone 96, a very useful building block for construction of a broad variety of biologically active compounds such as steroids, terpenoids, and taxol. On the basis of the proline-catalyzed approach described above Barbas et al. recently reported an optimized procedure for formation of the chiral Wieland-Miescher ketone, 96 [105]. It has been shown that this synthesis (which comprises three reactions) can be performed as a one-pot synthesis. The desired product is obtained in 49% yield with enantioselectivity of 76% ee (Scheme 6.43). Here L-proline functions as an efficient catalyst for all three reaction steps (Michael-addition, cydiza-tion, dehydration). It is also worth noting that although many other amino adds and derivatives thereof were tested as potential alternative catalysts, L-proline had the best catalytic properties for synthesis of 96. This result emphasizes the superior catalytic properties of proline reported after previous comparative studies by the Hajos group [100, 101]. 

This process provides the desired products with yields up to 80% and syn-diasteroselectivity. These derivatives are of considerable importance because they are incorporated into many biologically active peptides, such as bestahn, amas-tatin, norstatin, and taxol [33]. 

The structural complexity and biological activity of taxol and related taxanes have inspired a remarkable array of synthetic approaches the interested reader is directed to some leading references <2005JOC732, 2005RJ0315>. However, introduction of the D-ring oxetane is almost invariably achieved via intramolecular nucleophilic displacement, as illustrated in Section 2.06.9.5 (Equation 33). 

Swindell, C. S. Krauss, N. Horwitz, S. B. Ringel, I. Biologically active taxol analogues with deleted A-ring side chain substitutents and variable C-2 configurations. J. Med. Chem., 1991, 34 1176-1184. 

Chen, S.-H. Fairchild, C. Mamber, S. W. Farina, V. Taxol structure-activity relationships synthesis and biological evaluation of 10-deox3daxol. J. Org. Chem., 1993, 58 2927-2928. 

Boge, T. C. Himes, R. H. Vander Velde, D. G. Georg, G. I. The effect of the aromatic rings of taxol on biological activity and solution conformation synthesis and evaluation of saturated taxol and taxotere. J. Med. Chem., 1994, 37 3337-3343. 

The biological activity of some taxanes, especially that of taxol, together with the synthetic challenge of the strained and highly functionalized tricycles has led to constantly increasing interest, resulting in much preparative work. Partial structures as well as various concepts concerning the buildup of the tricyclic... 

The MEP pathway is the starting material of major plant terpenoids of economic value e.g., monoterpenes from essential oils, diterpenoids with potent biologic activity (taxol, ginkgolides), vitamins (tocopherol), or vitamin precursors (carotenoids). The first attempts to overexpress some of its genes (especially dxs or dxr) led to enhanced carotenoid production in tomato (18) or monoterpenes in mint (19). 

The taxane family of diteipenes with a unique tricyclic ring system has attracted interest in both the biological and chemical communities. Particularly, taxol (82) exhibits singular biological activity through its ability to promote microtubule assembly. It is a most promising antitumor agent, now in phase II clinical trials, obtained from the baik of the pacific yew tree. 

The biological activity of tubulin-interfering substances can be very high. The LC50 of taxol for cultured liver cells (HL-60 cells) is <0.001 pM, whereas thiabendazole at 80 pM completely inhibits mitosis in hyphae of Aspergillus nidulans, when growing in liquid culture. 

Taxol and the other extremely biologically active derivatives of yews and fungi associated with yews have no value as fungicides, but may have evolved as natural pesticides ... 

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