Baccatin core structure

The silyl protective groups on the baccatin core structure were removed under reaction conditions. Bac3 Pi = H, P2 = Bz, P4 = Ac, P7 = Pio = 2,2,2-trichloroethoxycarbonyl. 

With this knowledge of the three-dimensional orientation of the common pharmacophore, it is possible to design new and structurally simplified analogues of therapeutic interest. As an example, the hybrid derivative SB-TE-1120 (27), based on the baccatin core structure (Figure 7), has been synthesized [17]. This analogue has a good structural homology with epothilone B and eleutherobin, which is also indicated by a remarkable activity. 

In a hypothetical common pharmacophore for a nonaromatic analog of paclitaxel and other antimicrotubule agents, it was proposed that the baccatin core structure is not essential to activity but it acts as a scaffold for the substituents. A more recent report noted the importance of the baccatin structure and the usefulness of C-13 and C-2 side chains in enhancing the binding of taxoid to its receptor. ... 

The most relevant structural difference between the a and p monomers is located in the loop S9-S10, which is 8 residues longer in a-tub than in p-tub owing to an insertion. In the a-subunit, the long S9-S10 loop stabilizes the M loop. In the P-subunit, the equivalent position is occupied by the PTX binding site. This suggests that PTX mimics the 8-residue insertion of the a-subunit loop. In fact, the atomic model shows that the PTX molecule acts as a linker between helix H7 and the M loop, possibly stabilizing an M loop conformation that favors the lateral interprotofilament interaction and contributes to MT stabilization [24, 25], Both side chains and the baccatin core of PTX participate in these interactions [25],... 

Fortunately, the medicinal chemical efforts applied to understand and improve the biological activity of epothilones have been enormous. Epothilones, unlike PTX with its baccatin core, can be produced through several synthetic approaches discussed in this volume. Accordingly, the structural variety of analogs tested has been vast. Three excellent reviews have highlighted developments over the past decade [40-421. Many hundreds of analogs have been produced and tested, but very few have significantly better potency than the natural products. 

At present, the controversial role of the oxetane in taxanes is considered not to be so essential as supposed in the past, due to the increase in biological data availability for paclitaxel derivatives, especially taxuspine and derivatives lacking this feature. Its main role is suggested to be the structural effect exerted in defining the bioactive confonnation and the arrangement of the baccatin core, while an electrostatic effect could not be excluded. 

It has been found that the C-11,12 double bond in paclitaxel was resistant to many reaction conditions, including catalytic hydrogenation and ozonolysis. Harriman et al. reasoned that C-10 acetate may hamper the epoxidation from the p-face and the cupshaped core structure prevents the epoxidation from the ot-face. By removal of 10-acetate in paclitaxel, the 11,12-p-epoxide was formed quantitatively. The 11,12-epoxidized taxoid 27 was only one third as cytotoxic as paclitaxel against B16 melanoma cells. The 11,12 double bond in baccatin was reducible by zinc in acidic conditions. Since treatment of 11,12-dihydro baccatin 28b with base only yielded 13-acetyl-4-... 

Myers Squibb, New York, NY). Since its isolation, the complexity of pachtaxel s structure made it irresistible as a target for total synthesis. For example, syntheses have been published by Nicolaou et al., " Holton et al., and others. ° Solid-phase synthesis has been used in the context of combinatorial derivatization of the resin-bound paclitaxel skeleton to provide analogs for structure activity relationship (SAR) studies. For example, Xiao et al. and Nicolaou et al. attached paclitaxel core 181, previously accessed from baccatin III, to chlorotrityl resin 182 to give 183 (Scheme 3.34). ° Resin 183 was divided among 400 MicroKan reactors, and the Fmoc group was then removed... 

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