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Structural and molecular modeling studies, as well as the evaluation of confor-mationally restricted analogs, have been undertaken to explain these SAR. The taxane core has a rigid conformation, and the side chain is the only portion of the molecule with rotational freedom. It can adopt a variety of conformations, two of which were identified as the potential active conformations and differ only in the value of the H2'-C2'-C3'-H3' dihedral angle. Further research based on electron crystallographic analysis of tubulin sheets has led to evidence showing that taxol adopts a T-shaped conformation when it is bound to tubulin.39 This binding model has been confirmed by the synthesis of a macrocyclic analog that adopts the T-taxol conformation and is significantly more active than paclitaxel in both cytotoxicity and tubulin polymerization assays.40 The model is being used in the design of new taxanes. 1

The clinical success of taxanes, many of which are under clinical develop-ment,42 has prompted an intensive search for drugs with a related mechanism of action. This search has led to the identification of several families of natural products that bind to the taxane site and share the ability of taxol to promote microtubule assembly and induce mitotic arrest, and will be discussed in Sections 3.2 and 3.3.

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