Epothilones structure activity relationship

With the synthesis of epothilones A and B secured, subsequent studies concentrated on the preparation of analogs of the natural molecules. In addition to providing structure-activity relationships, it was anticipated that these studies would provide a further test for the generality of the RCM process. In this context, a general strategy was developed by Nicolaou et al. [20] to investigate the... 

Tab. 2.2 Structure-activity relationships for epothilone and various epothilone analogs.

Scheme 3 Four sections of epothilone B used to evaluate structure activity relationships of analogs... 

Derivatives of Epothilones Syntheses and Structure-Activity Relationship... 

With the established synthetic routes in hand, many of the more obvious derivatives have been synthesized in order to obtain a quantitative structure-activity relationship (QSAR) and to maybe enhance the activitiy and pharmacological profile of epothilones. These derivatives also include epothilone E (2e, Scheme 13), which is emphasized because it also is an active natural derivative, hydroxylated at C21. 

Structure-activity relationships of published epothilone derivatives have been included in the review article and publications of Nicolaou et al. [57, 58] and Danishefsky et al. [2, 59, 60]. 

The chemistry, biology, and structure activity relationship (SAR) of epothilones have been extensively discussed in recent review articles. it is thus not the intention of this chapter to provide a detailed review of these different facets of epothilone-related research. Rather, this chapter will focus on some selected aspects of the chemistry, biology, and clinical evaluation of natural epothilones and their synthetic analogs, with particular emphasis on SAR work performed in our... 

In the study of the structure-activity relationships of the epothilones, solid-phase synthesis of combinatorial libraries has been used to probe regions of the molecule important to retention of inq>rovement of activityThe combinatorial approach, using an active natural product as the central scaffold, can also be applied to the generation of large numbers of analogs for structure-activity studies, the so-called parallel synthetic approach. ... 

Fig. 10. Structure activity relationships of epothilone provided by combinatorial natural product chemistry...

Petersen, F., Schinzer, D., Altmann, K.-H., Griesinger, C.,The high-resolution solution structure of epothilone a bound to tubulin An understanding of the structure-activity relationships for a powerful class of antitumor agents, Angew. Chem. Int. Ed. 2003, 42, 2511-2515. 

Scheme 26. Structure-activity relationships (SAR) for the epothilones and examples of novel analogues (87-90).

Epothilones Mechanism of Action and Structure-Activity Relationships... 

Since the discovery of the epothilones in 1993, an impressive structure-activity relationship (SAR) profile has emerged from the efforts of many synthetic teams [6-8]. This first led to the definition of a common pharmacophore and SAR for the structurally diverse epothilones [9-12], then to the rational design of new structures. 

Epothilones have been widely pursued targets for total chemical synthesis (for reviews see ref. 34-39) and their structure-activity relationship (SAR) has been broadly evaluated this research has been reviewed extensively (ref. 1, 34, 36, 38 and 40-46). It is not the objective of this chapter to provide yet another all-encompassing collection of SAR and synthetic data. Rather, after a brief summary of the in vitro and in vivo biological properties of Epo B, the discussion will focus on the chemistry of those modifications that have led to clinical development compounds and the most important preclinical features of these analogs. 

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