Extensive vs. Peripheral Structural Modifications of Natural Products

3 Extensive vs. Peripheral Structural Modifications of Natural Products 

Natural epothilones have been structurally modified by various teams, making use of the broad stractural scope of natural product-based drag discovery in this field. Generally, this approach includes the de novo construction of libraries of natural product-like compoimds through diversity orientated synthesis (DOS) [17]. A concept for the design of natiual product-based libraries, introduced by H. Waldmann [18], has been developed over the last few years [19] (see also Sects. 1.2.1 and 1.2.2 in the introductory chapter). 

The synthetic approach to epothilone analogues is an example of extensive structural modification of the lead from nature. This approach, rather than simple peripheral derivatization of existing leads, is characterized by the replacement of 

At this point, it should be noted that the concept of extensive structural modification is imbedded in the invention of the first aza-macrolide, the antibiotic azithromycin, discovered in 1982 by PLIVA chemists in Zagreb, Croatia [21, 22]. Azithromycin became a multibillion drug on the world market, and represents an early example of therapeutic success with a non-natural natural compound , available via extensive structural modification. 

Formally, the N-atom of azithromycin is inserted into the macrolide ring of erythromycin, and the carbonyl group is reduced to methylene. In contrast, in 12-aza-epothilones, the C12 atom in natural epothilones is replaced by an N-atom, and epoxide oxygen is reduced. While the first substantial alteration of the macrolactone ring was achieved in a few steps firom erythromycin, the second epothilone modification cannot be made with compoxmds from the natural pool, and required total synthesis of the target stmctures. 

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