Epothilones analogs

For reviews, see (a) Mulzer J (2000) Monatsh Chem 131 205 (b) Nicolaou KC, Ritzen A, Namoto K (2001) Chem Communl523 (c) For more recent leading references on epothilone analogs, see Nicolaou KC, Sasmal PK, Rassias G, Reddy MV, Altmann K-H, Wartmann M, O Brate A, Giannakakou P (2003) Angew Chem Int Ed 42 3515... 

For the synthesis of ring-enlarged epothilone analogs by the same principle, see (a) Rivkin A, Njardarson JT, Biswas K, Chou T-C, Danishefsky SJ (2002) J Org Chem 67 7737 (b) Rivkin A, Biswas K, Chou T-C, Danishefsky SJ (2002) Org Lett 4 4081... 

Scheme 13.81. Combinatorial Synthesis of Epothilone Analogs Using Microreactors3...

The epothilone synthesis in Scheme 13.59 (p. 1221) has been used as the basis for a combinatorial approach to epothilone analogs.69 The acyclic precursors were... 

US patent 6,689,802, Polymorphs of an epothilone analog [100]. This invention describes two crystalline polymorphs, as well as mixtures of these, of an epothilone analog. Also provided are methods of forming the novel polymorphs, therapeutic methods utilizing them, and pharmaceutical dosage forms containing them. 

The resin-bound trienes 83 (Scheme 11) were prepared in a similar fashion to the solution-phase studies (Sect. 2.2.2) and underwent tandem RCM resin-cleavage to liberate four macrolactones 84a,b and 85a,b in a combined yield of 52%. Although, as expected, a large amount of initiator 3 was required to effect this transformation, the procedure constituted a novel and efficient route to the epothilones which paved the way for the generation of a library of epothilone analogs. The library synthesis was achieved using the recently developed SMAR-I9 microreactors (SMART=single or multiple addressable radiofrequency tag) [25] (Scheme 12). 

Fig. 2.2 Fully synthetic epothilone analogs that were prepared...

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

Aghajanian C, Burris III HA, Jones S, Spriggs DR, Cohen MB, Peck R, Sabbatini P, Hensley ML, Greco FA, Dupont J, O Connor OA. (2007) Phase I study of the novel epothilone analog ixabepilone (BMS-247550) in patients with advanced solid tumors and lymphomas. J Clin Oncol 25 1082-1088. 

The epothilone synthesis in Scheme 13.49 has been used as the basis for a combinatorial approach to epothilone analogs. 167 The acyclic precursors were synthesized and attached to a solid support resin by steps A-E in Scheme 13.58. The cyclization and disconnection from the resin were then done by the olefin metathesis reaction. The aldol condensation in step D is not highly stereoselective. Similarly, olefin metathesis gives a mixture of E- and Z-stereoisomers so that the product of each combinatorial sequence is a mixture of four isomers. These were separated by thin-layer chromatography prior to bioassay. In this project, reactants A (3 variations), B (3 variations), and C (5 variations) were used, generating 45 possible combinations. The stereoisomeric products increase this to 180 (45 x 4). 

In contrast to these disappointing early findings, several highly potent epothilone analogs with structural variations in the C9-C11 trimethylene region have been described more recently, some of which have also been found to exhibit favorable in vivo pharmacological properties. 

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