Modifications in the C9-C11 Region

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. 

These analogs were obtained through several different approaches, including heterologous expression of the modified epothilone polyketide synthases in Myccococus xanthus total chemical synthesis (spearheaded by the Danishefsky group),or biotransformation of Epo For example, the in vitro antipro- 

Apart from the discovery of the potent in vivo activity of 6, recent work of the Danishefsky laboratory has also shown that the presence of a tranj -double bond between CIO and Cll allows the insertion of an additional methylene group 

As for other modifications in the Northern part of the epothilone macrocycle, the replacement of CIO by oxygen has recently been shown to be detrimental for biological activity, whereas the incorporation of a furan moiety incorporating C8, C9, and CIO seems to be better tolerated.  

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