SAR Analysis of Epothilones The Zone Approach

First we consider the acyl sector of the epothilones, which proved to be intolerant of modification. For example, inversion of stereochemistry at C3 (S toR), or reduction at C5 results in serious arrest of activity. Analogs with functionality at C3, C5, C6, C7 and C8 removed demonstrate both diminished tubulin-binding activity and cytotoxidty (structures not shown). Ddetion of the single methyl group at C8 has a highly pronounced deleterious effect on activity. Removal of the C9 methylene group resulting in a 15-membered macrolide, 87, results in a major loss of activity in tubulin polymerization/depolymerization assays. 

O-alkyl sector is remarkably tolerant of modification with basic maintenance of in vitro function. 

In Vitro Analysis Comparison to Paditaxel and Related Agents 

Compound CCRF-CEM ICS0(nM)° CCRF-CEM/VBL lCso (nM)° Tubulin binding1  

Subsequently, we expanded on these efforts by studying the effects of various formulations, routes, and schedules of i.v. administration. We discovered that slow infusion (6 h, Q2D, 30 mg/kg x 5 doses) of dEpoB in nude mice bearing human xenograft tumors with a Cremophor-ethanol vehicle was the most beneficial in terms of efficacy and decreased toxicity. 

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