Structure–Activity Relationships in Side‐Chain‐Modified Epothilone Analogues—How Important is the Position of the Nitrogen Atom?

Abstract

Side-chain-modified epothilone analogues 1 b, 2 b, and 3 b were prepared through stereoselective total synthesis to assess the importance of N-atom positioning in the side chain for tubulin polymerization and antiproliferative activity. Surprisingly, 1 b, 2 b, and 3 b appear to induce tubulin polymerization with activities similar to those of 1 a, 2 a, and 3 a, respectively. Substantial differences in antiproliferative activity were observed between 1 a and 2 a, and 1 b and 2 b, but not between 3 a and 3 b.