Synthesis and antiproliferative activity of novel erythromycin derivatives

Abstract

A new series of dimers of de(N-methyl) erythromycin derivatives, joined by a -COCH₂- or -CH₂CH₂- linker, was synthesized and their in vitro antiproliferative activity against three human cancer cell lines was evaluated. Structure–activity relationships indicated that transformation of the linker -COCH₂- into -CH₂CH₂- led to an increase in the potency of the compound; removal of cladinose and conversion of the carbonyl group at the C9 position to 9(S)-hydroxyl- or 9(S)-amino-containing groups resulted in a marked decrease in activity. Among the compounds synthesized, compounds 3d and 3e, both had C9 oxime groups and showed strong inhibitory activity against the three cell lines. Flow cytometry studies on HT-1080 cells indicated that the mechanism underlying the dimers' antiproliferative activity involved inducing cell cycle arrest in the G₀/G₁ phase. It was discovered that the percentage of HT-1080 cells arrested depended on the concentration of the erythromycin derivative dimer and on the length of time of treatment.