Multidrug resistance (MDR), for which the mechanisms are not yet fully clear, is one of the major obstacles to
cancer treatment. In recent years,
signal transducer and activator of transcription 3 (STAT3) were found to be one of the important MDR mechanism pathways. Based on the previous research,
zhankuic acid A, B, and C were found to have collateral sensitivity effects on MDR
cancer cells, and MDR inhibitory activity of zhankuic
acid methyl
ester was found to be better than that of its
acid. Therefore, we executed a systematic examination of the structure-activity relationship of zhankuic
acid methyl
ester derivatives to collateral sensitivity in MDR
cancer cells. The results showed that compound 12 is the best in terms of chemoreversal activity, where the reversal fold was 692, and the IC50 value of
paclitaxel combined with 10 μM compound 12 treatment was 1.69 nM in MDR KBvin cells. Among all the derivatives, methyl
ester compounds were found to be better than their
acids, and a detailed discussion of the structure-activity relationships of all of the derivatives is provided in this work. In addition, compounds 8, 12, and 26 were shown to influence the activation of STAT3 in KBvin cells, accounting for part of their chemoreversal effects. Our results may provide a new combined
therapy with
paclitaxel to treat multidrug-resistant
cancers and provide a new
therapy option for patients.