Synthesis and anti-tumor activity evaluation of salinomycin C20-O-alkyl/benzyl oxime derivatives

Seventeen C20-O-alkyl/benzyl oxime derivatives were synthesized by a concise and effective method. Most of these derivatives showed tens to several hundred nanomolar IC50 values against HT-29 colorectal, HGC-27 gastric and MDA-MB-231 breast cancer cells, whose antiproliferative activity is 15-240 fold better than that of salinomycin. The C20-oxime etherified derivatives can coordinate potassium ions, and further adjust the cytosolic Ca2+ concentrations in HT-29 cells. The significant improvement of the potency should be attributed to the better ion binding and transport ability of the modified derivatives. In addition, the C20-O-alkyl/benzyl oxime derivatives showed much better selectivity indexes (SI) than salinomycin, indicating that they present lower neurotoxic risk.

Automated summary

Seventeen C20-O-alkyl/benzyl oxime derivatives were synthesized by a concise and effective method, and showed improved antiproliferative activity against colorectal, gastric, and breast cancer cells compared to salinomycin. The derivatives can coordinate potassium ions and adjust cytosolic Ca2+ concentrations, potentially due to their better ion binding and transport ability. Additionally, they exhibited lower neurotoxic risk, indicating higher selectivity indexes.