Thiazolidinedione-based structure modification of ergosterol peroxide provides thiazolidinedione-conjugated derivatives as potent agents against breast cancer cells through a PI3K/AKT/mTOR pathway.

Ergosterol peroxide (EP) is a steroidal compound isolated from the traditional Chinese medicine Ganoderma lucidum. However, EP is limited by its solubility and moderate potency in antitumor studies. In the present study, a series of novel ergosterol peroxide-3-thiazolidinedione derivatives were designed and synthesized, by changing the linker between ergosterol peroxide and thiazolidinedione, it is expected to obtain compounds with better antitumor activity. The cytotoxicity screening showed that compound 13o is the most active derivative against the MCF-7 cell line with an IC50 of 3.06 μM, and exhibited stronger antitumor activity compared to the parent EP. Further in vitro and vivo studies showed that compound 13o may reduced the mitochondrial membrane potential, increased the reactive oxygen species level and blocked the cell cycle in G0/G1 phase, and induced apoptosis of tumor cells by inhibiting the PI3K/Akt/mTOR pathway. In vivo 4T1 mouse model of breast cancer showed that 13o not only continued to inhibit tumor proliferation but also had a stronger effect than the marketed drug 5-fluorouracil, compound 13o had a good safety profile in vivo. The results suggest that compound 13o may represent a novel, highly potent and low-toxicity structural lead for the development of new breast cancer chemotherapies.