Efficient construction of novel D-ring modified steroidal dienamides and their cytotoxic activities

•Two series of novel steroidal dienamides were synthesized.•All these compounds exhibited broad-spectrum cytotoxic activities.•Most of them were more potent than 5-Fu against five human cancer cell lines.•Compounds 4j and 4k were highly selective in their cytotoxic activities.•Compound 4c showed cell cycle arrest at G2/M phase and induced early apoptosis.

Two series of steroidal dienamides 4a–q and 5a–f were designed, synthesized and evaluated for cytotoxic activities against five human cancer cell lines (MGC-803, EC109, PC-3, SMMC-7721 and MCF-7). The protocol developed efficiently achieved the construction of carbon–carbon double bond and selective conversion of nitrile group into carboxamide in one-pot procedure. Besides, compounds 4a–q and 5a–f showed moderate to excellent cytotoxic activities with the IC50 values ranging from 0.1 to 40 μM and most of them were more potent than 5-fluorouracil. Particularly, four compounds 4d, 4e, 4q and 5a showed excellent selectivity against MGC-803 with the IC50 values less than 1 μM. Flow cytometry analysis demonstrated that compound 4c caused the cellular early apoptosis and cell cycle arrest in G2/M phase in a concentration-independent manner.

Graphical abstractAll the compounds showed moderate to excellent cytotoxic activities against five human cancer cell lines. Four compounds showed excellent selectivity against MGC-803 (IC50 < 1 μM). Compound 4c induced G2/M arrest and early apoptosis.Figure optionsDownload full-size imageDownload as PowerPoint slide