Design, synthesis, and evaluation of novel heteroaromatic analogs of curcumin as anti-cancer agents

• 29 new and 3 known basic curcumin analogs were prepared.
• Analogs showed superior cytotoxicity against prostate cancer cells.
• Analogs demonstrate no significant toxicity towards normal cells.
• A new scaffold was identified for the potential treatment of prostate cancer.
• N-containing heteroaromatic rings are promising bioisosteres of phenyl rings.

To improve the potential of curcumin to treat advanced hormone-refractory prostate cancer, three series (A–C) of heteroaromatic analogs (thirty two compounds) with different monoketone linkers have been synthesized and evaluated for cytotoxicity against two human androgen-independent prostate cancer cell lines (PC-3 and DU-145). Among them, thirty analogs are more potent than curcumin against PC-3 cells, and twenty one analogs are more cytotoxic towards DU-145 cells relative to curcumin. The most potent compounds (44, 45, 51, and 52) also showed impressive cytotoxicity against three other metastatic cancer cell lines (MDA-MB-231, HeLa, and A549), with IC50 values ranging from 50 nM to 390 nM. All four most potent analogs exhibited no apparent cytotoxicity towards the MCF-10A normal mammary epithelial cells. Taken together, selective enhancement of cell death in prostate cancer cell lines and other aggressive cancer cell lines suggests that nitrogen-containing heteroaromatic rings are promising bioisosteres of the substituted phenyl ring in curcumin.

The novel curcumin analogs 44, 45, and 51 are significantly more potent than curcumin against aggressive prostate cancer cells and other three metastatic cancer cell lines. They demonstrate no apparent toxicity towards normal cells.Figure optionsDownload as PowerPoint slide