Background: Natural products have been an exemplary source of new drugs as they
have served as direct or indirect precursors for many currently available medicines. The natural
product β -elemene has been used clinically in the treatment of various cancers; however, its
efficacy is hampered by its poor solubility and bioavailability.
Methods: An aldehyde metabolite of β-elemene, 13-β-elemenal, was further identified and proved
to exhibit significantly better anti-proliferative activity than β -elemene. A series of prodrug-like
13- and 14-substituted ester derivatives, as well as their alcohol and aldehyde intermediates, were
rational designed, synthesized and biologically evaluated.
Results: The intermediates and ester derivatives of β-elemene displayed comparable to better antiproliferative
activity on human cancer cell lines (A549, HepG-2 and U87). Notably, ester
compounds 10d, 10m-o, 10s, 10t, 13d, 13h and 13m-o were superior over β-elemene in their antiproliferation
effects, while the predicted in vivo metabolites of the designed ester compounds, 13-
β-elemental (8) and 14-β-elemental (11), demonstrated the most potent anti-proliferative effect.
Conclusion: Most of the esters displayed better antitumor effects than β -elemene, which were
predicted to play more significant roles in the in vivo treatment by being metabolized continuously
to β -elemental. More importantly, these compounds showed better drug-like properties, such as
decreased LogP values and improved solubility.