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Background  Glycyrrhetinic acid (GA) derivatives had shown not only cytotoxicity but also could trigger apoptosis in various human cancer cell lines. Moreover, cinnamic acid (CA) and its phenolic analogues as potent antitumor agents were employed in the design of anti-tumor drugs. To further improve the anti-tumor activity of GA and CA derivatives, a series of novel compounds were designed and synthesized using GA and CA derivatives fragments.    Results  The result showed that all the novel glycyrrhetinic acid-cinnamoyl (GA–CA) hybrids presented higher antitumor activity on the tumor cell lines of HepG2, HT-29, Hela and lower cytotoxicity on three non-tumor cells lines MDCK, HY926, H9C2 than the parent compounds (IC 50  > 50 μM). It was worth noting that  8a  had a superior cytotoxicity effect on Hela cells (IC 50  = 8.54 μM) than on other cancer cell lines (IC 50  > 15 μM). And it also indicated that  8a  showed lower cytotoxicity (IC 50  > 27 μM) towards MDCK, HY926 and H9C2 cells than cisplatin (DDP, IC 50  < 10 μM). Moreover, according to the acute toxicity, it could be indicated that the LD 50  of  8a  exceeded 3.0 g/kg by oral administration in mice. The further research using Giemsa, H33342 staining, flow cytometric analysis and caspase-3 assay showed that  8a  could cause Hela cell damage, nuclei lysis and apoptosis. In addition, the structure–activity relationships of these hybrids were briefly discussed.    Conclusions  Compared with GA, target compounds demonstrated better anti-tumor activity, among which  8a  was the most active one. What’s more, structure–activity relationship analysis also revealed that hybrids with  trans  olefinic bond group show higher antitumor activity than those without olefinic bond, such as  1a   >   1b ,  6a   >   2b ,  8a   >   3b ,  9a   >   4b . In addition, it was found that the methoxy substituent might enhance selectivity of GA–CA hybrids towards regular non-cancerous cells MDCK, HY926 and H9C2, such as  4a ,  6a ,  7a ,  8a . However, there might be less relationship between the cytotoxicity and the quantity, position of methoxy moiety. Hence, it is urgent need to synthesize efficient, low toxicity and multi-target anti-tumor compounds based on the structure combination principle.

Design, synthesis, and biological evaluation of the novel glycyrrhetinic acid-cinnamoyl hybrids as anti-tumor agents