Structure-Activity Relationships of the Antitumor C(5)-Curcuminoid GO-Y030

1,5-Bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadiene-3-one (2) was isolated from Curcuma domestica as a curcumin (1)-related compound, which we named C(5)-curcumin. Intrigued by the potent antitumor activity of C(5)-curcumin (2)-related 1,5-bisaryl-1,4-pentadiene-3-ones [bis(arylmethylidene)acetones, termed C(5)-curcuminoids], we previously conducted a structure–activity relationship study of C(5)-curcuminoids and showed that highly active GO-Y030 [1,5-bis(3,5-bis(methoxymethoxy)phenyl)-1,4-pentadiene-3-one (4)] is the most promising antitumor compound. In this study, a panel of C(5)-curcuminoids based on GO-Y030, consisting of 30 new and 10 known compounds, was synthesized to elucidate in detail which moiety of GO-Y030 is significant for antitumor activity. The results confirmed that both the cross-conjugated dienone moiety and the 3,5-bis(methoxymethoxy) substituent are important for the antitumor activity.