Synthesis and biological evaluation of γ-alkylidenebutenolides isolated from <i>Melodorum fruticosum</i> : the role of the propylidene-type side chain structure on anti-melanogenic activity

The first structure-activity relationship study on γ-alkylidenebutenolides [(4<i>Z</i>)- and (4<i>E</i>)-6,7-dihydroxyhepta-2,4-dien-4-olide 6-monobenzoate] (4<i>Z</i>, 3 and 4<i>E</i>, 4) and 7-monobenzoate (4<i>Z</i>, 1 and 4<i>E</i>, 2) which are potent melanogenesis inhibitors (IC₅₀ = 0.3-2.9 μM) isolated from the medicinal plant <i>Melodorum fruticosum</i>, was carried out using the related analogous (7-21). The inhibitory activities of the (4<i>Z</i>)- and (4<i>E</i>)-6,7-dideoxylated compounds (7) completely disappeared, while those of the 6-oxo-7-hydroxy-type compounds (4<i>Z</i>, 20 and 4<i>E</i>, 21) were significantly attenuated compared with those of 1-4. By contrast, the 6,7-dihydroxylated compounds (4<i>Z</i>, 8 and 4<i>E</i>, 9; IC₅₀ = 5.8-1.5 μM) showed inhibitory activities similar to those of 1-4, suggesting that the two hydroxyl groups at positions C6 and C7 on the side chain play an essential role in the onset of potent inhibitory activity. The inhibitory activities of the 6,7-diacylated analogues (10-19, acyl group = Ac, Piv, or Bz; IC₅₀ = 0.7-3.3 μM) were also nearly identical to those of the 6- or 7-monobenzoates (1, 3, and 4), regardless of the geometry of the double bond. However, acylation of the strongest inhibitor (4<i>E</i>, 2; IC₅₀ = 0.3 μM) at position C6, reduced the activity by approximately 1/3 to 1/5. This result suggests the importance of the cooperative role of the acyl moiety at position C7 and the hydroxyl group at position C6 in the <i>E</i>-configured double bond. The total synthesis of the natural products melodorinone A (20) and melodorinone B (21) was also achieved during the synthesis of the γ-alkylidenebutenolide analogues.