Jatrophane Diterpenoids from Euphorbia esula as Inhibitors of RANKL-Induced Osteoclastogenesis

Abstract

Eighteen new jatrophane diterpenoids, euphoesulatins A–R (1–18), and three known diterpenoids (19–21) were isolated from Euphorbia esula. Compounds 1–7, 14, and 18 represent a rare type of jatrophane-type diterpenoid containing a nicotinoyloxy group. The absolute configuration of 1 was determined by X-ray crystallography. The compounds were assayed for their antiosteoporotic activity in a bone-marrow-derived macrophage cell line, and compounds 1, 8, and 10 significantly inhibited the formation of osteoclasts, with IC50 values of 1.2, 3.5, and 2.3 μM, respectively. These three compounds also dose-dependently reduced the activity of nuclear factor activated T-cell cytoplasmic 1. This study reveals the antiosteoporotic effects of jatrophane diterpenoids for the first time.

Euphorbia Diterpenes: An Update of Isolation, Structure, Pharmacological Activities and Structure–Activity Relationship

“…Jatrophane diterpenes can be polyacrylate derivatives, with the number of ester groups varying from three, as in guyonianin E, to eight, as in esulatin H. The acyl groups common to jatrophane diterpenes include benzoyl, acetyl, isobutanoyl, or nicotinoyl 2-methylbutanoyl, and propionyl, butanoyl, tigloyl, angeloyl, or cinnamoyl. Phytochemical analysis of E. esula extracts afforded rare euphoesulatins A–R ( 184 – 201 ) [ 100 ], belonging to the jatrophane class but differing only in their functional groups bearing oxygen such as hydroxyl, epoxy, carbonyl, and polyester. Hence, are categorized into exotypes or endotype conformers, depending on how the Δ 6 (17) double bond is oriented within the macrocycles.…”

“…Hence, are categorized into exotypes or endotype conformers, depending on how the Δ 6 (17) double bond is oriented within the macrocycles. The compounds with the double bond outside the ring system were classified as exotypes, like euphoesulatin A-N ( 184 – 197 ) [ 100 ] while euphoesulatin O-R ( 198 – 201 ) [ 100 ] were classified as esulone B (2 02 ), kansuinine B ( 203 ), and esulone A ( 204 ) [ 100 ], whose double bonds outside the ring were classified as endotypes. Euphoesulatin A-N ( 184 – 197 ) [ 100 ] and euphoesulatin R ( 201 ) [ 100 ] were found to uniquely possess nicotinoyloxy groups, further expanding the skeletal diversity of Euphorbia jatrophane diterpenoids isolated from E. esula .…”

“…Euphoesulatin A–C ( 184 – 186 ), from E. esula, exhibited antiosteoporotic activity on BMM cells. Euphoesulatin A ( 184 ), euphoesulatin F–G ( 189 – 190 ) showed significant activities with IC 50 values of 1.20, 6.10, and 10 µM respectively compared to receptor activator of nuclear factor kappa B ligand (RANKL) control [ 100 ]. Other euphoesulatins diterpenes displayed some antiosteoporotic activities, while some, like esulone B ( 202 ), showed no activity, as demonstrated in Table 2 .…”

“…All isolated euphoesulatins A–R ( 184 – 201 ) [ 100 ] from E. esula were evaluated for their inhibition abilities of receptor activators of the nuclear factor kappa B ligand (RANKL)-induced osteoclastogenesis of the macrophage cells derived in bone marrow. Strong activities were reported for euphoesulatin A ( 184 ), euphoesulatin D–H ( 187 – 191 ), euphoesulatin J ( 193 ), M ( 196 ), and O ( 198 ) against RANKL-induced osteoclastogenesis (BMM) cells.…”

Diterpenoids from the Whole Plants of Ajuga nipponensis and Their Inhibition of RANKL‐Induced Osteoclastogenesis

“…As an ongoing searching for anti-osteoporosis active natural products, [36,37] chemical constituents of A. nipponensis and their activities were evaluated for their ability against RANKL-induced osteoclastogenesis. Fifteen compounds, including two new diterpenoids (1 and 14) and thirteen known ones (2 -13 and 15), were isolated from the whole plants of A. nipponensis ( Figure 1).…”