Tigliane Diterpenoids as a New Type of Antiadipogenic Agents Inhibit GRα-Dexras1 Axis in Adipocytes

Abstract

The phytochemical study of Euphorbia prolifera led to the isolation of two tiglianes (1 and 2) and 23 mysrinanes (3−25). Most of these isolates showed significant antiadipogenic activity in 3T3-L1 adipocyte without apparent cytotoxicity. Subsequent structural modification yielded 10 derivatives, among which 1a, the 5-O-acetyl derivative of 1, turned out to be the most active compound with improved triglyceride-lowering activity (EC 50 for 1 and 1a: 0.61 and 0.32 μM, respectively) and reduced cytotoxicity (selectivity index for 1 and 1a: 28 and 312, respectively). The structure−activity relationship study revealed that the trans-fused 5/7/6 ring system in an angular shape was important to the activity. A mechanistic study indicated that 1 and 1a could inhibit the glucocorticoid receptor α-Dexras1 axis in adipocyte, leading to the retardation of cell differentiation at the early stage. These findings may provide a new type of lipid-lowering agents for future antiobesity drug development.

Bioactive Compounds from Euphorbia usambarica Pax. with HIV-1 Latency Reversal Activity

“…The known compounds were identified as isoterracinolide A ( 10 ) [ 36 ], isoterracinolide B ( 11 ) [ 36 ], 12- O -benzoyl-13-acetoxy-4,20-dideoxyphorbol-4-ene ( 12 ) [ 51 , 52 ], crotignoid K ( 13 ) [ 42 ], 16- nor -abieta-8,11,13-trien-3,15-dione ( 18 ) [ 53 ], helioscopinolide E ( 21 ) [ 54 ], helioscopinolide C ( 22 ) [ 54 ], helioscopinolide A ( 23 ) [ 54 ], ent -kauran-16 β -ol-3-one ( 24 ) [ 55 ], cleomiscosin A ( 25 ) [ 56 ], (+)-syringaresinol ( 26 ) [ 57 ], dimeric coniferyl acetate ( 27 ) [ 58 ], vanillin ( 28 ) [ 59 ], 4-hydroxybenzaldehyde ( 29 ) [ 60 ], coniferol alcohol ( 30 ) [ 61 ], and indole-3-carboxaldehyde ( 31 ) [ 62 ] by comparison of the NMR data with those of the literature.…”

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

“…Most of the studied species contained both polycyclic and macrocyclic diterpenes and included E. lathyris [ 31 ], E. stracheyi [ 32 ], E. royleana [ 33 ], E. antiquorum [ 34 ], E. kansuensis [ 35 , 36 ], E. prolifera [ 37 ], E. peplus [ 38 ], E. aellenii [ 39 ], E. pilosa [ 40 ], E. saudiarabica [ 28 ], E. marginata [ 41 ], E. neriifolia [ 42 ], E. resinifera [ 43 ], E. pekinensis [ 44 ], E. hylonoma [ 45 ], E. milii [ 46 ], E. wallichii [ 47 ], and E. ebracteolata [ 48 ]. While others contained only macrocyclic diterpenes like E. esula [ 49 ], E. helioscopia [ 50 ], E. yinshanica [ 51 ], E. grandicornis [ 52 ], and E. kansui [ 53 ].…”

“…Jatrophane diterpenes are common in the Jatropha species of the Euphorbiaceae family [ 101 ]. Other subtypes of diterpenoids, such as pimaranes ( 326 – 328 ) [ 32 ] mysrinanes ( 316 – 322 ) [ 37 ], rosanes ( 332 – 338 ) [ 48 , 71 ], mysrinanes ( 316 – 322 ) [ 37 ], paralianones ( 323 – 325 ) [ 38 ], premyrsinane ( 329 – 331 ) [ 26 ], and tiglianes ( 339 – 342 ) [ 71 , 102 ] were isolated and identified for the first time.…”

“…Examples of modified jatrophane diterpenes isolated from Euphorbia species were mysrinanes from E. prolifera ( 316 – 322 ) [ 37 ], paralianones from E. peplus ( 323 – 325 ) [ 38 ], pimaranes from E. stracheyi ( 326 – 328 ) [ 32 ], and premyrsinanes from E. sanctae-catharinae ( 329 – 331 ) [ 26 ]. Others were myrsinol from root extracts of E. prolifera ( 347 – 350 ) [ 74 ] and from the aerial extracts of E. dracunculoides ( 351 – 352 ) [ 58 ], paralianes from E. esula ( 353 ) [ 49 ] and E. peplus ( 354 – 361 ) [ 72 ] and pepluane ( 362 – 365 ) [ 72 ].…”

“…Structural modification of these constituents by esterification of hydroxyl groups revealed that the 5- O -acetyl derivative presented triglyceride-lowering abilities with an EC 50 value of 0.61 μM. Structure–activity relationships showed that the trans-fused 5/7/6 ring system occurring in an angular shape was relevant to these activities [ 37 ]. In addition, the presence of a cyclopropane ring, an isopropyl substituent, and cyclobutane ring on these diterpenes did not have an effect.…”