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

Abstract

Euphorbia species have a rich history of ethnomedicinal use and ethnopharmacological applications in drug discovery. This is due to the presence of a wide range of diterpenes exhibiting great structural diversity and pharmacological activities. As a result, Euphorbia diterpenes have remained the focus of drug discovery investigations from natural products. The current review documents over 350 diterpenes, isolated from Euphorbia species, their structures, classification, biosynthetic pathways, and their structure–activity relationships for the period covering 2013–2020. Among the isolated diterpenes, over 20 skeletal structures were identified. Lathyrane, jatrophane, ingenane, ingenol, and ingol were identified as the major diterpenes in most Euphorbia species. Most of the isolated diterpenes were evaluated for their cytotoxicity activities, multidrug resistance abilities, and inhibitory activities in vitro, and reported good activities with significant half-inhibitory concentration (IC50) values ranging from 10–50 µM. The lathyranes, isopimaranes, and jatrophanes diterpenes were further found to show potent inhibition of P-glycoprotein, which is known to confer drug resistance abilities in cells leading to decreased cytotoxic effects. Structure–activity relationship (SAR) studies revealed the significance of a free hydroxyl group at position C-3 in enhancing the anticancer and anti-inflammatory activities and the negative effect it has in position C-2. Esterification of this functionality, in selected diterpenes, was found to enhance these activities. Thus, Euphorbia diterpenes offer a valuable source of lead compounds that could be investigated further as potential candidates for drug discovery.

The Role of Ingenane Diterpenes in Cancer Therapy: From Bioactive Secondary Compounds to Small Molecules

“…Thus, what is currently known is that possibly the structureactivity relationship of these diterpenes revealed that acetylation and esterification of hydroxyl groups, particularly at C-3 and C-8, positively affect these activities. 135 Due to the various substitution patterns in isolated ingenoltype diterpenoids, structure-activity relationships remain under investigation. The rigid ingenol scaffold conveys several structural features, including the 5-and 20-hydroxyl groups, which may be essential for biological activity.…”

“…Thus, what is currently known is that possibly the structure–activity relationship of these diterpenes revealed that acetylation and esterification of hydroxyl groups, particularly at C-3 and C-8, positively affect these activities. 135…”

Biological Properties of Latex, Aqueous Extracts and Bee Products of Euphorbia officinarum L.: A Short Review

“…Ingol 7,8,12-triacetate 3-phenylacetate ( 1 ), ingol 7,8,12-triacetate 3-(4-methoxy-phenyl) acetate ( 2 ) and 8-methoxyingol 7,12-diacetate 3-phenylacetate ( 3 ) have the lathyrane skeleton, that is, tricyclic diterpenes with a 4/11/3-ring system, an epoxy functionality at C- 4 and C- 15 and a double bond between C- 5 and C- 6 ( Figure 3 ) [ 33 ], which precursors are most likely the ones just mentioned. Further, those ingol diterpenoids underwent redox, etherification and esterification modifications of the 5- and 11-membered rings ( Figure 3 ).…”

Euphocactoside, a New Megastigmane Glycoside from Euphorbia cactus Growing in Saudi Arabia

“…However, the most representative and diverse class of Euphorbia secondary metabolites are undoubtedly diterpenes. A wide array of typical structural frameworks, from macrocyclic to polycyclic architectures, have been identified, including tiglianes, ingenanes, daphnanes, lathyranes, jatrophanes, and myrsinanes [ 4 ]. These compounds have been identified as the components mainly responsible for the potent skin-irritating and tumor-promoting effects associated with Euphorbia latex [ 5 ].…”