Lathyrane, Premyrsinane, and Related Diterpenes from Euphorbia boetica: Effect on in Vitro Neural Progenitor Cell Proliferation

Abstract

Lathyrane-type diterpenes previously have been proven to promote proliferation of neural precursor cells (NPCs) by targeting and activating one or more protein kinase C (PKC) isozymes. Aiming to find new drug candidates with a lathyrane skeleton to modulate adult neurogenesis through PKC activation, a phytochemical study of a methanol extract of the aerial parts of Euphorbia boetica was carried out. Seven new diterpenes, representing the premyrsinane (1–3), myrsinane (4, 5), and cyclomyrsinane types (6, 7), along with three known diterpenes, belonging to the cyclomyrsinane (8) and lathyrane types (9, 10), were isolated. The chemical structures and relative configurations of the new compounds were determined by extensive NMR spectroscopic studies and comparison with known compounds. The absolute configurations for compounds 2, 3, 6, and 7 were proposed, based on a comparison of the experimental ECD spectra of compounds 2 and 7 with those of known related compounds. The activity of lathyrane compounds 9 and 10 as promoters of NPC proliferation was evaluated using a neurosphere assay. Both compounds increased the size of neurospheres in a dose-dependent manner when proliferation was stimulated by the epidermal growth factor and the basic fibroblast growth factor.

A novel PKC activating molecule promotes neuroblast differentiation and delivery of newborn neurons in brain injuries

“…The lathyrane EOF2 (CAS number 2230806-06-9) was previously described by our group as a diterpene with no effect on NPC proliferation 22 . Since other diterpenes induced proliferation of NPC 24 via classical PKC activation 23 , we analyzed its capacity to activate PKC and to facilitate the generation of neurospheres. Although EOF2 treatment increased PKC activity by twofold in neurosphere cultures (supplementary fig.…”

Targeting Protein Kinase C in Glioblastoma Treatment

“…PKC activation has been proven to be crucial for NSC proliferation and differentiation, although not all isoenzymes behave identically during these processes [97]. For example, the proliferation of NSCs isolated from the SVZ of induced adult mice is stimulated with classical PKC activating diterpenes with a 12-deoxyphorbols or lathyrane structure [109,110,112]. This facilitates the ADAM17-mediated release of EGFR ligands such as TGFα [113] and activates the PI3K-AKT and MAPK pathways [114], in addition to also activating cyclin D1 expression [109].…”

Acyl Derivatives of Eudesmanolides To Boost their Bioactivity: An Explanation of Behavior in the Cell Membrane Using a Molecular Dynamics Approach

“…For example, sesquiterpene lactones with a guaiane-type skeleton, for example, cynaropicrin (12) and its derivatives, have shown anti-proliferation of leukocyte cancer cell lines. [11] In the case of benzoxazinoids, like APO (14) and its mimics (16 and 18), application against prostate cancer not only showed favorable results in cell lines, [12] but even in human assays where a benzoxazinoid-rich diet was applied. [13] Diterpenes such as gummiferolic acid (20) also have broad applications in medicine, specifically to promote proliferation of neural precursor cells when tested in neurosphere assays.…”

“…[13] Diterpenes such as gummiferolic acid (20) also have broad applications in medicine, specifically to promote proliferation of neural precursor cells when tested in neurosphere assays. [14] In the work described here, costunolide was isolated from the roots of Saussurea costus and reynosin was synthesized to obtain acyl derivatives by reaction with the hydroxy functional group. A structure-activity relationship study was performed to evaluate the effect of bioavailability of the reynosin derivatives, and the IC 50 values were obtained for cytotoxicity on HeLa cells.…”