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.
Highlights
P lants of the genus Euphorbia (Euphorbiaceae) are well known for the extraordinary chemical diversity of their diterpenoids and the wide variety of pharmacological properties they possess.1−3 In particular, diterpenes with tigliane, ingenane, and lathyrane skeletons, frequently found in plants of this genus, are known protein kinase C (PKC) activators
Prostratin and related tigliane esters are potentially useful in the treatment of HIV-1, in combination with antiretroviral therapies,8,9 since they reactivate replication of latent viral reservoirs in CD4+ T-cells,10 by activating NF-κB through a PKC-dependent pathway
Given the limited ability of the brain to generate neurons in damaged brain areas, compounds promoting neural precursor cells (NPCs) proliferation may be suitable for the development of therapies aimed to replace dead neurons in patients with disorders that occur with neuronal death
Summary
Article is important to shed some light on the structural features that contribute to the activity of this type of compound, as well as to their mechanism of action in the interaction with the molecular target. This paper reports on the isolation and structural elucidation of seven new diterpenes from this plant, belonging to the premyrsinane (1−3), myrsinane [4, 5], and cyclomyrsinane types [6, 7], together with three known diterpenes, belonging to the cyclomyrsinane [8] and lathyrane types [9, 10]. Their chemical structures were established on the basis of the interpretation of their spectroscopic data, including HRESIMS and 1D and 2D NMR. The biological activity of lathyranes 9 and 10 as facilitators of NPC proliferation is described
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