Effect of lathyrane-type diterpenoids in neural stem cell physiology: Microbial transformations, molecular docking and dynamics studies

Promoting endogenous neurogenesis for brain repair is emerging as a promising strategy to mitigate the functional impairments associated with various neurological disorders characterized by neuronal death. Diterpenes featuring tigliane, ingenane, jatrophane and lathyrane skeletons, frequently found in Euphorbia plant species, are known protein kinase C (PKC) activators and exhibit a wide variety of pharmacological properties, including the stimulation of neurogenesis. Microbial transformation of these diterpenes represents a green and sustainable methodology that offers a hitherto little explored approach to obtaining novel derivatives and exploring structure-activity relationships. In the present study, we report the biotransformation of euphoboetirane A (4) and epoxyboetirane A (5), two lathyrane diterpenoids isolated from Euphorbia boetica, by Mucor circinelloides MC NRRL3631. Our findings revealed the production of nine biotransformation products (6-14), including jatrophane derivatives originated through an unprecedented rearrangement from the parent lathyranes. The chemical structures and absolute configurations of the new compounds were elucidated through comprehensive analysis using NMR and ECD spectroscopy, as well as MS. The study evaluated how principal metabolites and their derivatives affect TGFα and NRG1 release, as well as their potential to promote proliferation or differentiation in cultures of NSC isolated from the SVZ of adult mice. In order to shed some light on the mechanisms underlying the ability of 12 as a neurogenic compound, the interactions of selected compounds with PKC δ-C1B were analyzed through molecular docking and molecular dynamics. Based on these, it clearly appears that the ability of compound 12 to form both acceptor and donor hydrogen bonds with certain amino acid residues in the enzyme pocket leads to a higher affinity compound-PKC complex, which correlates with the observed biological activity.