Lathyrane, Premyrsinane, and Related Diterpenes from <i>Euphorbia boetica</i>: 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 <i>Euphorbia boetica</i> was carried out. Seven new diterpenes, representing the premyrsinane (<b>1</b>-<b>3</b>), myrsinane (<b>4</b>, <b>5</b>), and cyclomyrsinane types (<b>6</b>, <b>7</b>), along with three known diterpenes, belonging to the cyclomyrsinane (<b>8</b>) and lathyrane types (<b>9</b>, <b>10</b>), 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 <b>2</b>, <b>3</b>, <b>6</b>, and <b>7</b> were proposed, based on a comparison of the experimental ECD spectra of compounds <b>2</b> and <b>7</b> with those of known related compounds. The activity of lathyrane compounds <b>9</b> and <b>10</b> 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.