Saudiarabicains A-E, bioactive 19-acetoxyingol diterpenoids from Euphorbia saudiarabica

Highlights

• New saudiarabicains were isolated from aerial parts of Euphorbia saudiarabica.

• Saudiarabicains A-E are 19-acetoxyingol diterpenoids.

• Saudiarabicains inhibited activity of α-glucosidase.

• Saudiarabicains inhibited activity of P-glycoprotein.

Abstract

Five new 19-acetoxyingols were isolated from the aerial parts of Euphorbia saudiarabica. They included two uncommon pentacyclic acetoxyingols (1, 2) and two 2,3-diepimers (3, 4), representing the first report of 19-acetoxyingols epimers. Their structures were determined by analysis of extensive 1D and 2D NMR spectroscopic data. The absolute configurations were established by experimental and calculated CD analysis. Compounds 3–5 showed α-glucosidase inhibitory effects superior to the positive control, acarbose (IC₅₀ 9.1, 8.0, 1.8 vs 147 µM, respectively). Compounds 1, 2, 4, and 5 showed inhibitory effects on human P-glycoprotein comparable to the positive control, valspodar (IC₅₀ 0.1–1.4 vs 0.2 µM, respectively).

Introduction

The Euphorbia L. (Euphorbiaceae) genus has been extensively studied and its members are reported to produce a wide diversity of diterpenoids [1], [2] with a wide range of biological activities including anti-α-glucosidase [3], anti-multidrug resistance [4], anti-HIV [5], anti-inflammatory [6] and anti-microbial [7]. Euphorbia saudiarabica, first identified in 2007, is endemic to Saudi Arabia distributed in its southwestern parts close to the Red Sea [8]. To date, there has been no previously reported phytochemical investigation of E. saudiarabica.

Ingol-type diterpenoids are tetracyclic diterpenoids produced only by members of the Euphorbia genus and they are most commonly found with a C-19 methyl group [3], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21]. Among these ingol diterpenoids, only twelve are found as epimers (at C-2 and C-3) [18], [14], [15], [16]. Furthermore, C-19 oxygenated ingol diterpenoids are very uncommon with only nine of these compounds reported [10], [11], [13], [22], [23] among which only one pentacyclic 19-acetoxyingol has been previously reported [11]. Herein, we report the structure elucidation and biological evaluations of five new 19-acetoxyingols from the aerial parts of E. saudiarabica. The structures of the compounds were established by extensive NMR spectroscopic data and their absolute configurations by experimental and calculated CD analysis. The isolates were evaluated for inhibitory effects against yeast α-glucosidase enzyme and human P-glycoprotein (P-gp) activities and for cytotoxicity effects against murine and human skin cancer cell lines.