New ursane triterpenoids from Ficus pandurata and their binding affinity for human cannabinoid and opioid receptors

Abstract

Phytochemical investigation of Ficus pandurata Hance (Moraceae) fruits has led to the isolation of two new triterpenoids, ficupanduratin A [1β-hydroxy-3β-acetoxy-11α-methoxy-urs-12-ene] (11) and ficupanduratin B [21α-hydroxy-3β-acetoxy-11α-methoxy-urs-12-ene] (17), along with 20 known compounds: α-amyrin acetate (1), α-amyrin (2), 3β-acetoxy-20-taraxasten-22-one (3), 3β-acetoxy-11α-methoxy-olean-12-ene (4), 3β-acetoxy-11α-methoxy-12-ursene (5), 11-oxo-α-amyrin acetate (6), 11-oxo-β-amyrin acetate (7), palmitic acid (8), stigmast-4,22-diene-3,6-dione (9), stigmast-4-ene-3,6-dione (10), stigmasterol (12), β-sitosterol (13), stigmast-22-ene-3,6-dione (14), stigmastane-3,6-dione (15), 3β,21β-dihydroxy-11α-methoxy-olean-12-ene (16), 3β-hydroxy-11α-methoxyurs-12-ene (18), 6-hydroxystigmast-4,22-diene-3-one (19), 6-hydroxystigmast-4-ene-3-one (20), 11α,21α-dihydroxy-3β-acetoxy-urs-12-ene (21), and β-sitosterol-3-O-β-D-glucopyranoside (22). Compound 21 is reported for the first time from a natural source. The structures of the 20 compounds were elucidated on the basis of IR, 1D ((1)H and (13)C), 2D ((1)H-(1)H COSY, HSQC, HMBC and NOESY) NMR and MS spectroscopic data, in addition to comparison with literature data. The isolated compounds were evaluated for their anti-microbial, anti-malarial, anti-leishmanial, and cytotoxic activities. In addition, their radioligand displacement affinity on opioid and cannabinoid receptors was assessed. Compounds 4, 11, and 15 exhibited good affinity towards the CB2 receptor, with displacement values of 69.7, 62.5 and 86.5 %, respectively. Furthermore, the binding mode of the active compounds in the active site of the CB2 cannabinoid receptors was investigated through molecular modelling.

Keywords: Anti-leishmanial; Anti-malarial; Cannabinoid receptors; Ficus pandurata; Opioid receptors; Triterpenes.

Fig. 1

Structure of isolated compounds 1–22

Fig. 2

¹H–¹H COSY and HMBC correlations of 11, 17 and 21

Fig. 3

Displacement of [³H]-CP55,940 binding by compounds 4, 11, and 15 in CB2 receptors

Fig. 4

Molecular surface analysis of CB2 model. The protein is shown with the N-terminus at the top and the residues forming the binding pocket are shown in space-filling mode among the transmembrane helices and isolated figure as a surface with colour-coded features: H bonding (magenta), lipophilic (green), mild polar (blue)

Fig. 5

Hypothetical binding modes of the docked compounds a 4, b 11, c 15, and d CP-55,940 ligand. The figures exhibit the residues in the proposed binding pocket of CB2 model with corresponding hydrogen bonding interactions and hydrophobic contact