Newly synthesised oxime and lactone derivatives from Dipterocarpus alatus dipterocarpol as anti-diabetic inhibitors: experimental bioassay-based evidence and theoretical computation-based prediction

Abstract

Dipterocarpus alatus-derived products are expected to exhibit anti-diabetes properties. Natural dipterocarpol (1) was isolated from Dipterocarpus alatus collected in Quang Nam province, Vietnam; afterwards, 20 derivatives including 13 oxime esters (2 and 3a-3m) and 7 lactones (4, 5, 6a-6e) were semi-synthesised. Their inhibitory effects towards diabetes-related proteins were investigated experimentally (α-glucosidase) and computationally (3W37, 3AJ7, and PTP1B). Except for compound 2, the other 19 compounds (3a-3m, 4, 5, and 6a-6d) are reported for the first time, which were modified at positions C-3, C-24 and C-25 of the dipterocarpol via imidation, esterification, oxidative cleavage and lactonisation reactions. A framework based on docking-QSARIS combination was proposed to predict the inhibitory behaviour of the ligand-protein complexes. Enzyme assays revealed the most effective α-glucosidase inhibitors, which follow the order 5 (IC₅₀ of 2.73 ± 0.05 μM) > 6c (IC₅₀ of 4.62 ± 0.12 μM) > 6e (IC₅₀ of 7.31 ± 0.11 μM), and the computation-based analysis confirmed this, i.e., 5 (mass: 416.2 amu; polarisability: 52.4 ų; DS: -14.9 kcal mol^-1) > 6c (mass: 490.1 amu; polarisability: 48.8 ų; DS: -13.7 kcal mol^-1) > 6e (mass: 549.2 amu; polarisability: 51.6 ų; DS: -15.2 kcal mol^-1). Further theoretical justifications predicted 5 and 6c as versatile anti-diabetic inhibitors. The experimental results encourage next stages for the development of anti-diabetic drugs and the computational strategy invites more relevant work for validation.

Fig. 1. (a) α-Glucosidase protein 3W37. (b) Oligo-1,6-glucosidase protein 3W37. (c) Protein tyrosine phosphatase 1B PTP1B.

Fig. 2. (a) Dipterocarpus alatus tree. (b) Collection of dammar resin from Dipterocarpus alatus. (c) Structure of dipterocarpol.

Fig. 3. Designed structures of dipterocarpol derivatives.

Scheme 1. Synthesis of oxime ester derivatives at C-3 of dipterocarpol. (a) NH₂OH·HCl, TEA, C₂H₅OH, 24 h, rt (83%). (b) Synthesis of 3a–3i: DCC, DMAP, RCOOH, CH₂Cl₂, 5 h, rt (48–80%); 3k: pyridine, Ac₂O, 24 h, rt (81%); 3l, 3m: RCOCl, CH₂Cl₂, 19 h, rt (80–83%).

Scheme 2. Synthesis of lactone derivatives of dipterocarpol. (a) CrO₃, CH₃COOH, H₂O, 40 min, rt (85.5%). (b) NaBH₄, MeOH, 20 min, rt (74%). (c) Synthesis of 6a: Ac₂O, pyridine, 24 h, rt (73%); 6b and 6c: RCOCl, CH₂Cl₂, 20 h, rt (60–75%); 6d and 6e: RCOOH, DCC, DMAP, CH₂Cl₂, rt, 48 h for 6d (66%) or reflux, 28 h for 6e (61%).

Fig. 4. Quaternary structures of proteins (a) 3W37, (b) 3AJ7 and (c) PTP1B with their approachable sites by investigated compounds (1, 2, 3a–3m, 4, 5, and 6a–6e): site 1 (yellow), site 2 (cyan), site 3 (green), and site 4 (blue).

Fig. 5. Visual presentation and in-pose interaction map of ligand–3W37 inhibitory complexes.

Fig. 6. Visual presentation and in-pose interaction maps of the ligand–3AJ7 inhibitory complexes.

Fig. 7. Visual presentation and in-pose interaction maps of the ligand–PTP1B7 inhibitory complexes.