Regulating insulin and leptin levels using a protein tyrosine phosphatase 1B (PTP1B) inhibitor is an attractive strategy to treat diabetes and obesity. Glycyrrhetinic acid (GA), a triterpenoid, may weakly inhibit this enzyme. Nonetheless, semisynthetic derivatives of GA have not been developed as PTP1B inhibitors to date. Herein we describe the synthesis and evaluation of two series of indole- and N-phenylpyrazole-GA derivatives (4a–f and 5a–f). We measured their inhibitory activity and enzyme kinetics against PTP1B using p-nitrophenylphosphate (pNPP) assay. GA derivatives bearing substituted indoles or N-phenylpyrazoles fused to their A-ring showed a 50% inhibitory concentration for PTP1B in a range from 2.5 to 10.1 µM. The trifluoromethyl derivative of indole-GA (4f) exhibited non-competitive inhibition of PTP1B as well as higher potency (IC50 = 2.5 µM) than that of positive controls ursolic acid (IC50 = 5.6 µM), claramine (IC50 = 13.7 µM) and suramin (IC50 = 4.1 µM). Finally, docking and molecular dynamics simulations provided the theoretical basis for the favorable activity of the designed compounds.

The main diterpenoid of Acacia schaffneri, 7,8-seco-7,8-oxacassa-13,15-dien-7-ol-17-al (1), has two aldehydes of which one is protected as a ε-lactol.The free aldehyde resisted to afford the carboxylic acid using reagents with different oxidative strength, although 1 gave oxime 2 when treated with hydroxylamine, β-hydroxyketone 3 after addition of acetone, aldo-ε-lactone 4 whereby only the lactol was oxidized when using Jones reagent, and epoxyformate 5 after Baeyer-Villiger treatment. Hydrolysis of 5 with NaHCO3 gave 6. Structures 2-6 followed from physical and spectral data including X-ray diffraction. All compounds showed antiproliferative activity similar to some chemotherapeutic drugs against C2C12, L929, SiHa, and MDA-MB-231 cell lines. RESULTS AND DISCUSSIONDiterpenoid 1 was obtained in adequate amounts for the preparation of 2-6 from the aerial parts of A.schaffneri. 1 Nucleophilic addition of hydroxylamine to 1 gave 2 in 66% yield, while aldol condensation of 1 with acetone in basic medium led to β-hydroxyketone 3 in 43% yield. The corresponding 1 H NMR spectra did not evidence both syn and anti oximes for 2, nor the absolute configuration (AC) of C-17 in the case of 3. However, the anti oxime geometry in 2 and the (17S) AC in 3 followed from the X-ray diffraction (XRD) studies detailed below. Although 3 was not the only expected condensation product, the γ,δ-unsaturated carbonyl compound could not be obtained even when using large excesses of acetone and NaOH.