Natural Phosphodiesterase-4 Inhibitors with Potential Anti-Inflammatory Activities from Millettia dielsiana.

The results of in silico screening of the 50 isolated compounds from Millettia dielsiana against the target proteins PDE4 (PDE4A, PDE4B, and PDE4D) showed binding affinity ranges from -5.81 to -11.56, -5.27 to -13.01, and -5.80 to -12.12 kcal mol-1, respectively, with median values of -8.83, -8.84, and -8.645 kcal mol-1, respectively. Among these compounds, Millesianin F was identified as the most promising PDE4A inhibitor due to its strongest binding affinity with the target protein PDE4A. (-11.56 kcal mol-1). This was followed by the compound 5,7,4'-trihydroxyisoflavone 7-O-ß-d-apiofuranosyl-(1→6)-ß-d-glucopyranoside (D50) with the binding affinity value of -11.35 kcal mol-1. For the target protein PDE4B, compound D50 exhibited the strongest binding affinity value of -13.01 kcal mol-1, while showing poorer inhibition ability for PDE4D. The 100 ns MD simulation examination (radius of gyration, Solvent Accessible Surface Area (SASA), Root-Mean-Square Deviation (RMSD), Root-Mean-Square Fluctuation (RMSF), and hydrogen bonding) was carried out to examine the overall stability and binding efficiency of the protein-ligand complex between compounds (Millesianin F, Millesianin G, Claclrastin-7-O-ß-d-glucopyranoside, 7-hydroxy-4',6 dimethoxyisoflavone-7-O-ß-d-apiofuranosyl-(1→6)-ß-d-glucopyranoside, 7-hydroxy-4',8-dimethoxyisoflavone 7-O-ß-d-apiofuranosyl-(1→6)-ß-d-glucopyranoside, Odoratin-7-O-ß-d-glucopyranoside, and 5,7,4'-trihydroxyisoflavone 7-O-ß-d-apiofuranosyl-(1→6)-ß-d-glucopyranoside) and PDE4 (A, B) subtype proteins. Compound D50 has shown strong anti-inflammatory activity, as evidenced by experimental results. It effectively inhibits PDE4B and PDE4D, with IC50 values of 6.56 ± 0.7 µM and 11.74 ± 1.3 µM, respectively. Additionally, it reduces NO production, with an IC50 value of 5.40 ± 0.9 µM. Based on these findings, it is promising and considered a potential novel anti-inflammatory drug for future development.

Hepatoprotective Effect of Millettia dielsiana: In Vitro and In Silico Study.

In silico docking studies of 50 selected compounds from Millettia dielsiana Harms ex Diels (family Leguminosae) were docked into the binding pocket of the PI3K/mTOR protein. In there, compounds trans-3-O-p-hydroxycinnamoyl ursolic acid (1) and 5,7,4'-trihydroxyisoflavone 7-O-ß-D-apiofuranosyl-(1→6)-ß-D-glucopyranoside (2) are predicted to be very promising inhibitors against PI3K/mTOR. They direct their cytotoxic activity against Hepatocellular carcinoma with binding affinity (BA) values, the pulling work spent to the co-crystallized ligand from the binding site of PI3K/mTOR (W and Fmax), and the non-equilibrium binding free energy (∆GneqJar) as BA values = -9.237 and -9.083 kcal/mol, W = 83.5 ± 10.6 kcal/mol with Fmax = 336.2 ± 45.3 pN and 126.6 ± 21.7 kcal/mol with Fmax = 430.3 ± 84.0 pN, and ∆GneqJar = -69.86074 and -101.2317 kcal/mol, respectively. In molecular dynamic simulation, the RMSD value of the PI3K/mTOR complex with compounds (1 and 2) was in the range of 0.3 nm to the end of the simulation. Therefore, the compounds (1 and 2) are predicted to be very promising inhibitors against PI3K/mTOR. The crude extract, ethyl acetate fraction and compounds (1 and 2) from Millettia dielsiana exhibited moderate to potent in vitro cytotoxicity on Hepatocellular carcinoma cell line with IC50 values of 81.2 µg/mL, 60.4 µg/mL, 23.1 µM, and 16.3 µM, respectively, and showed relatively potent to potent in vitro antioxidant activity on mouse hepatocytes with ED50 values of 24.4 µg/mL, 19.3 µg/mL, 30.7 µM, and 20.5 µM, respectively. In conclusion, Millettia dielsiana and compounds (1 and 2) are predicted to have very promising cytotoxic activity against Hepatocellular carcinoma and have a hepatoprotective effect.

Two new terpenoids from the leaves of callicarpa macrophylla.

Two new terpenoids (1-2) and seven known compounds (3-9) were isolated from methanol extract of Callicarpa macrophylla leaves. Their structures were determined to be ent-7α,16ß,17,18-tetrahydroxykaur-15-one (1), 3ß-acetoxy-urs-12-ene-11-one-12-ol (2), ent-1ß-acetoxy-7α,14ß-dihydroxykaur-16-en-15-one (3), 3ß-acetoxy-11α,13ß-dihydroxyolean-12-one (4), ß-amyrin (5), spinasterol (6), ursolic acid (7), ß-sitosterol (8), and daucosterol (9) by analyses of their MS, NMR spectroscopic data and by comparison with those reported in the literature. Compounds 1 - 4, and 7 displayed potential cytotoxic activity towards HepG-2, LU-1, and MCF-7 human cancer cell lines with IC50 values ranging from 0.46 ± 0.21 to 18.14 ± 0.33 µM. Compound 6 showed IC50 values of 14.17 ± 0.21 and 5.72 ± 0.42 µM against Hep-G2 and MCF-7 cell lines, respectively.