Sparteine sulfate

The identification of new natural products is a critical step in the discovery of lead compounds, and is a prerequisite for the development of novel pharmaceuticals. Traditional Chinese medicines (TCMs) are renowned for their diverse pharmacological activities, and represent a valuable source of novel chemicals. The quinolizidine alkaloids are abundant in plants of the Fabaceae family and exhibit significant bioactivities, including anticancer and anti-inflammatory effects. However, the structural diversity of quinolizidine alkaloids and the chemical complexity associated with TCMs pose great challenges in the discovery of novel quinolizidine alkaloids. In the present study, Sophora flavescens Ait. was used as a model to establish a comprehensive strategy for characterizing quinolizidine alkaloids. A simple and selective method was developed using an FC8HL column for the efficient enrichment of polar quinolizidine alkaloids. Through the integration of high-resolution multi-stage mass spectrometry and feature-based molecular networking, the enriched alkaloids were thoroughly characterized, including matrine-type, cystine-type, aloperine-type, anagyrine-type, lupinine-type, and dimeric species. A total of 186 quinolizidine alkaloids were identified, including 131 newly discovered compounds. A series of novel substituents was also identified for the first time. The findings of this study not only deepen our understanding of the structural diversity of quinolizidine alkaloids, but they also offer a novel research strategy for the comprehensive characterization of quinolizidine alkaloids in other plants, potentially facilitating the discovery of new drug candidates.

Excessive aldose reductase activity drives the polyol-pathway damage that underlies diabetic cataract, neuropathy and nephropathy, yet few safe, potent AR inhibitors have reached the clinic. Here we integrated virtual screening, atomistic simulation and enzymology to evaluate six natural alkaloids-calycanthine, rutaecarpine, glaucine, sparteine, berbamine and tetrandrine-as prospective AR antagonists. A 2500-compound AutoDock Vina screen singled out these scaffolds for high predicted affinity (≤ - 7.0 kcal mol^-1), chemotype diversity and favorable in silico developability. Docking located all ligands within the catalytic cleft; 200-ns MD trajectories plus free-energy landscapes revealed that rutaecarpine and the bis-benzylisoquinolines tetrandrine and berbamine clamp the anion-binding and specificity pockets simultaneously, collapsing conformational space into a single deep basin. MM/PBSA analysis ranked tetrandrine highest (ΔG_total = -35.8 ± 2.5 kcal mol^-1) followed by rutaecarpine (-23.0 ± 1.3 kcal mol^-1) and berbamine (-19.4 ± 2.7 kcal mol^-1); per-residue decomposition highlighted Phe122, Trp219 and Leu300 as recurring hot-spots. In vitro, the same hierarchy emerged: tetrandrine inhibited recombinant human AR with an IC₅₀ of 1.56 ± 0.23 μM, outperforming quercetin (2.37 ± 0.27 μM), while rutaecarpine and berbamine yielded IC₅₀ values of 4.84 ± 0.81 and 7.35 ± 0.78 μM, respectively. Lineweaver-Burk and Michaelis-Menten plots demonstrated non-competitive inhibition, aligning with the MD-inferred pocket-clamping mechanism. ADMET profiling identified rutaecarpine as the most balanced lead (Lipinski-compliant, moderate hERG/CYP risk), whereas tetrandrine's hERG liability and low solubility call for scaffold refinement. This study validates bis-benzylisoquinoline and indolo-quinazolinone frameworks as privileged AR inhibitory chemotypes and showcases an end-to-end computational-experimental pipeline that rapidly converts ethnopharmacological molecules into mechanistically characterized leads for managing diabetic complications.