ABSTRACT
Salvia przewalskii Maxim is a perennial plant from the genus Salvia (family Lamiaceae). The roots of S. przewalskii were long used as a traditional herb to treat blood circulation related illnesses in China. As part of our continuing interest in polycyclic natural products from medicinal plants, two unprecedented adducts comprised of a dinor-diterpenoid and a 9'-nor-rosmarinic acid derivative, linked by a 1,4-benzodioxane motif (1 and 2), were isolated from the roots of S. przewalskii. Their structures were established by extensive spectroscopic approaches including 1D, 2D NMR, and HRFABMS. Their cytotoxic activities against five human tumor cell lines were evaluated.
Subject(s)
Cinnamates/analysis , Depsides/analysis , Diterpenes/analysis , Salvia/chemistry , Antineoplastic Agents, Phytogenic/analysis , Antineoplastic Agents, Phytogenic/pharmacology , Cell Line, Tumor , Cinnamates/pharmacology , Depsides/pharmacology , Diterpenes/pharmacology , Humans , Neoplasms/drug therapy , Plant Roots/chemistry , Plants, Medicinal/chemistry , Rosmarinic AcidABSTRACT
This work describes the rational discovery of novel chemotypes of p38α MAPK inhibitors using a funnel approach consisting of several computer-aided drug discovery methods and biological experiments. Among the identified hits, four compounds belonging to different chemical families showed IC50 values lower than 10⯵M. In particular, the 1,4-benzodioxane derivative 5 turned out to be a potent and efficient p38α MAPK inhibitor having IC50â¯=â¯0.07⯵M, and LEexp and LipE values of 0.38 and 4.8, respectively; noteworthy, the compound had also a promising kinase selectivity profile and the capability to suppress p38α MAPK effects in human immune cells. Overall, the collected findings highlight that the applied strategy has been successful in generating chemical novelty in the inhibitor kinase field, providing suitable chemical candidates for further inhibitor optimization.
Subject(s)
Drug Discovery , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Healthy Volunteers , Humans , Mitogen-Activated Protein Kinase 14/metabolism , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
Phytoestrogens derived from plants have attracted the attention of the general public and the medical community due to their potentially beneficial role in relieving menopausal symptoms. The deciduous tree Acer tegmentosum Maxim (Aceraceae) has long been utilized in Korean folk medicine to alleviate many physiological disorders, including abscesses, surgical bleeding, and liver diseases. In order to explore structurally and/or biologically new constituents from Korean medicinal plants, a comprehensive phytochemical study was carried out on the bark of A. tegmentosum. One new phenolic compound with a 1,4-benzodioxane scaffold, isoamericanoic acid B (1), as well as with nine known phenolic compounds (2â»10), were successfully isolated from the aqueous extracts of the bark of A. tegmentosum. A detailed analysis using 1D and 2D NMR spectroscopy, electronic circular dichroism (ECD) spectral data, and LC/MS afforded the unambiguous structural determination of all isolated compounds, including the new compound 1. In addition, compounds 2, 4, 5, and 9 were isolated and identified from the bark of A. tegmentosum for the first time. All isolated compounds were tested for their estrogenic activities using an MCF-7 BUS cell proliferation assay, which revealed that compounds 1, 2, and 10 showed moderate estrogenic activity. To study the mechanism of this estrogenic effect, a docking simulation of compound 1, which showed the best estrogenic activity, was conducted with estrogen receptor (ER) -α and ER-ß, which revealed that it interacts with the key residues of ER-α and ER-ß. In addition, compound 1 had slightly higher affinity for ER-ß than ER-α in the calculated Gibbs free energy for 1:ER-α and 1:ER-ß. Thus, the present experimental evidence demonstrated that active compound 1 from A. tegmentosum could be a promising phytoestrogen for the development of natural estrogen supplements.
Subject(s)
Acer/chemistry , Dioxanes/chemistry , Phenols/chemistry , Phytoestrogens/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dioxanes/isolation & purification , Dioxanes/metabolism , Dioxanes/pharmacology , Humans , Molecular Docking Simulation , Phenols/isolation & purification , Phenols/metabolism , Phenols/pharmacology , Phytoestrogens/isolation & purification , Phytoestrogens/metabolism , Phytoestrogens/pharmacology , Plant Bark/chemistry , Plant Extracts/chemistry , Protein Binding , Receptors, Estrogen/chemistry , Receptors, Estrogen/metabolismABSTRACT
The active fraction from the EtOH extract of Hyptis rhomboides against xanthine oxidase was identified by use of an HPLC microfractionation-centrifugal vacuum evaporation-bioassay hyphenated technique. Scale-up separation of the active subfractions using semi-preparative RP-HPLC provided 13 phenylpropanoid compounds, including O-styrenylneolignans, hyprhombins A-C, epihyprhombin B, and hyprhombin B methyl ester, and O-caffeoylnorneolignans, hyprhombins D and E. All of these compounds shared a common 1,4-benzodioxane skeleton, as established by spectroscopic analyses. Hyprhombin C and epihyprhombin B exhibited better anti-xanthine oxidase activity than allopurinol, with IC50 values of 0.6 and 2.0 µM, respectively.