ABSTRACT
Coumestan represents a biologically relevant structural motif distributed in a number of natural products, and the rapid construction of related derivatives as well as the characterization of targets would accelerate lead compound discovery in medicinal chemistry. In this work, a general and scalable approach to 8,9-dihydroxycoumestans via two-electrode constant current electrolysis was developed. The application of a two-phase (aqueous/organic) system plays a crucial role for success, protecting the sensitive o-benzoquinone intermediates from over-oxidation. Based on the structurally diverse products, a primary SAR study on coumestan scaffold was completed, and compound 3 r exhibited potent antiproliferative activities and a robust topoisomerase I (Top1) inhibitory activity. Further mechanism studies demonstrates that compound 3 r was a novel Top1 poison, which might open an avenue for the development of Top1-targeted antitumor agent.
Subject(s)
Antineoplastic Agents , Coumarins , DNA Topoisomerases, Type I , Topoisomerase I Inhibitors , Topoisomerase I Inhibitors/chemistry , Topoisomerase I Inhibitors/pharmacology , Topoisomerase I Inhibitors/chemical synthesis , DNA Topoisomerases, Type I/metabolism , DNA Topoisomerases, Type I/chemistry , Humans , Structure-Activity Relationship , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Coumarins/chemistry , Coumarins/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Oxidation-Reduction , Umbelliferones/chemistry , Umbelliferones/pharmacology , Drug Screening Assays, AntitumorABSTRACT
A new coumestan named 7,5'-dihydroxy-4'-(3''-hydroxy-3''-methyl-trans-isobut-1''-enyl) coumestan (1), together with five known compounds (2-6), was isolated from the EtOAc-soluble extract of the stems of Acanthopanax senticosus. Their structures were elucidated based on extensive spectroscopic analyses. All the isolates were evaluated for in vitro cytotoxic activities against four human cancer cells including HepG2, A549, HeLa and MCF-7. Among them, the new compound 1 was found to exhibit significant cytotoxic activity on HeLa cells with IC50 value of 6.5 µM.
Subject(s)
Antineoplastic Agents , Eleutherococcus , Eleutherococcus/chemistry , HeLa Cells , Humans , Molecular Structure , Plant Extracts/chemistryABSTRACT
PURPOSE: Cisplatin resistance is a major concern in ovarian cancer treatment. The aim of this study was to investigate if wedelolactone could perform better in resistant ovarian cancer cells when used in combination with cisplatin. METHODS: Growth inhibitory potential of wedelolactone and cisplatin was investigated through MTT reduction assay in ovarian cancer cell lines including A2780 (sensitive), A2780cisR (cisplatin resistant) and A2780ZD0473R. Resistance factor (RF) of drugs was determined in these three cell lines. Combination index (CI) was calculated as a measure of combined drug action. Effect of this combination on changes in the cellular accumulation of platinum levels and platinum-DNA binding was also determined in vitro using AutoDock Vina while the effect of wedelolactone on inhibition of possible key culprits of resistance including Chk1, CD73, AT tip60, Nrf2, Brd1, PCAF, IGF1, mTOR1 and HIF2α was investigated in silico. RESULTS: Cisplatin and wedelolactone showed a dose-dependent growth inhibitory effect. RF value of wedelolactone was 1.1 in the case of A2780cisR showing its potential to bring more cell death in cisplatin-resistant cells. CI values were found to vary showing antagonistic to additive outcomes. Additive effect was observed for all sequences of administration (0/0, 0/4 and 4/0 h) in A2780cisR. Enhanced cellular accumulation of cisplatin was observed in parent and resistant cells on combination. Docking results revealed that among the selected oncotargets, Chk1, CD73, Nrf2, PCAF and AT tip60 were more vulnerable to wedelolactone than their respective standard inhibitors. CONCLUSION: These findings have shown that additive outcome of drug combination in A2780cisR and raised levels of platinum accumulation followed a clear pattern. This observation indicates that the presence of wedelolactone might have contributed to sensitize A2780cisR. However, in silico results point to the possible effects of this compound on epigenetic factors involving tumor microenvironment, epithelial mesenchymal transition, and immune-checkpoint kinases.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Cisplatin/pharmacology , Coumarins/pharmacology , Epigenesis, Genetic/drug effects , Ovarian Neoplasms/drug therapy , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Resistance, Neoplasm/drug effects , Drug Screening Assays, Antitumor , Female , Humans , Molecular Docking Simulation , Ovarian Neoplasms/pathologyABSTRACT
Naturally occurring coumestans are known as a collection of plant-derived polycyclic aromatic secondary metabolites which are characterized by the presence of an oxygen heterocyclic four-ring system comprising a coumarin moiety and a benzofuran moiety sharing a CËC bond. Recently, there is an increasing attention in excavating the medicinal potential of coumestans, particularly coumestrol, wedelolactone, psoralidin and glycyrol, in a variety of diseases. This review is a comprehensive inventory of the chemical structures of coumestans isolated from various plant sources during the period of 1956-2020, together with their reported biological activities. 120 molecules were collected and further classified as coumestans containing core skeleton, dimethylpyranocoumestans, furanocoumestans, O-glycosylated coumestans and others, which showed a wide range of pharmacological activities including estrogenic, anti-cancer, anti-inflammatory, anti-osteoporotic, organ protective, neuroprotective, anti-diabetic and anti-obesity, antimicrobial, immunosuppressive, antioxidant and skin-protective activities. Furthermore, this review focuses on the counteraction of coumestans against bone diseases and organ damages, and the involved molecular mechanisms, which could provide important information to better understand the medicinal values of these compounds. This review is intended to be instructive for the rational design and development of less toxic and more effective drugs with a coumestan scaffold.
Subject(s)
Coumarins/therapeutic use , Animals , Coumarins/adverse effects , Coumarins/isolation & purification , Coumarins/pharmacology , Humans , Molecular Structure , Phytochemicals/adverse effects , Phytochemicals/isolation & purification , Phytochemicals/pharmacology , Phytochemicals/therapeutic use , Structure-Activity RelationshipABSTRACT
A new prenylated coumestan, campylohirtin A (1), along with fifteen phenolic known compounds (2â16) and four other known compounds (17â20), was obtained from the 95% ethanol extract of roots of Campylotropis hirtella. Their structures were elucidated based on extensive spectroscopic analysis (1 D and 2 D-NMR, MS, UV and IR). In vitro antimalarial activities of compounds 1-3, 5-14 and 16 were evaluated by ß-hematin formation inhibition assay. Compared with the positive control chloroquine diphosphate, compounds 8, 11 and 16 exhibited strong antimalarial activity with the IC50 values of 69.9, 33.2 and 75.4 µM, respectively. Compounds 1-3, 5-7 and 12 showed moderate antimalarial activities with IC50 values ranging from 134.6 µM to 578.6 µM.[Formula: see text].
Subject(s)
Chrysobalanaceae , Fabaceae , Coumarins , Molecular Structure , Plant RootsABSTRACT
Glycine tabacina (Labill.) Benth is an edible medicinal herb for rheumatoid arthritis (RA) treatment in folk medicine. Current phytochemical research on this dried herb led to the isolation of eight new coumestans, named glytabastan A-H (1-8), and twenty-three known compounds 9-31. Their structures were elucidated using spectroscopic methods. The antiarthritic activities of all isolates were evaluated, and the results showed that coumestans 1-6 and 8-10 could inhibit arthritic inflammation in vitro, while coumestans 1, 2, 9, and 10 significantly blocked the osteoclastogenesis induced by receptor activator of nuclear factor (NF) κB ligand (RANKL). Moreover, network pharmacological analysis revealed that the anti-RA effect of G. tabacina involved multitargets, multipathways such as PI3K/Akt and MAPK signaling pathways, and various biological processes such as inflammatory response and cytokine-mediated signaling pathways. These results suggested that this species and its novel coumestans could serve as potential antiarthritic agents for functional food or medicinal use.
Subject(s)
Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/pharmacology , Fabaceae/chemistry , Animals , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/genetics , Arthritis, Rheumatoid/immunology , Arthritis, Rheumatoid/physiopathology , Drugs, Chinese Herbal/isolation & purification , Humans , MAP Kinase Signaling System/drug effects , Macrophages/drug effects , Macrophages/immunology , Mice , Osteoclasts/cytology , Osteoclasts/drug effects , Osteoclasts/immunology , Osteogenesis/drug effects , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/immunology , RANK Ligand/genetics , RANK Ligand/immunology , RAW 264.7 Cells , Synovial Membrane/drug effects , Synovial Membrane/immunologyABSTRACT
A new coumestan named bavacoumestan D (1), together with five known compounds (2-6), was isolated from EtOAc-soluble extract of seeds of Psoralea corylifolia. Their structures were elucidated on the basis of spectroscopic and physico-chemical analyses. All compounds were evaluated for in vitro inhibitory activity against DGAT1, DGAT2 and α-glucosidase. Among them, compounds 1-2, 5-6 showed potential inhibitory activity on DGAT1 with IC50 values ranging from 52.3 ± 1.3 to 81.0 ± 1.0 µM. Compounds 1-3, 6 displayed the significant inhibitory activity on α-glucosidase with IC50 values ranging from 31.2 to 89.1 µM.[Formula: see text].
Subject(s)
Psoralea , Coumarins , Molecular Structure , SeedsABSTRACT
Concerns pertaining to the risk of estrogen exposure through HT have prompted an increase in the use of natural alternatives. Phytoestrogens may provide postmenopausal women with a practical alternative and many women have already begun to utilize phytoestrogen supplements. However, research regarding the efficacy of phytoestrogens as a hormone therapy alternative has been previously pessimistic or questionable at best. This review scrutinizes the most current research regarding the efficacy of three types of phytoestrogens, isoflavones, lignans and coumestans, and their specific effect on the reduction of climacteric symptoms, specifically vasomotor symptoms, vaginal atrophy, insomnia and osteoporosis. A discussion of the research pertaining to the relative safety of each phytoestrogen in terms of breast and endometrial health is also included. Overall, current research demonstrates that phytoestrogens are effective in reducing the intensity of hot flushes, and some phytoestrogen combinations result in a decreased frequency. Certain phytoestrogens have also been shown to decrease vaginal atrophy, improve sleep and cognition, and positively affect bone health. Even though initial research was generally unconvincing, the more recent evidence reviewed here is rather positive. In terms of safety and reports of adverse reactions, trials have not shown an increase in breast cancer risk or increase in endometrial hyperplasia following phytoestrogen use, but trials explicitly designed to find neoplasia have not been reported. Moreover, unlike hormone therapy, lignans may not increase clotting risk in postmenopausal women, thus supplements may serve as a treatment option for patients who have contraindications to hormone therapy. Phytoestrogens may provide a safe and partially effective alternative to HT. However, because research regarding phytoestrogens is relatively new, pharmaco-vigilence is still required, as these products are not yet FDA-approved. This article is part of a Special Issue entitled 'Phytoestrogens'.