ABSTRACT
Type 2 diabetes mellitus (T2DM) is a complex disease characterized by impaired glucose homeostasis and serious long-term complications. First-line therapeutic options for T2DM treatment are monodrug therapies, often replaced by multidrug therapies to ensure that non-responding patients maintain target glycemia levels. The use of multitarget drugs instead of mono- or multidrug therapies has been emerging as a main strategy to treat multifactorial diseases, including T2DM. Therefore, modern drug discovery in its early stages aims to identify potential modulators for multiple targets; for this purpose, exploration of the chemical space of natural products represents a powerful tool. Our study demonstrates that avarone, a sesquiterpene quinone obtained from the sponge Dysidea avara, is capable of inhibiting in vitro PTP1B, the main negative regulator of the insulin receptor, while it improves insulin sensitivity, and mitochondria activity in C2C12 cells. We observe that when avarone is administered alone, it acts as an insulin-mimetic agent. In addition, we show that avarone acts as a tight binding inhibitor of aldose reductase (AKR1B1), the enzyme involved in the development of diabetic complications. Overall, avarone could be proposed as a novel natural hit to be developed as a multitarget drug for diabetes and its pathological complications.
ABSTRACT
The chemical analysis of the sponge Dysidea avara afforded the known sesquiterpene quinone avarone, along with its reduced form avarol. To further explore the role of the thiazinoquinone scaffold as an antiplasmodial, antileishmanial and antischistosomal agent, we converted the quinone avarone into the thiazinoquinone derivative thiazoavarone. The semisynthetic compound, as well as the natural metabolites avarone and avarol, were pharmacologically investigated in order to assess their antiparasitic properties against sexual and asexual stages of Plasmodium falciparum, larval and adult developmental stages of Schistosoma mansoni (eggs included), and also against promastigotes and amastigotes of Leishmania infantum and Leishmania tropica. Furthermore, in depth computational studies including density functional theory (DFT) calculations were performed. A toxic semiquinone radical species which can be produced starting both from quinone- and hydroquinone-based compounds could mediate the anti-parasitic effects of the tested compounds.
Subject(s)
Cyclohexenes/pharmacology , Leishmania/drug effects , Plasmodium falciparum/drug effects , Quinones/pharmacology , Schistosoma mansoni/drug effects , Sesquiterpenes/pharmacology , Thiazines/pharmacology , Animals , Antiparasitic Agents/pharmacology , Dysidea/chemistry , Leishmania infantum/drug effects , Leishmania tropica/drug effectsABSTRACT
Five known cycloartane-type glycosides were isolated from the roots of A. tmoleus Boiss. var. tmoleus. The identification of these compounds was mainly achieved by 1D and 2D NMR spectroscopic techniques and FABMS. The results of our studies confirm that triterpene saponins with the cycloartane-type skeleton might be chemotaxonomically significant for the genus Astragalus.
Subject(s)
Astragalus Plant/chemistry , Saponins/chemistry , Astragalus Plant/classification , Magnetic Resonance Spectroscopy , Plant Roots/chemistryABSTRACT
Two triterpenoid saponins with two known ones have been isolated from the roots of Gypsophila arrostii var. nebulosa, and two new ones from the roots of Gypsophila bicolor. Their structures were established by extensive NMR and mass spectroscopic techniques as 3-O-ß-d-galactopyranosyl-(1â2)-[ß-d-xylopyranosyl-(1â3)]-ß-d-glucuronopyranosylquillaic acid 28-O-ß-d-xylopyranosyl-(1â4)-[ß-d-glucopyranosyl-(1â3)]-α-l-rhamnopyranosyl-(1â2)-[ß-d-glucopyranosyl-(1â4)]-ß-d-fucopyranosyl ester (1), 3-O-ß-d-galactopyranosyl-(1â2)-[ß-d-xylopyranosyl-(1â3)]-ß-d-glucuronopyranosylgypsogenin 28-O-ß-d-xylopyranosyl-(1â4)-[ß-d-glucopyranosyl-(1â3)]-α-l-rhamnopyranosyl-(1â2)-[ß-d-glucopyranosyl-(1â4)]-ß-d-fucopyranosyl ester (2), 3-O-ß-d-galactopyranosyl-(1â2)-[ß-d-xylopyranosyl-(1â3)]-ß-d-glucuronopyranosylgypsogenin 28-O-ß-d-xylopyranosyl-(1â3)-ß-d-xylopyranosyl-(1â4)-α-l-rhamnopyranosyl-(1â2)-[(4-O-acetyl)-ß-d-quinovopyranosyl-(1â4)]-ß-d-fucopyranosyl ester (3), gypsogenic acid 28-O-ß-d-glucopyranosyl-(1â3)-{6-O-[3-hydroxy-3-methylglutaryl]-ß-d-glucopyranosyl-(1â6)}-ß-d-galactopyranosyl ester (4). Three compounds were evaluated against one human colon cancer cell line SW480 and one rat cardiomyoblast cell line H9c2.
Subject(s)
Antineoplastic Agents/pharmacology , Caryophyllaceae/chemistry , Plant Roots/chemistry , Saponins/pharmacology , Triterpenes/pharmacology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/isolation & purification , Cell Line , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Molecular Conformation , Rats , Saponins/chemistry , Saponins/isolation & purification , Species Specificity , Stereoisomerism , Structure-Activity Relationship , Triterpenes/chemistry , Triterpenes/isolation & purificationABSTRACT
Two novel secondary metabolites, compounds (1-2) were isolated from the roots of Paronychia chionaea. On the basis of spectroscopic data including 1D and 2D NMR experiments (COSY, TOCSY, HSQC, and HMBC), and mass spectroscopy, their structures were established as 6-C-[alpha-L-arabinopyranosyl-( 1 --> 2)-beta-D-glucopyranosyl]-7-O-[beta-D-glucopyranosyl]-luteolin 3'-methyl ether (1), and 2-(methoxy)-2-(3,5-dimethoxy 4-hydroxyphenyl)-ethane-1,2-diol 1-O-beta-D-glucopyranoside (2).
Subject(s)
Glycosides/isolation & purification , Paronychia/metabolism , Glycosides/chemistry , Magnetic Resonance Spectroscopy , Plant Roots/metabolismABSTRACT
Six new triterpene saponins, 3-O-alpha-L-rhamnopyranosyl-(1-->2)-beta-D-xylopyranosyl-(1-->2)-beta-D-glucuronopyranosyl-21-epi-kudzusapogenol A (1), 3-O-alpha-L-rhamnopyranosyl-(1-->2)-beta-D-glucopyranosyl-(1-->2)-beta-D-glucuronopyranosyl-21-epi-kudzusapogenol A (2), 3-O-alpha-L-rhamnopyranosyl-(1-->2)-beta-D-xylopyranosyl-(1-->2)-beta-D-glucuronopyranosyl-22-O-beta-D-glucopyranosyl-21-epi-kudzusapogenol A (3), 3-O-alpha-L-rhamnopyranosyl-(1-->2)-beta-D-glucopyranosyl-(1-->2)-beta-D-glucuronopyranosyl-22-O-beta-D-glucopyranosyl-21-epi-kudzusapogenol A (4), 3-O-alpha-L-rhamnopyranosyl-(1-->2)-beta-D-xylopyranosyl-(1-->2)-beta-D-glucuronopyranosyl-22-O-alpha-L-arabinopyranosyl-21-epi-kudzusapogenol A (5), and 3-O-alpha-L-rhamnopyranosyl-(1-->2)-beta-D-glucopyranosyl-(1-->2)-beta-D-glucuronopyranosyl-22-O-alpha-L-arabinopyranosyl-21-epi-kudzusapogenol A (6), were isolated from the roots of Astragalus flavescens, together with the known trajanoside B, azukisaponin V, and astragalosides IV, VII, and VIII. Their structures were established mainly by 2D NMR techniques and mass spectrometry.
Subject(s)
Astragalus Plant/chemistry , Plants, Medicinal/chemistry , Saponins/chemistry , Saponins/isolation & purification , Triterpenes/chemistry , Triterpenes/isolation & purification , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Plant Roots/chemistry , Stereoisomerism , TurkeyABSTRACT
Four new triterpenoid saponins, chionaeosides A-D (1-4) were isolated from the roots of Paronychia chionaea. On the basis of their spectroscopic data, the structures of the new saponins were established as 3-O-alpha-L-arabinopyranosylgypsogenic acid 28-O-beta-D-glucopyranosyl-(1-->3)-beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranoside (1), 3-O-alpha-L-arabinopyranosylgypsogenic acid 28-O-beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranoside (2), 3-O-alpha-L-arabinopyranosylgypsogenic acid 28-O-beta-D-glucopyranoside (3), and 3-O-alpha-L-arabinopyranosylgypsogenic acid (4).