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[This corrects the article DOI: 10.1021/acscentsci.9b01125.].
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Subtype selectivity and functional bias are vital in current drug discovery for G protein-coupled receptors (GPCRs) as selective and biased ligands are expected to yield drug leads with optimal on-target benefits and minimal side-effects. However, structure-based design and medicinal chemistry exploration remain challenging in part because of highly conserved binding pockets within subfamilies. Herein, we present an affinity mass spectrometry approach for screening herbal extracts to identify active ligands of a GPCR, the 5-HT2C receptor. Using this method, we discovered a naturally occurring aporphine 1857 that displayed strong selectivity for activating 5-HT2C without activating the 5-HT2A or 5-HT2B receptors. Remarkably, this novel ligand exhibited exclusive bias toward G protein signaling for which key residues were identified, and it showed comparable in vivo efficacy for food intake suppression and weight loss as the antiobesity drug, lorcaserin. Our study establishes an efficient approach to discovering novel GPCR ligands by exploring the largely untapped chemical space of natural products.
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Fourteen compounds, including rubiprasin D (1), rubiprasin B (2), rubiprasin C (3), oleanolic acid (4), methyl-5-hydroxy-dinaphtho[1, 2-2'3']furan-7, 12-dione-6-carboxylate (5), rubioncolin C (6), mollugin (7), furomollugin (8), 3-amino-2-methoxycarbonyl-1, 4-naphthoquinone (9), 1-hydroxy-2-methyl-9, 10-anthraquinone (10), 2-hydroxy-6-methyl-9, 10-anthraquinone (11), 1, 4-dihydroxy-2-hydroxymethyl-9, 10-anthraquinone (12), 2-hydroxy-1-methoxy-9, 10-anthraquinone (13), and 1-hydroxy-2-methoxy-6-methyl-9, 10-anthraquinone(14), were isolated from the methanol extract of the roots and rhizomes of Rubia oncotricha using various column chromatographies. Their structures were mainly determined on basis of NMR and MS spectroscopic data analyses. Among them, 1 is a new oleanane triterpene, and compounds 2-5, 9 and 11-13 were obtained from this plant for the first time. Cytotoxic and nematicidal activities of all these compounds were evaluated, and the results showed that only 4, 6, 11 and 12 exhibited cytotoxicities against A549, SGC-7901 and HeLa cancer cell lines. The IC50 of 6 were 19.42, 2.74, 8.07 µmol·L⻹, respectively.
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Naftoquinonas , Rubia , Estructura Molecular , Extractos Vegetales , Raíces de Plantas , RizomaRESUMEN
cGAS-STING signaling is essential for innate immunity. Its misregulation promotes cancer or autoimmune and autoinflammatory diseases, and it is imperative to identify effective lead compounds that specifically downregulate the pathway. We report here that astin C, a cyclopeptide isolated from the medicinal plant Aster tataricus, inhibits cGAS-STING signaling and the innate inflammatory responses triggered by cytosolic DNAs. Moreover, mice treated with astin C are more susceptible to HSV-1 infection. Consistently, astin C markedly attenuates the autoinflammatory responses in Trex1-/- BMDM cells and in Trex1-/- mouse autoimmune disease model. Mechanistically, astin C specifically blocks the recruitment of IRF3 onto the STING signalosome. Collectively, this study characterizes a STING-specific small-molecular inhibitor that may be applied for potentially manipulating the STING-mediated clinical diseases.
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Inmunidad Innata/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Nucleótidos/metabolismo , Péptidos Cíclicos/farmacología , Animales , Antiinfecciosos/metabolismo , Enfermedades Autoinmunes/tratamiento farmacológico , Citosol/metabolismo , ADN/metabolismo , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Células HEK293 , Herpesvirus Humano 1/efectos de los fármacos , Humanos , Inflamación/patología , Factor 3 Regulador del Interferón/metabolismo , Listeria monocytogenes/efectos de los fármacos , Masculino , Proteínas de la Membrana/química , Ratones , Ratones Endogámicos C57BL , Péptidos Cíclicos/química , Péptidos Cíclicos/uso terapéutico , Células RAW 264.7 , Transducción de SeñalRESUMEN
Four previously undescribed naphthohydroquinone dimers named rubipodanones A-D, together with 19 known quinones containing three known napthohydroquinone dimers named rubioncolin C, methyl 5-hydroxy-dinaphtho[1,2-2',3']furan-7,12-dione-6-carboxylate and rubialatin B, were isolated from the roots and rhizomes of Rubia podantha. Their structures and absolute configurations were determined mainly by NMR, X-ray diffraction, and computational methods. Rubipodanones C and D, the glycosides of rubipodanone A and a pair of C-3 epimer, are the first identified dimeric napthohydroquinone glycosides from the Rubia plants. All naphthohydroquinone dimers were evaluated for their cytotoxicities against ten tumor cell lines and effects on the tumor-associated NF-κB signaling pathway, and rubioncolin C showed the best cytotoxicity with IC50 value of 1.53 µM and NF-κB inhibitory activity with IC50 value of 2.97 µM. These results also demonstrated that the key roles of C-3 configuration and sugar group for biological activities of rubipodanone C.
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Antineoplásicos Fitogénicos/farmacología , Hidroquinonas/farmacología , Raíces de Plantas/química , Rubia/química , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Dimerización , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Hidroquinonas/química , Hidroquinonas/aislamiento & purificación , Estructura Molecular , FN-kappa B/antagonistas & inhibidores , FN-kappa B/metabolismo , Extractos Vegetales/química , Relación Estructura-ActividadRESUMEN
One new cyclic hexapeptide named rubipodanin A (1), which is the first identified natural N-desmonomethyl Rubiaceae-type cyclopeptide, together with six known Rubiaceae-type cyclopeptides (2-7) were obtained using the TLC cyclopeptide protosite detection method with ninhydrin from the roots and rhizomes of Rubia podantha. The cyclopeptide structures were elucidated by extensive spectroscopic analysis, including 1D-NMR, 2D-NMR, IR, UV and MS. The solution conformation and biological activities of 1 and RA-V (4) were evaluated, and the results demonstrated that the N9-methyl group plays a vital role in the maintenance of the conformation and bioactivity.
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Péptidos Cíclicos/química , Extractos Vegetales/química , Raíces de Plantas/química , Rubia/química , Línea Celular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células HEK293 , Células HeLa , Humanos , Estructura Molecular , Péptidos Cíclicos/farmacología , Extractos Vegetales/farmacologíaRESUMEN
Two novel naphthohydroquinone dimers with unprecedented skeletons, rubialatins A (1) and B (2), were isolated from the herbal plant Rubia alata together with their precursor, mollugin (3). The structures were elucidated on the basis of NMR spectra and crystal X-ray diffraction. Compound 1, a racemate, was separated by chiral column chromatography, and the absolute configurations of the enantiomers were determined by the computational methods. Cytotoxicity of 1-3 was evaluated as well as the effect on the NF-κB pathway. Compound (+)-1 showed cytotoxicity and could inhibit NF-κB pathway. Meanwhile, 2 showed cytotoxicity and a synergistic effect with TNF-α on NF-κB activation.
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Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Hidroquinonas/química , Hidroquinonas/farmacología , Hidroquinonas/toxicidad , FN-kappa B/química , FN-kappa B/efectos de los fármacos , Extractos Vegetales/química , Extractos Vegetales/farmacología , Raíces de Plantas/química , Piranos/química , Rubia/química , Factor de Necrosis Tumoral alfa/química , Factor de Necrosis Tumoral alfa/efectos de los fármacos , Línea Celular Tumoral , Humanos , Hidroquinonas/aislamiento & purificación , Espectroscopía de Resonancia Magnética , Estructura Molecular , Piranos/aislamiento & purificación , Estereoisomerismo , Factor de Necrosis Tumoral alfa/metabolismo , Difracción de Rayos XRESUMEN
Two new coumarins, clauexcavatins A (1) and B (2), along with seven known ones (3-9), were isolated from the roots of Clausena excavata Burm. f. (Rutaceae). Their structures were elucidated on the basis of spectral data.
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Clausena/química , Cumarinas/aislamiento & purificación , Medicamentos Herbarios Chinos/aislamiento & purificación , Carbazoles/química , Carbazoles/aislamiento & purificación , Cumarinas/química , Medicamentos Herbarios Chinos/química , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Raíces de Plantas/químicaRESUMEN
OBJECTIVE: To separate and identify cyclopeptides of tubers of Rubia schumanniana. METHOD: The 70% methanol extracts from tubers of Rubia schumanniana were separated and purified by silica gel, RP-18, Sephedax LH-20 and HPLC. Their structures were identified by spectral analysis. RESULT: Nine cyclopeptides were separated and identified as RA- II (1), RA-V (2), RA-VIII (3), rubiyunnanin C (4), RA-X (5), RY-II (6), RA- I (7), RA-XIII (8) and RA-XIII-OMe (9), respectively. CONCLUSION: All of nine cyclopeptides were separated from R. schumanniana for the first time.
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Medicamentos Herbarios Chinos/química , Péptidos Cíclicos/análisis , Rubia/química , Medicamentos Herbarios Chinos/aislamiento & purificación , Estructura Molecular , Péptidos Cíclicos/aislamiento & purificaciónRESUMEN
Twelve new arborinane-type triterpenoids (1-12) and four new anthraquinones (13-16), together with 50 known compounds, were isolated from the roots of Rubia yunnanensis. The structures of 1-16 were elucidated by spectroscopic data analysis and chemical methods. All compounds were evaluated for their cytotoxic, antibacterial, and antifungal activities. Rubiyunnanol C (5) is the first example of an arborinane-type triterpenoid with a double bond at C-8-C-9.