Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 109
Filtrar
Más filtros

País/Región como asunto
Tipo del documento
Intervalo de año de publicación
1.
J Am Chem Soc ; 146(9): 6189-6198, 2024 03 06.
Artículo en Inglés | MEDLINE | ID: mdl-38386630

RESUMEN

Polyketides with the isochroman-3-one pharmacophore are rare among fungal natural products as their biosynthesis requires an unorthodox S-type aromatic ring cyclization. Genome mining uncovered a conserved gene cluster in select leotiomycetous fungi that encodes the biosynthesis of cytosporones, including isochroman-3-one congeners. Combinatorial biosynthesis in total biosynthetic and biocatalytic formats in Saccharomyces cerevisiae and in vitro reconstitution of key reactions with purified enzymes revealed how cytosporone structural and bioactivity diversity is generated. The S-type acyl dihydroxyphenylacetic acid (ADA) core of cytosporones is assembled by a collaborating polyketide synthase pair. Thioesterase domain-catalyzed transesterification releases ADA esters, some of which are known Nur77 modulators. Alternatively, hydrolytic release allows C6 hydroxylation by a flavin-dependent monooxygenase, yielding a trihydroxybenzene moiety. Reduction of the C9 carbonyl by a short chain dehydrogenase/reductase initiates isochroman-3-one formation, affording cytosporones with cytotoxic and antimicrobial activity. Enoyl di- or trihydroxyphenylacetic acids are generated as shunt products, while isocroman-3,4-diones are formed by autoxidation. The cytosporone pathway offers novel polyketide biosynthetic enzymes for combinatorial synthetic biology to advance the production of "unnatural" natural products for drug discovery.


Asunto(s)
Productos Biológicos , Policétidos , Hongos/genética , Saccharomyces cerevisiae/metabolismo , Sintasas Poliquetidas/metabolismo , Policétidos/química , Productos Biológicos/metabolismo
2.
J Nat Prod ; 87(3): 583-590, 2024 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-38414352

RESUMEN

Treatment of 27-O-acetylwithaferin A (2) with the non-nucleophilic base, 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU), afforded 5ß,6ß-epoxy-4ß-hydroxy-1-oxo-witha-2(3),23(24),25(27)-trienolide (3) and 4, a homodimer of withaferin A resulting from a Diels-Alder [4 + 2] type cycloaddition of the intermediate α,ß-dimethylene-δ-lactone (9). Structures of 3 and 4 were elucidated using HRMS and 1D and 2D NMR spectroscopic data. The structure of 4 was also confirmed by single crystal X-ray crystallographic analysis of its bis-4-O-p-nitrobenzoate (8). Formation of withaferin A homodimer (4) as the major product suggests regio- and stereoselectivity of the Diels-Alder [4 + 2] cycloaddition reaction of 9. Acetylation of 2-4 afforded their acetyl derivatives 5-7, respectively. Compounds 2-4 and 6-8 were evaluated for their cytotoxic activities against four prostate cancer (PC) cell lines (LNCaP, 22Rv1, DU-145, and PC-3) and normal human foreskin fibroblast (HFF) cells. Significantly, 4 exhibited improved activity compared to the other compounds for most of the tested cell lines.


Asunto(s)
Ácido Acético , Witanólidos , Masculino , Humanos , Reacción de Cicloadición , Witanólidos/farmacología , Witanólidos/química , Espectroscopía de Resonancia Magnética , Estructura Molecular
3.
Molecules ; 27(3)2022 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-35164184

RESUMEN

Withanolides constitute one of the most interesting classes of natural products due to their diversity of structures and biological activities. Our recent studies on withanolides obtained from plants of Solanaceae including Withania somnifera and a number of Physalis species grown under environmentally controlled aeroponic conditions suggested that this technique is a convenient, reproducible, and superior method for their production and structural diversification. Investigation of aeroponically grown Physalis coztomatl afforded 29 withanolides compared to a total of 13 obtained previously from the wild-crafted plant and included 12 new withanolides, physacoztolides I-M (9-13), 15α-acetoxy-28-hydroxyphysachenolide C (14), 28-oxophysachenolide C (15), and 28-hydroxyphysachenolide C (16), 5α-chloro-6ß-hydroxy-5,6-dihydrophysachenolide D (17), 15α-acetoxy-5α-chloro-6ß-hydroxy-5,6-dihydrophysachenolide D (18), 28-hydroxy-5α-chloro-6ß-hydroxy-5,6-dihydrophysachenolide D (19), physachenolide A-5-methyl ether (20), and 17 known withanolides 3-5, 8, and 21-33. The structures of 9-20 were elucidated by the analysis of their spectroscopic data and the known withanolides 3-5, 8, and 21-33 were identified by comparison of their spectroscopic data with those reported. Evaluation against a panel of prostate cancer (LNCaP, VCaP, DU-145, and PC-3) and renal carcinoma (ACHN) cell lines, and normal human foreskin fibroblast (WI-38) cells revealed that 8, 13, 15, and 17-19 had potent and selective activity for prostate cancer cell lines. Facile conversion of the 5,6-chlorohydrin 17 to its 5,6-epoxide 8 in cell culture medium used for the bioassay suggested that the cytotoxic activities observed for 17-19 may be due to in situ formation of their corresponding 5ß,6ß-epoxides, 8, 27, and 28.


Asunto(s)
Antineoplásicos Fitogénicos/metabolismo , Antineoplásicos Fitogénicos/farmacología , Physalis/crecimiento & desarrollo , Witanólidos/metabolismo , Witanólidos/farmacología , Antineoplásicos Fitogénicos/química , Vías Biosintéticas , Biotecnología , Línea Celular Tumoral , Humanos , Masculino , Physalis/química , Physalis/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Witanólidos/química
4.
J Nat Prod ; 84(8): 2321-2335, 2021 08 27.
Artículo en Inglés | MEDLINE | ID: mdl-34445874

RESUMEN

Multiple myeloma (MM) is a hematological cancer in which relapse and resistance are highly frequent. Therefore, alternatives to conventional treatments are necessary. Withaferin A, a withanolide isolated from Withania somnifera, has previously shown promising activity against various MM models. In the present study, structure-activity relationships (SARs) were evaluated using 56 withanolides. The antiproliferative activity was assessed in three MM cell lines and in a 3D MM coculture model to understand the in vitro activity of compounds in models of various complexity. While the results obtained in 2D allowed a quick and simple evaluation of cytotoxicity used for a first selection, the use of the 3D MM coculture model allowed filtering compounds that perform better in a more complex setup. This study shows the importance of the last model as a bridge between 2D and in vivo studies to select the most active compounds and ultimately lead to a reduction of animal use for more sustained in vivo studies. NF-κB inhibition was determined to evaluate if this could be one of the targeted pathways. The most active compounds, withanolide D (2) and 38, should be further evaluated in vivo.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Mieloma Múltiple/tratamiento farmacológico , Witanólidos/farmacología , Antineoplásicos Fitogénicos/química , Línea Celular Tumoral , Técnicas de Cocultivo , Humanos , Estructura Molecular , Relación Estructura-Actividad , Withania/química , Witanólidos/química
5.
J Nat Prod ; 84(2): 187-194, 2021 02 26.
Artículo en Inglés | MEDLINE | ID: mdl-33586438

RESUMEN

Aeroponically grown Physalis acutifolia afforded five new and six known withanolides including 10 physalins. The structures of the new withanolides, acutifolactone (1), 5ß,6ß-epoxyphysalin C (2), 5α-chloro-6ß-hydroxyphysalin C (3), and an inseparable mixture of 5ß,6ß-epoxy-2,3-dihydrophysalin F-3ß-O-sulfate (4) and 5ß,6ß-epoxy-2,3-dihydrophysalin C-3ß-O-sulfate (5), were elucidated by analysis of their spectroscopic data and chemical interconversions. The known withanolides were identified as physalins B (6), D (7), F (8), H (9), I (10), and U (11) by comparison of their spectroscopic data with those reported. Evaluation of 1-11 and the derivatives, 13 and 13a, obtained from 4 and 5 against a panel of four human cancer cell lines [NCI-H460 (non-small-cell lung), SF-268 (CNS glioma), PC-3 (prostate adenocarcinoma), and MCF-7 (breast adenocarcinoma)] and normal human lung fibroblast (WI-38) cells revealed that physalins 2, 3, 8, and 9 exhibited selective cytotoxic activity to at least one of the cancer cell lines tested compared to the normal cells and that 7, 10, and 11 were inactive up to a concentration of 10.0 µM. These data provided some preliminary structure-activity relationships and suggested that the mechanism of cytotoxic activity of physalins may differ from other classes of withanolides.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Physalis/química , Witanólidos/farmacología , Antineoplásicos Fitogénicos/aislamiento & purificación , Arizona , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Fitoquímicos/aislamiento & purificación , Fitoquímicos/farmacología , Relación Estructura-Actividad , Witanólidos/aislamiento & purificación
6.
J Nat Prod ; 84(12): 3029-3038, 2021 12 24.
Artículo en Inglés | MEDLINE | ID: mdl-34851111

RESUMEN

Physachenolide C (1) is a 17ß-hydroxywithanolide natural product with a unique anticancer potential, as it exhibits potent and selective in vitro antiproliferative activity against prostate cancer (PC) cells and promotes TRAIL-induced apoptosis of renal carcinoma (RC) and poly I:C-induced apoptosis of melanoma cells. To explore the effect of ring A/B modifications of physachenolide C (1) on these biological activities, 23 of its natural and semisynthetic analogues were evaluated. Analogues 4-23 were prepared by chemical transformations of a readily accessible compound, physachenolide D (2). Compound 1 and its analogues 2-23 were evaluated for their antiproliferative activity against PC (LNCaP and 22Rv1), RC (ACHN), and melanoma (M14 and SK-MEL-28) cell lines and normal human foreskin fibroblast (HFF) cells. Most of the active analogues had selective and potent activity in reducing cell number for PC cell lines, some showing selectivity for androgen-independent and enzalutamide-resistant 22Rv1 cells compared to androgen-dependent LNCaP cells. Analogues with IC50s below 5.0 µM against ACHN cells, when tested in the presence of TRAIL, showed a significantly increased ability to reduce cell number, and those analogues active against the M14 and SK-MEL-28 cell lines exhibited enhanced activity when combined with poly I:C. These data provide additional structure-activity relationship information for 17ß-hydroxywithanolides and suggest that selective activities of some analogues may be exploited to develop natural products-based tumor-specific agents for cancer chemotherapy.


Asunto(s)
Antineoplásicos/uso terapéutico , Proliferación Celular/efectos de los fármacos , Inmunoterapia , Neoplasias Renales/terapia , Melanoma/terapia , Neoplasias de la Próstata/tratamiento farmacológico , Witanólidos/uso terapéutico , Humanos , Masculino , Neoplasias de la Próstata/patología , Witanólidos/química
7.
Proc Natl Acad Sci U S A ; 115(22): E4980-E4989, 2018 05 29.
Artículo en Inglés | MEDLINE | ID: mdl-29760061

RESUMEN

Glycosylation is a prominent strategy to optimize the pharmacokinetic and pharmacodynamic properties of drug-like small-molecule scaffolds by modulating their solubility, stability, bioavailability, and bioactivity. Glycosyltransferases applicable for "sugarcoating" various small-molecule acceptors have been isolated and characterized from plants and bacteria, but remained cryptic from filamentous fungi until recently, despite the frequent use of some fungi for whole-cell biocatalytic glycosylations. Here, we use bioinformatic and genomic tools combined with heterologous expression to identify a glycosyltransferase-methyltransferase (GT-MT) gene pair that encodes a methylglucosylation functional module in the ascomycetous fungus Beauveria bassiana The GT is the founding member of a family nonorthologous to characterized fungal enzymes. Using combinatorial biosynthetic and biocatalytic platforms, we reveal that this GT is a promiscuous enzyme that efficiently modifies a broad range of drug-like substrates, including polyketides, anthraquinones, flavonoids, and naphthalenes. It yields both O- and N-glucosides with remarkable regio- and stereospecificity, a spectrum not demonstrated for other characterized fungal enzymes. These glucosides are faithfully processed by the dedicated MT to afford 4-O-methylglucosides. The resulting "unnatural products" show increased solubility, while representative polyketide methylglucosides also display increased stability against glycoside hydrolysis. Upon methylglucosidation, specific polyketides were found to attain cancer cell line-specific antiproliferative or matrix attachment inhibitory activities. These findings will guide genome mining for fungal GTs with novel substrate and product specificities, and empower the efficient combinatorial biosynthesis of a broad range of natural and unnatural glycosides in total biosynthetic or biocatalytic formats.


Asunto(s)
Antineoplásicos , Descubrimiento de Drogas , Hongos , Glicosiltransferasas , Metiltransferasas , Animales , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Chlorocebus aethiops , Proteínas Fúngicas/química , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Hongos/enzimología , Hongos/genética , Hongos/metabolismo , Glicosilación , Glicosiltransferasas/química , Glicosiltransferasas/genética , Glicosiltransferasas/metabolismo , Humanos , Metiltransferasas/química , Metiltransferasas/genética , Metiltransferasas/metabolismo , Sintasas Poliquetidas/química , Sintasas Poliquetidas/genética , Sintasas Poliquetidas/metabolismo , Policétidos/metabolismo , Células Vero
8.
J Am Chem Soc ; 142(40): 17093-17104, 2020 10 07.
Artículo en Inglés | MEDLINE | ID: mdl-32833442

RESUMEN

Combinatorial biosynthesis with fungal polyketide synthases (PKSs) promises to produce unprecedented bioactive "unnatural" natural products (uNPs) for drug discovery. Genome mining of the dothideomycete Rhytidhysteron rufulum uncovered a collaborating highly reducing PKS (hrPKS)-nonreducing PKS (nrPKS) pair. These enzymes produce trace amounts of rare S-type benzenediol macrolactone congeners with a phenylacetate core in a heterologous host. However, subunit shuffling and domain swaps with voucher enzymes demonstrated that all PKS domains are highly productive. This contradiction led us to reveal novel programming layers exerted by the starter unit acyltransferase (SAT) and the thioesterase (TE) domains on the PKS system. First, macrocyclic vs linear product formation is dictated by the intrinsic biosynthetic program of the TE domain. Next, the chain length of the hrPKS product is strongly influenced in trans by the off-loading preferences of the nrPKS SAT domain. Last, TE domains are size-selective filters that facilitate or obstruct product formation from certain priming units. Thus, the intrinsic programs of the SAT and TE domains are both part of the extrinsic program of the hrPKS subunit and modulate the observable metaprogram of the whole PKS system. Reconstruction of SAT and TE phylogenies suggests that these domains travel different evolutionary trajectories, with the resulting divergence creating potential conflicts in the PKS metaprogram. Such conflicts often emerge in chimeric PKSs created by combinatorial biosynthesis, reducing biosynthetic efficiency or even incapacitating the system. Understanding the points of failure for such engineered biocatalysts is pivotal to advance the biosynthetic production of uNPs.


Asunto(s)
Ascomicetos/enzimología , Proteínas Fúngicas/química , Sintasas Poliquetidas/biosíntesis , Sintasas Poliquetidas/química , Aciltransferasas/química , Secuencia de Aminoácidos , Vías Biosintéticas , Técnicas Químicas Combinatorias , Modelos Moleculares , Familia de Multigenes/genética , Fenilacetatos/química , Conformación Proteica , Saccharomyces cerevisiae/metabolismo , Tioléster Hidrolasas/química
9.
Tetrahedron ; 76(43)2020 Oct 23.
Artículo en Inglés | MEDLINE | ID: mdl-33716326

RESUMEN

Incorporation of the epigenetic modifier suberoylanilide hydroxamic acid (SAHA) into a potato dextrose broth culture of the endophytic fungus Aspergillus sp. AST0006 affected its polyketide biosynthetic pathway providing two new 3-(4-oxopyrano)-chromen-2-ones, aspyranochromenones A (1) and B (2), and the isocoumarin, (-)-6,7-dihydroxymellein (3). Eight additional metabolites (4-11) and two biotransformation products of SAHA (12-13) were also encountered. The planar structures and relative configurations of the new metabolites 1-2 were elucidated with the help of high-resolution mass, 1D and 2D NMR spectroscopic data and the absolute configurations of 1-3 were determined by comparison of experimental and calculated ECD data. Possible biosynthetic pathways to 1 and 2 are presented.

10.
Molecules ; 25(21)2020 Oct 30.
Artículo en Inglés | MEDLINE | ID: mdl-33143346

RESUMEN

Bioassay-guided fractionation of a cytotoxic extract derived from a solid potato dextrose agar (PDA) culture of Teratosphaeria sp. AK1128, a fungal endophyte of Equisetum arvense, afforded three new naphtho-γ-pyrone dimers, teratopyrones A-C (1-3), together with five known naphtho-γ-pyrones, aurasperone B (4), aurasperone C (5), aurasperone F (6), nigerasperone A (7), and fonsecin B (8), and two known diketopiperazines, asperazine (9) and isorugulosuvine (10). The structures of 1-3 were determined on the basis of their spectroscopic data. Cytotoxicity assay revealed that nigerasperone A (7) was moderately active against the cancer cell lines PC-3M (human metastatic prostate cancer), NCI-H460 (human non-small cell lung cancer), SF-268 (human CNS glioma), and MCF-7 (human breast cancer), with IC50s ranging from 2.37 to 4.12 µM while other metabolites exhibited no cytotoxic activity up to a concentration of 5.0 µM.


Asunto(s)
Antineoplásicos , Ascomicetos/química , Endófitos/química , Equisetum/microbiología , Neoplasias/tratamiento farmacológico , Pironas , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Antineoplásicos/farmacología , Ascomicetos/metabolismo , Endófitos/metabolismo , Femenino , Humanos , Células MCF-7 , Masculino , Neoplasias/metabolismo , Neoplasias/patología , Células PC-3 , Pironas/química , Pironas/aislamiento & purificación , Pironas/farmacología
11.
Biochemistry ; 58(30): 3225-3231, 2019 07 30.
Artículo en Inglés | MEDLINE | ID: mdl-31298844

RESUMEN

A library of natural products and their derivatives was screened for inhibition of protein tyrosine phosphatase (PTP) 1B, which is a validated drug target for the treatment of obesity and type II diabetes. Of those active in the preliminary assay, the most promising was compound 2 containing a novel pyrrolopyrazoloisoquinolone scaffold derived by treating radicicol (1) with hydrazine. This nitrogen-atom augmented radicicol derivative was found to be PTP1B selective relative to other highly homologous nonreceptor PTPs. Biochemical evaluation, molecular docking, and mutagenesis revealed 2 to be an allosteric inhibitor of PTP1B with a submicromolar Ki. Cellular analyses using C2C12 myoblasts indicated that 2 restored insulin signaling and increased glucose uptake.


Asunto(s)
Inhibidores Enzimáticos/química , Macrólidos/química , Nitrógeno/química , Proteína Tirosina Fosfatasa no Receptora Tipo 1/antagonistas & inhibidores , Proteína Tirosina Fosfatasa no Receptora Tipo 1/química , Animales , Inhibidores Enzimáticos/metabolismo , Macrólidos/metabolismo , Ratones , Nitrógeno/metabolismo , Unión Proteica/fisiología , Isoformas de Proteínas/química , Isoformas de Proteínas/metabolismo , Estructura Terciaria de Proteína , Proteína Tirosina Fosfatasa no Receptora Tipo 1/metabolismo
12.
J Am Chem Soc ; 141(10): 4355-4364, 2019 03 13.
Artículo en Inglés | MEDLINE | ID: mdl-30767524

RESUMEN

O-Methylation modulates the pharmacokinetic and pharmacodynamic (PK/PD) properties of small-molecule natural products, affecting their bioavailability, stability, and binding to targets. Diversity-oriented combinatorial biosynthesis of new chemical entities for drug discovery and optimization of known bioactive scaffolds during drug development both demand efficient O-methyltransferase (OMT) biocatalysts with considerable substrate promiscuity and tunable regioselectivity that can be deployed in a scalable and sustainable manner. Here we demonstrate efficient total biosynthetic and biocatalytic platforms that use a pair of fungal OMTs with orthogonal regiospecificity to produce unnatural O-methylated benzenediol lactone polyketides. We show that rational, structure-guided active-site cavity engineering can reprogram the regioselectivity of these enzymes. We also characterize the interplay of engineered regioselectivity with substrate plasticity. These findings will guide combinatorial biosynthetic tailoring of unnatural products toward the generation of diverse chemical matter for drug discovery and the PK/PD optimization of bioactive scaffolds for drug development.


Asunto(s)
Lactonas/síntesis química , Metiltransferasas/química , Policétidos/síntesis química , Sustitución de Aminoácidos , Ascomicetos/enzimología , Dominio Catalítico , Humanos , Cinética , Metilación , Metiltransferasas/genética , Metiltransferasas/metabolismo , Simulación del Acoplamiento Molecular , Unión Proteica , Ingeniería de Proteínas , Especificidad por Sustrato , Zearalenona/análogos & derivados , Zearalenona/metabolismo , Zeranol/análogos & derivados , Zeranol/metabolismo
13.
Nat Chem Biol ; 12(10): 867-75, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27571477

RESUMEN

There is an urgent need for new strategies to treat invasive fungal infections, which are a leading cause of human mortality. Here, we establish two activities of the natural product beauvericin, which potentiates the activity of the most widely deployed class of antifungal against the leading human fungal pathogens, blocks the emergence of drug resistance, and renders antifungal-resistant pathogens responsive to treatment in mammalian infection models. Harnessing genome sequencing of beauvericin-resistant mutants, affinity purification of a biotinylated beauvericin analog, and biochemical and genetic assays reveals that beauvericin blocks multidrug efflux and inhibits the global regulator TORC1 kinase, thereby activating the protein kinase CK2 and inhibiting the molecular chaperone Hsp90. Substitutions in the multidrug transporter Pdr5 that enable beauvericin efflux impair antifungal efflux, thereby impeding resistance to the drug combination. Thus, dual targeting of multidrug efflux and TOR signaling provides a powerful, broadly effective therapeutic strategy for treating fungal infectious disease that evades resistance.


Asunto(s)
Antifúngicos/farmacología , Depsipéptidos/farmacología , Hongos/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Transducción de Señal/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Antifúngicos/química , Depsipéptidos/síntesis química , Depsipéptidos/química , Farmacorresistencia Fúngica/efectos de los fármacos , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Hongos/metabolismo , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Proteínas HSP90 de Choque Térmico/metabolismo , Pruebas de Sensibilidad Microbiana , Micosis/tratamiento farmacológico , Micosis/microbiología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Bibliotecas de Moléculas Pequeñas/química , Serina-Treonina Quinasas TOR/metabolismo
14.
J Nat Prod ; 81(4): 825-837, 2018 04 27.
Artículo en Inglés | MEDLINE | ID: mdl-29537263

RESUMEN

Withanolides constitute a valuable class of bioactive natural products because some members of the class are known to exhibit cytotoxic activity and also induce a cytoprotective heat-shock response. In order to understand the relationship between their structures and these dual bioactivities of the withanolide scaffold, we obtained 25 analogues of withaferin A (WA) and withanolide D (WD) including 17 new compounds by semisynthesis involving chemical and microbial transformations. Hitherto unknown 16ß-hydroxy analogues of WA and WD were prepared by their reaction with triphenylphosphine/iodine, providing unexpected 5ß-hydroxy-6α-iodo analogues (iodohydrins) followed by microbial biotransformation with Cunninghamella echinulata and base-catalyzed cyclization of the resulting 16ß-hydroxy iodohydrins. Evaluation of these 25 withanolide analogues for their cytotoxicity and heat-shock-inducing activity (HSA) confirmed the known structure-activity relationships for WA-type withanolides and revealed that WD analogues were less active in both assays compared to their corresponding WA analogues. The 5ß,6ß-epoxide moiety of withanolides contributed to their cytotoxicity but not HSA. Introduction of a 16ß-OAc group to 4,27-di- O-acetyl-WA enhanced cytotoxicity and decreased HSA, whereas introduction of the same group to 4- O-acetyl-WD decreased both activities.


Asunto(s)
Productos Biológicos/farmacología , Citotoxinas/farmacología , Respuesta al Choque Térmico/efectos de los fármacos , Witanólidos/farmacología , Línea Celular , Línea Celular Tumoral , Células HEK293 , Humanos , Yodo/metabolismo , Compuestos Organofosforados/metabolismo , Sarcoma de Ewing/tratamiento farmacológico , Relación Estructura-Actividad
15.
J Nat Prod ; 81(3): 616-624, 2018 03 23.
Artículo en Inglés | MEDLINE | ID: mdl-29373790

RESUMEN

A new naphthoquinone, teratosphaerone A (1), four new naphthalenones, namely, teratosphaerone B (2), structurally related to 1, iso-balticol B (3), iso-balticol B-4,9-acetonide (4), and (+)-balticol C (5), a new furanonaphthalenone, (3a S,9 R,9a S)-1(9a),3(3a),9-hexahydromonosporascone (6), and the known metabolite monosporascone (7) were isolated from Teratosphaeria sp. FL2137, a fungal strain inhabiting the internal tissue of recently dead but undecomposed foliage of Pinus clausa. The structures of 1-6 were elucidated on the basis of their spectroscopic data including 2D NMR, and absolute configurations of 2, 3, and 6 were determined by the modified Mosher's ester method. When evaluated in a panel of five tumor cell lines, metabolites 1 and 7 isolated from a cytotoxic fraction of the extract exhibited moderate selectivity for metastatic breast adenocarcinoma cell line MDA-MB-231. Of these, 1 showed cytotoxicity to this cell line with an IC50 of 1.2 ± 0.1 µM.


Asunto(s)
Ascomicetos/química , Citotoxinas/química , Pinus/microbiología , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Citotoxinas/farmacología , Ensayos de Selección de Medicamentos Antitumorales/métodos , Humanos , Espectroscopía de Resonancia Magnética/métodos , Naftoquinonas/química , Naftoquinonas/farmacología
16.
Cancer Immunol Immunother ; 66(2): 223-231, 2017 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-27286684

RESUMEN

The selective killing of cancer cells without toxicity to normal nontransformed cells is an idealized goal of cancer therapy. Thus, there has been much interest in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a protein that appears to selectively kill cancer cells. TRAIL has been reported to trigger apoptosis and under some circumstances, an alternate death signaling pathway termed necroptosis. The relative importance of necroptosis for cell death induction in vivo is under intensive investigation. Nonetheless, many cancer cells (particularly those freshly isolated from cancer patients) are highly resistant to TRAIL-mediated cell death. Therefore, there is an underlying interest in identifying agents that can be combined with TRAIL to improve its efficacy. There are numerous reports in which combination of TRAIL with standard antineoplastic drugs has resulted in enhanced cancer cell death in vitro. However, many of these chemotherapeutic drugs are nonspecific and associated with adverse effects, which raise serious concerns for cancer therapy in patients. By contrast, natural products have been shown to be safer and efficacious alternatives. Recently, a number of studies have suggested that certain natural products when combined with TRAIL can enhance cancer cell death. In this review, we highlight molecular pathways that might be targeted by various natural products to promote cell death, and focus on our recent work with withanolides as TRAIL sensitizers. Finally, we will suggest synergistic approaches for combining active withanolides with various forms of immunotherapy to promote cancer cell death and an effective antitumor immune response.


Asunto(s)
Productos Biológicos/farmacología , Caspasa 8/metabolismo , Muerte Celular/genética , Neoplasias/tratamiento farmacológico , Neoplasias/enzimología , Animales , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Humanos , Neoplasias/patología , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología
17.
Bioorg Med Chem ; 25(6): 1860-1866, 2017 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-28202316

RESUMEN

Incorporation of the histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA), to a culture broth of the endophytic fungus Phoma sp. nov. LG0217 isolated from Parkinsonia microphylla changed its metabolite profile and resulted in the production of (10'S)-verruculide B (1), vermistatin (2) and dihydrovermistatin (3). When cultured in the absence of the epigenetic modifier, it produced a new metabolite, (S,Z)-5-(3',4'-dihydroxybutyldiene)-3-propylfuran-2(5H)-one (4) together with nafuredin (5). The structure of 4 was elucidated by spectroscopic analyses and its absolute configuration was determined by application of the modified Mosher's ester method. The absolute structure of (10'S)-verruculide B was determined as 5-[(10'S,2'E,6'E)-10',11'-dihydroxy-3',7',11'-trimethyldodeca-2',6'-dien-1'-yl]-(3R)-6,8-dihydroxy-3-methylisochroman-1-one (1) with the help of CD and NOE data. Compound 1 inhibited the activity of protein tyrosine phosphatases (PTPs) 1B (PTP1B), Src homology 2-containing PTP 1 (SHP1) and T-cell PTP (TCPTP) with IC50 values of 13.7±3.4, 8.8±0.6, and 16.6±3.8µM, respectively. Significance of these activities and observed modest selectivity of 1 for SHP1 over PTP1B and TCPTP is discussed.


Asunto(s)
Ascomicetos/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Epigénesis Genética/efectos de los fármacos , Fabaceae/microbiología , Proteínas Tirosina Fosfatasas/antagonistas & inhibidores , Sesquiterpenos/metabolismo , Ascomicetos/metabolismo , Cromatografía Líquida de Alta Presión , Inhibidores Enzimáticos/química , Espectroscopía de Resonancia Magnética , Sesquiterpenos/química , Sesquiterpenos/farmacología
18.
J Nat Prod ; 80(2): 427-433, 2017 02 24.
Artículo en Inglés | MEDLINE | ID: mdl-28139929

RESUMEN

Investigation of Alternaria sp. AST0039, an endophytic fungus obtained from the leaf tissue of Astragalus lentiginosus, led to the isolation of (-)-(10E,15S)-4,6-dichloro-10(11)-dehydrocurvularin (1), (-)-(10E,15S)-6-chloro-10(11)-dehydrocurvularin (2), (-)-(10E,15S)-10(11)-dehydrocurvularin (3), and alterperylenepoxide A (4) together with scytalone and α-acetylorcinol. Structures of 1 and 4 were established from their spectroscopic data, and the relative configuration of 4 was determined with the help of nuclear Overhauser effect difference data. All metabolites were evaluated for their cytotoxic activity and ability to induce heat-shock and unfolded protein responses. Compounds 2 and 3 exhibited cytotoxicity to all five cancer cell lines tested and increased the level of the pro-apoptotic transcription factor CHOP, but only 3 induced the heat-shock response and caused a strong unfolded protein response.


Asunto(s)
Alternaria/química , Planta del Astrágalo/microbiología , Zearalenona/química , Zearalenona/aislamiento & purificación , Ensayos de Selección de Medicamentos Antitumorales , Endófitos/química , Humanos , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Zearalenona/análogos & derivados
19.
J Nat Prod ; 80(1): 76-81, 2017 01 27.
Artículo en Inglés | MEDLINE | ID: mdl-28099011

RESUMEN

Seven azaphilones, montagnuphilones A-G (1-7), together with previously known azaphilones 8-11, were encountered in Montagnulaceae sp. DM0194, an endophytic fungus isolated from submerged roots of Persicaria amphibia. The structures of 1-7 were elucidated on the basis of their MS and NMR spectroscopic analysis. Compounds 1-8 were evaluated for their cytotoxicity and ability to inhibit nitric oxide (NO) production in lipopolysaccharide-activated RAW264.7 macrophage cells. Among these, none were found to be cytotoxic to RAW264.7 cells up to 100.0 µM, but 8, 5, and 2 showed NO inhibitory activity with IC50 values of 9.2 ± 0.9, 25.5 ± 1.1, and 39.6 ± 1.8 µM, respectively.


Asunto(s)
Anfibios/microbiología , Ascomicetos/química , Benzopiranos/química , Endófitos/química , Lipopolisacáridos/química , Macrófagos/efectos de los fármacos , Óxido Nítrico/biosíntesis , Pigmentos Biológicos/química , Raíces de Plantas/química , Animales , Benzopiranos/aislamiento & purificación , Lipopolisacáridos/aislamiento & purificación , Lipopolisacáridos/farmacología , Macrófagos/química , Espectroscopía de Resonancia Magnética , Estructura Molecular , Óxido Nítrico/química , Pigmentos Biológicos/aislamiento & purificación
20.
J Nat Prod ; 80(7): 1981-1991, 2017 07 28.
Artículo en Inglés | MEDLINE | ID: mdl-28617598

RESUMEN

Investigation of aeroponically grown Physalis peruviana resulted in the isolation of 11 new withanolides, including perulactones I-L (1-4), 17-deoxy-23ß-hydroxywithanolide E (5), 23ß-hydroxywithanolide E (6), 4-deoxyphyperunolide A (7), 7ß-hydroxywithanolide F (8), 7ß-hydroxy-17-epi-withanolide K (9), 24,25-dihydro-23ß,28-dihydroxywithanolide G (10), and 24,25-dihydrowithanolide E (11), together with 14 known withanolides (12-25). The structures of 1-11 were elucidated by the analysis of their spectroscopic data, and 12-25 were identified by comparison of their spectroscopic data with those reported. All withanolides were evaluated for their cytotoxic activity against a panel of tumor cell lines including LNCaP (androgen-sensitive human prostate adenocarcinoma), 22Rv1 (androgen-resistant human prostate adenocarcinoma), ACHN (human renal adenocarcinoma), M14 (human melanoma), SK-MEL-28 (human melanoma), and normal human foreskin fibroblast cells. Of these, the 17ß-hydroxywithanolides (17-BHWs) 6, 8, 9, 11-13, 15, and 19-22 showed selective cytotoxic activity against the two prostate cancer cell lines LNCaP and 22Rv1, whereas 13 and 20 exhibited selective toxicity for the ACHN renal carcinoma cell line. These cytotoxicity data provide additional structure-activity relationship information for the 17-BHWs.


Asunto(s)
Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Neoplasias Renales/tratamiento farmacológico , Physalis/química , Neoplasias de la Próstata/tratamiento farmacológico , Witanólidos/aislamiento & purificación , Witanólidos/farmacología , Antineoplásicos Fitogénicos/química , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Masculino , Melanoma/tratamiento farmacológico , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Physalis/crecimiento & desarrollo , Relación Estructura-Actividad , Witanólidos/química
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA