Renato Murillo

University of Freiburg, Freiburg, Baden-Württemberg, Germany

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Publications (40)108.82 Total impact

  • Planta Medica 11/2015; 81(16). DOI:10.1055/s-0035-1565801 · 2.15 Impact Factor
  • LMC Cursino · NM Lima · R Murillo · I Merfort · M Humar · CV Nunez ·

    Planta Medica 11/2015; 81(16). DOI:10.1055/s-0035-1565526 · 2.15 Impact Factor
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    ABSTRACT: Abstract Pentacyclic triterpene mono- and diesters have been isolated from Calendula officinalis flowers. GC-MS, APCI-Exactive Orbitrap HR-MS and NMR allowed to identify the triterpene skeleton in various samples (different triterpene mixtures from Calendula n-hexane extract). NMR provided evidence that triterpene diesters are present in the samples as well. However, the corresponding quasi-molecular ions could not be detected by APCI-Exactive Orbitrap HR-MS. Instability of triterpene diesters and loss of a fatty acid residue, respectively, in the ion-source made their MS detection challenging. Thus, a set of new APCI-QTOF-MS methods (using the TripleTOF 5600+ mass spectrometer) were developed which made it eventually possible to solve this problem and confirm the diester structures by MS via quasi-molecular ion [M+H]+ detection. Direct infusion APCI-QTOF MS experiments in MS/MS high sensitivity scan mode with low collision energy and multi-channel averaging acquisition (MCA) allowed the detection of quasi-molecular ions of triterpene diesters for the first time and unequivocally confirmed the presence of faradiol 3,16-dimyristate and -dipalmitate, as well as the corresponding mixed diesters faradiol 3-myristate,16-palmitate and faradiol 3-palmitate,16-myristate. Preferential loss of the fatty acid in 16-position made it possible to distinguish the mixed diesters by MS/MS spectra. Their chromatographic separations turned out to be challenging due to their bulkiness and extended molecular dimensions. However, separation could be achieved by an uncommon non-aqueous RPLC mode with an in-house synthesized C30 phase. Finally, two (U)HPLC-APCI-QTOF-MS methods with C18- and C30-based non-aqueous RPLC provided suitable, sensitive assays to monitor the presence of monoesters and diesters of various triterpenes (faradiol, maniladiol, arnidiol, arnitriol A and lupane-3β,16β,20-triol esters) in n-hexane extract of C. officinalis with high mass resolution and good mass accuracy.
    Journal of Pharmaceutical and Biomedical Analysis 11/2015; DOI:10.1016/j.jpba.2015.10.025 · 2.98 Impact Factor
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    ABSTRACT: Recently we described an unusual way of activating a cryptic gene cluster when we explored the origin of the bald phenotype of Streptomyces calvus. Complementation of S. calvuswith a correct copy of bldA restored sporulation and additionally promoted production of a new natural products. In this study we report on the expression of bldA in several Streptomyces strains which have been described as "poor sporulating" strains. In 7 out of 15 cases HPLC profiling revealed the production of new compounds, and in two cases the overproduction of known compounds. Two compounds were isolated and their structures were determined. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
    ChemBioChem 08/2015; 16(15). DOI:10.1002/cbic.201500297 · 3.09 Impact Factor
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    ABSTRACT: Tricyclic clerodane diterpenes (TCDs) are natural compounds that often show potent cytotoxicity for cancer cells, but their mode of action remains elusive. A computationally based similarity search (CDRUG), combined with principal component analysis (ChemGPS-NP) and docking calculations (GOLD 5.2), suggested TCDs to be inhibitors of the sarco/endoplasmic reticulum Ca 2+-ATPase (SERCA) pump, which is also the target of the sesquiterpene lactone thapsigargin. Biochemical studies were performed with 11 TCDs on purified rabbit skeletal muscle sarcoplasmic reticulum membranes, which are highly enriched with the SERCA1a isoform. Casearborin D (2) exhibited the highest affinity, with a K D value of 2 μM and giving rise to complete inhibition of SERCA1a activity. Structure−activity relationships revealed that functionalization of two acyl side chains (R 1 and R 4) and the hydrophobicity imparted by the aliphatic chain at C-9, as well as a C-3,C-4 double bond, play crucial roles for inhibitory activity. Docking studies also suggested that hydrophobic interactions in the binding site, especially with Phe256 and Phe834, may be important for a strong inhibitory activity of the TCDs. In conclusion, a novel class of SERCA inhibitory compounds is presented. C ancer is a major public health problem, associated in particular with increased aging of populations. 1 Although mortality rates have declined, there is still a strong urgency to find new and effective anticancer drugs. Antibodies have an increasing impact in the market, but small-molecule natural product derived drugs constitute a large proportion of the chemotherapeutic agents used up to the present. 2−4
    Journal of Natural Products 05/2015; 78(6). DOI:10.1021/acs.jnatprod.5b00062 · 3.80 Impact Factor
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    ABSTRACT: Four new flavonol glycosides were isolated from the leaves of Brugmansia suaveolens: kaempferol 3-O-β-D-glucopyranosyl-(1'''→2'')-O-α-L-arabinopyranoside (1), kaempferol 3-O-β-D-glucopyranosyl-(1'''→2'')-O-α-L-arabinopyranoside-7-O-į-D-gluco-pyranoside (2), kaempferol 3-O-β-D-[6'''-O-(E-caffeoyl)]-glucopyranosyl-(1'''→2'')-O-α-l-arabinopyranoside-7-O-β-D-glucopyranoside (3), and kaempferol 3-O-β-D-[2'''-O-(E-caffeoyl)]-glucopyranosyl-(1'''→2'')-O-α-l-arabinopyranoside-7-O-β-D-glucopyranoside (4). The structure elucidation was performed by MS, 1D and 2D NMR analyses.
    Planta Medica 05/2014; 19(5):6727-6736. DOI:10.3390/molecules19056727 · 2.15 Impact Factor
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    ABSTRACT: The leaves of Zuelania guidonia yielded eight new clerodane diterpenes, namely, zuelaguidins A-H (1-8), and the known clerodane diterpene esculentin A (9). Some of these structures contained a 3,6-dihydro-1,2-dioxin moiety. The new compounds were isolated and identified using 1D- and 2D-NMR experiments. All compounds were evaluated for cytotoxicity against the CCRF-CEM (human acute lymphocytic leukemia), CEM-ADR5000 (human acute lymphocytic leukemia resistant to doxorubicin), and MIA-PaCa-2 (human pancreatic carcinoma) cell lines as well as for their selectivity against peripheral blood mononuclear cells from healthy human subjects. Zuelaguidins B, C, and E were the most potent compounds against the CCRF-CEM cell line, with IC50 values ranging from 1.6 to 2.5 μM.
    Journal of Natural Products 01/2014; 77(3). DOI:10.1021/np400672g · 3.80 Impact Factor
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    ABSTRACT: Background: The rainforest is an important source of natural compounds with therapeutic properties. Although there are many anti-inflammatory and antineoplastic drugs available to the clinician, there is an ongoing need for new therapeutic drugs with fewer serious adverse effects. Aim: To evaluate the in vitro cytotoxic effects of lupeol and casearin G on tumor cells, on phagocytic activity and nitric oxide (NO) production by blood mononuclear cells. Material and Methods: The cytotoxic effect of these compounds on cell lines MCF-7 (human breast adenocarcinoma) and PC-3 (human prostate cancer) was measured by a colorimetric assay (MTS/PMS) and the sulphorhodamine B assay. Peripheral blood mononuclear cells were obtained from eight healthy volunteers. The effect of these compounds on nitric oxide (NO) production was measured using the Griess reaction. Their effect on phagocytic activity of PBMC was also evaluated. Results: Lupeol (≥ 2 mM) resulted in a reduction of both the phagocytic index and the percentage of phagocytic monocytes and macrophages. Treatment of monocytes/macrophages with lupeol (72 µM) and casearin G (4 µM) reduced the production of NO. Neither lupeol (< 969 µM) nor casearin G (< 55 µM) had cytotoxic effects on PBMC. Casearin G showed both cytotoxic (IC50, LC50) and cytostatic (GI50) effects against tumor cells, PC-3 (IC50 = 12.5 µM; GI50 = 13.3 µM; LC50 = 51.9 µM) and MCF-7 (IC50 = 112.8 µM; GI50 = 11.8 µM; LC50 = 49.4 µM), as well as a hemolytic effect (≥ 182 µM). Conclusions: These observations indicate that lupeol and casearin G might be useful compounds in the preparation of anti-inflammatory drugs, whereas casearin G might be useful in the elaboration of antitumor drugs.
    Revista medica de Chile 09/2013; 141(9):1150-7. DOI:10.4067/S0034-98872013000900007 · 0.30 Impact Factor
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    ABSTRACT: The majority of snakebite envenomations in Central America are caused by the viperid species Bothrops asper, whose venom contains a high proportion of zinc-dependent metalloproteinases that play a relevant role in the pathogenesis of hemorrhage characteristic of these envenomations. Broad metalloproteinase inhibitors, such as the peptidomimetic hydroxamate Batimastat, have been shown to inhibit snake venom metalloproteinases (SVMP). However, the difficulty in having open public access to Batimastat and similar molecules highlights the need to design new inhibitors of SVMPs that could be applied in the treatment of snakebite envenomations. We have chosen the SVMP BaP1 as a model to search for new inhibitors using different strategies, that is, screening of the Prestwick Chemical Library and rational peptide design. Results from these approaches provide clues on the structural requirements for efficient BaP1 inhibition and pave the way for the design of new inhibitors of SVMP.
    ACS Medicinal Chemistry Letters 06/2012; 3(7). DOI:10.1021/ml300068r · 3.12 Impact Factor
  • Soledad Mora · Victor Castro · Luis Poveda · Max Chavarría · Renato Murillo ·
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    ABSTRACT: Following our phytochemical studies of Costa Rican plants, we report the isolation of two new 3,4-seco-ent-kaurenes from the aerial parts of Croton megistocarpus (Euphorbiaceae). The structures of the two compounds were elucidated as 14-[(2-methylbutanoyl)oxy]-3,4-seco-ent-kaura-4(19),16-dien-3-oic acid (1) and 14-{[(2Z)-2-methylbut-2-enoyl]oxy}-3,4-seco-ent-kaura-4(19),16-dien-3-oic acid (2). In addition, seven known diterpene clerodanes were also isolated and identified. The structures of the compounds were elucidated by spectroscopic methods, including HR-MS, 1H-NMR, 13C-NMR, COSY, HMQC, HMBC, and NOESY experiments.
    Helvetica Chimica Acta 10/2011; 94(10). DOI:10.1002/hlca.201100127 · 1.14 Impact Factor
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    ABSTRACT: Phytochemical investigations of the n-hexane extract from the roots of Peltodon longipes (Lamiaceae) resulted in the isolation of 12 known abietane diterpenes (1-12). Structures were established on the basis of one and two dimensional nuclear magnetic resonance spectroscopic data ((1)H and (13)C, COSY, HSQC and HMBC), electron ionization mass spectrometric analysis (EIMS) as well as comparison with data from literature. These compounds, as well as eight known diterpenes (13-19) from Salvia miltiorrhiza, and two from Salvia sahendica (20 and 21) were evaluated for their cytotoxic effects in human pancreatic (MIAPaCa-2) and melanoma (MV-3) tumor cell lines using the MTT assay. Tanshinone IIa (13), 7α-acetoxyroyleanone (1), 1,2-dihydrotanshinone (16) and cryptotanshinone (14) had the highest cytotoxic effects in MIAPaCa-2, displaying IC(50) of 1.9, 4.7, 5.6, and 5.8 μM, respectively. Structure-activity relationships of abietane diterpenoid quinones are discussed.
    Bioorganic & medicinal chemistry 08/2011; 19(16):4876-81. DOI:10.1016/j.bmc.2011.06.067 · 2.79 Impact Factor
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    ABSTRACT: Structure elucidation and conformation analysis of four proanthocyanidins isolated from the bark of Parapiptadenia rigida were performed by two-dimensional NMR spectroscopy, HRESIMS, CD, and molecular mechanics (MM+) force field calculations. The known prodelphinidin, epigallocatechin-(4β→8)-epigallocatechin-3-O-gallate (1) was accompanied by the new epigallocatechin-(4β→8)-4'-O-methylgallocatechin (2), epicatechin-(4β→8)-4'-O-methylgallocatechin (3), and (4α→8)-bis-4'-O-methylgallocatechin (4). Compound 4 was previously published but the earlier structure must presumably be revised to 4'-O-methylgallocatechin-(4α→8)-4'-O-methylepigallocatechin. Conformational studies showed the compact rotamer with B and E rings in quasi-equatorial orientations as the preferred conformation for compounds 1-3, whereas 4 consists of two stable rotamers, each with a quasi-equatorial orientation of ring B and E, respectively. The isolated compounds were studied for their wound-healing effects in a scratch assay and showed promising results.
    Journal of Natural Products 06/2011; 74(6):1427-36. DOI:10.1021/np200158g · 3.80 Impact Factor
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    ABSTRACT: Analysis of the ethanolic extract of the bark from Parapiptadenia rigida resulted in the isolation of the new catechin derivatives 4',3''-di-O-methylapocynin-D (10), 4',3''-di-O-methylapocynin-B (11), epigallocatechin-3-O-ferulate (8), and 4'-O-methylepigallocatechin-3-O-ferulate (9) and the catechins 4'-O-methylepigallocatechin-3-O-gallate (6) and 4'-O-methylepicatechin-3-O-gallate (7). These compounds, isolated for the first time from a natural source, are accompanied by the five known catechins 4'-O-methylgallocatechin (1), 4'-O-methylepigallocatechin (2), 3'-O-methylepicatechin (3), epigallocatechin-3-O-gallate (4), and epicatechin-3-O-gallate (5). Compounds 5 and 7 displayed promising wound-healing effects in a scratch assay. Some of the catechin derivatives showed inhibitory effects on NF-κB DNA binding and p38α MAPK activity.
    Journal of Natural Products 11/2010; 73(12):2035-41. DOI:10.1021/np100523s · 3.80 Impact Factor
  • M Fronza · S Günther · R Murillo · E Lamy · B Heinzmann · S Laufer · I Merfort ·

    Planta Medica 08/2010; 76(12). DOI:10.1055/s-0030-1264260 · 2.15 Impact Factor
  • C Schmidt · M Fronza · R Murillo · V Wray · G Bringmann · T Bruhn · B Heinzmann · S Laufer · I Merfort ·

    Planta Medica 08/2010; 76(12). DOI:10.1055/s-0030-1264187 · 2.15 Impact Factor
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    ABSTRACT: Phenalinolactones are novel terpene glycoside antibiotics produced by Streptomyces sp. Tü6071. Inactivation of three oxygenase genes (plaO2, plaO3 and plaO5), two dehydrogenase genes (plaU, plaZ) and one putative acetyltransferase gene (plaV) led to the production of novel phenalinolactone derivatives (PL HS6, PL HS7, PL HS2 and PL X1). Furthermore, the exact biosynthetic functions of two enzymes were determined, and their in vitro activities were demonstrated. PlaO1, an Fe(II)/alpha-ketoglutarate-dependent dioxygenase, is responsible for the key step in gamma-butyrolactone formation, whereas PlaO5, a cytochrome P450-dependent monooxygenase, catalyses the 1-C-hydroxylation of phenalinolactone D. In addition, stable isotope feeding experiments with biosynthetic precursors shed light on the origin of the carbons in the gamma-butyrolactone moiety.
    ChemBioChem 07/2010; 11(10):1383-91. DOI:10.1002/cbic.201000117 · 3.09 Impact Factor
  • Omar A Dupuy · Renato Murillo · José A Bonilla ·
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    ABSTRACT: Different species of the Asteraceae family are a potential source of sesquiterpene lactones with anti-inflammatory properties. Macrophages play a central role in the regulation of immune responses. In the present study, the in vitro effect of two sesquiterpene lactones, a millerenolide and a thieleanin, was assessed by measuring the production of nitric oxide (NO) by cell line RAW (murine macrophages) using the Griess reagent. Additionally, the effect of these sesquiterpene lactones on phagocytic capacity of latex particles and the reduction of nitroblue tetrazolium (NBT) were evaluated microscopically. Treatment of macrophages with > 2.5 microg/ml of both sesquiterpene lactones, reduced the production of NO. A decreased number of macrophages able to reduce NBT were observed when these cells were treated with 3 microg/ml of millerenolide or 7.5 microg/ml of thieleanin. Treatment of macrophages with 4 microg/ml ofmillerenolide or 7.5 microg/ml of thieleanin, reduced the phagocytic capacity of macrophages. Cytotoxic effects on the macrophages were only observed when the concentration was increased to 8 microg/ml of millerenolide or 25 microg/ml of thieleanin. Our results suggest that these sesquiterpene lactones could be useful compounds in the elaboration of anti-inflammatory drugs.
    Revista de biologia tropical 09/2008; 56(3):1063-73. · 0.52 Impact Factor
  • Max Chavarría · Victor Castro · Luis Poveda · Renato Murillo ·

    Revista de biologia tropical 09/2008; 56(3):1043-1051. DOI:10.15517/rbt.v56i3.5691 · 0.52 Impact Factor
  • Peter G Taylor · Omar A. Dupuy Loo · José A Bonilla · Renato Murillo ·
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    ABSTRACT: The present study was carried out in order to examine the anticancer properties of two sesquiterpene lactones, millerenolide and thieleanin, isolated from Viguiera sylvatica and Decachaeta thieleana, against cell lines in vitro, and on the growth B16/BL6 melanoma tumors in C57BL/6 mice. Millerenolide and thieleanin showed a similar pattern of cytotoxicity with the greatest effect on viability being evident with A549 human lung cancer cells (IC(50) - 40 and 32 microM respectively), and with the 3T3/HER2 cell line which are 3T3 mouse fibroblasts transfected with the HER2 oncogene (IC(50) - 16 and 28 microM respectively). The parent 3T3 cells and the B16/BL6 mouse melanoma cells were less sensitive to these compounds, with thieleanin showing an IC(50) with B16/BL6 greater than the highest dose tested (203 microM). Treatment with millerenolide (8 mg/kg, i.p. on days 0, 2 and 4 post-inoculation) significantly inhibited the growth of subcutaneous B16/BL6 tumors in C57BL/6 mice, (50% inhibition at day 25, P=0.015), as well as retarding the appearance of detectable tumor (millerenolide - day 15.2+/-0.4 vs control - day 12.8+/-0.5, mean+/-SEM, P=0.011). In contrast, treatment with thieleanin (8 mg/kg every other day up to the day of kill) neither retarded the appearance of the tumor nor its growth.
    Fitoterapia 07/2008; 79(6):428-32. DOI:10.1016/j.fitote.2007.07.019 · 2.35 Impact Factor
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    ABSTRACT: Sesquiterpene lactones are the active components of a variety of medicinal plants from the Asteraceae family. They possess biological activities such as the inhibition of NF-kappaB and the release inhibition of the vasoactive serotonin. On the basis of a data set of 54 SLs, we report the development of a quantitative model for the prediction of serotonin release inhibition. Comparing this model with a previous investigation of the target NF-kappaB, structural features necessary for specific compounds could be acquired. Atomic properties encoded by radial distribution function and molecular surface potentials encoded by autocorrelation were used as descriptors. Whereas some descriptors describe the structural requirements for both activities, other descriptors can be used to decide whether an SL is more active to NF-kappaB or to serotonin release. Again, counter propagation neural networks proved to be a valuable tool to establish structure-activity relationships that are necessary for the search for and optimization of lead structures.
    Journal of Medicinal Chemistry 04/2008; 51(5):1324-32. DOI:10.1021/jm701318x · 5.45 Impact Factor