37 results on '"Rakotondraibe LH"'
Search Results
2. Rhamnosyl gallates and proanthocyanidins produced by Inga species and their antioxidant and antitumoral potential
- Author
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Silva, DHS, primary, Lima, NM, additional, Marqui, SR, additional, Rodrigues, JI, additional, Rakotondraibe, LH, additional, and Soares, CP, additional
- Published
- 2015
- Full Text
- View/download PDF
3. Investigation of the antiproliferative activity of Linociera ramiflora and its isolates
- Author
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Benatrehina, PA, primary, Pan, L, additional, Naman, CB, additional, Chai, HB, additional, Ninh, TN, additional, Soejarto, DD, additional, Rakotondraibe, LH, additional, and Kinghorn, AD, additional
- Published
- 2015
- Full Text
- View/download PDF
4. Effects of capsicodendrin in MCF-7 hormone-dependent breast cancer cells
- Author
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Muñoz Acuña, U, primary, Rakotondraibe, LH, additional, and Carcache de Blanco, EJ, additional
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- 2014
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5. SAR study of drimane sesquiterpenes from three Cinnamosma species of Madagascar
- Author
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Rakotondraibe, LH, primary, Muñoz Acuña, U, additional, Dai, Y, additional, Chai, H, additional, Carcache de Blanco, EJ, additional, and Asakawa, Y, additional
- Published
- 2014
- Full Text
- View/download PDF
6. Discovery of Anticancer Agents of Diverse Natural Origin.
- Author
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Aldrich LN, Burdette JE, Carcache de Blanco E, Coss CC, Eustaquio AS, Fuchs JR, Kinghorn AD, MacFarlane A, Mize BK, Oberlies NH, Orjala J, Pearce CJ, Phelps MA, Rakotondraibe LH, Ren Y, Soejarto DD, Stockwell BR, Yalowich JC, and Zhang X
- Subjects
- Humans, Plants chemistry, Structure-Activity Relationship, Antineoplastic Agents chemistry, Biological Products chemistry, Neoplasms drug therapy
- Abstract
Research progress from mainly over the last five years is described for a multidisciplinary collaborative program project directed toward the discovery of potential anticancer agents from a broad range of taxonomically defined organisms. Selected lead compounds with potential as new antitumor agents that are representative of considerable structural diversity have continued to be obtained from each of tropical plants, terrestrial and aquatic cyanobacteria, and filamentous fungi. Recently, a new focus has been on the investigation of the constituents of U.S. lichens and their fungal mycobionts. A medicinal chemistry and pharmacokinetics component of the project has optimized structurally selected lead natural products, leading to enhanced cytotoxic potencies against selected cancer cell lines. Biological testing has shown several compounds to have in vivo activity, and relevant preliminary structure-activity relationship and mechanism of action studies have been performed. Several promising lead compounds worthy of further investigation have been identified from the most recent collaborative work performed.
- Published
- 2022
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7. Omphalines A-E: ent-Rosane-Type Diterpenoids from the Madagascar Endemic Plant, Omphalea oppositifolia.
- Author
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Kawakami S, Kanagawa C, Rakotondraibe LH, Inagaki M, Nishimura M, Otsuka H, Seyama T, Matsunami K, Rakotoarisoa FM, Rakotonandrasana SR, and Ratsimbason AM
- Subjects
- Madagascar, Circular Dichroism, Euphorbiaceae, Diterpenes, Diterpenes, Kaurane
- Abstract
From the less polar fraction of the MeOH extract of the leaves and twigs of Omphalea oppositifolia, five new ent-rosane-type diterpenoids, named omphalines A-E (1-5), were isolated together with one known compound, 7-keto-ent-kaurane-16β,17-diol (6), by a combination of various kinds of chromatography. The structure of omphaline A (1) was elucidated to be 19-nor-ent-rosane-4,15-diene-2β,6α-diol-3-one. Omphalines B (2), C (3), D (4), and E (5) possessed two double bonds at 5- and 15-positions, and hydroxy functional groups at 3β-, 2α,3α-, 2α,3β-, and 2α,19-positions, respectively. The absolute configuration of 1 was determined by the comparison of the experimental electronic circular dichroism (ECD) spectrum and calculated ECD spectra.
- Published
- 2022
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8. Activity in MCF-7 Estrogen-sensitive Breast Cancer Cells of Capsicodendrin from Cinnamosma fragrans .
- Author
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Acuna UM, Ezzone N, Rakotondraibe LH, and Carcache DE Blanco EJ
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- Antineoplastic Agents, Phytogenic chemistry, Caspases metabolism, Cell Cycle drug effects, Female, Humans, I-kappa B Kinase, Membrane Potential, Mitochondrial drug effects, Molecular Structure, NF-kappa B metabolism, Plant Extracts chemistry, Reactive Oxygen Species metabolism, Signal Transduction drug effects, Antineoplastic Agents, Phytogenic pharmacology, Cinnamomum chemistry, MCF-7 Cells drug effects, Plant Extracts pharmacology
- Abstract
Background/aim: Effect of capsicodendrin on the NF-κB pathway was studied in MCF-7 cancer cells., Materials and Methods: The transcription factor assay was used to screen for NF-κB activity. The effect on IKKβ, ICAM-1, and caspase-7 were studied using western blot. Caspase-1 was studied using Promega Caspase-Glo
® assay. Reactive oxygen species (ROS) were detected using the fluorescent probe DCFH-DA. The potentiometric dye JC-1 was used to assess mitochondrial membrane potential (ΔΨm) and the cell cycle was examined using a fluorescence-activated cell sorter., Results: NF-κB p65 inhibitory effect was IC50 =8.6 μM and cytotoxic activity was IC50 =7.5 μM. The upstream IKK and the downstream ICAM-1 were down-regulated. Sub G1 -phase population increased to 81% after 12 h of treatment with capsicodendrin (10 μM) and there was no loss of ΔΨM., Conclusion: Increased levels of intracellular ROS promoted activity of caspase-1 and induced cell death in MCF-7 cells. Capsicodendrin may be a future anticancer agent that prevents the progression of metastatic breast cancer., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)- Published
- 2021
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9. Structure-Activity Relationship of para -Carborane Selective Estrogen Receptor β Agonists.
- Author
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Sedlák D, Wilson TA, Tjarks W, Radomska HS, Wang H, Kolla JN, Leśnikowski ZJ, Špičáková A, Ali T, Ishita K, Rakotondraibe LH, Vibhute S, Wang D, Anzenbacher P, Bennett C, Bartunek P, and Coss CC
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- Boron Compounds chemical synthesis, Boron Compounds chemistry, Dose-Response Relationship, Drug, Estrogens chemical synthesis, Estrogens chemistry, HEK293 Cells, Humans, Molecular Structure, Structure-Activity Relationship, Boron Compounds pharmacology, Estrogen Receptor beta agonists, Estrogens pharmacology
- Abstract
Selective agonism of the estrogen receptor (ER) subtypes, ERα and ERβ, has historically been difficult to achieve due to the high degree of ligand-binding domain structural similarity. Multiple efforts have focused on the use of classical organic scaffolds to model 17β-estradiol geometry in the design of ERβ selective agonists, with several proceeding to various stages of clinical development. Carborane scaffolds offer many unique advantages including the potential for novel ligand/receptor interactions but remain relatively unexplored. We synthesized a series of para -carborane estrogen receptor agonists revealing an ERβ selective structure-activity relationship. We report ERβ agonists with low nanomolar potency, greater than 200-fold selectivity for ERβ over ERα, limited off-target activity against other nuclear receptors, and only sparse CYP450 inhibition at very high micromolar concentrations. The pharmacological properties of our para -carborane ERβ selective agonists measure favorably against clinically developed ERβ agonists and support further evaluation of carborane-based selective estrogen receptor modulators.
- Published
- 2021
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10. Stop the crop: Insights into the insecticidal mode of action of cinnamodial against mosquitoes.
- Author
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Kalsi M, Walter A, Lee B, DeLaat A, Trigueros RR, Happel K, Sepesy R, Nguyen B, Manwill PK, Rakotondraibe LH, and Piermarini PM
- Subjects
- Animals, Benzaldehydes, Female, Mosquito Control, Aedes, Insect Repellents, Insecticides pharmacology
- Abstract
Cinnamodial (CDIAL) is a drimane sesquiterpene dialdehyde found in the bark of Malagasy medicinal plants (Cinnamosma species; family Canellaceae). We previously demonstrated that CDIAL was insecticidal, antifeedant, and repellent against Aedes aegypti mosquitoes. The goal of the present study was to generate insights into the insecticidal mode of action for CDIAL, which is presently unknown. We evaluated the effects of CDIAL on the contractility of the ventral diverticulum (crop) isolated from adult female Ae. aegypti. The crop is a food storage organ surrounded by visceral muscle that spontaneously contracts in vitro. We found that CDIAL completely inhibited spontaneous contractions of the crop as well as those stimulated by the agonist 5-hydroxytryptamine. Several derivatives of CDIAL with known insecticidal activity also inhibited crop contractions. Morphometric analyses of crops suggested that CDIAL induced a tetanic paralysis that was dependent on extracellular Ca
2+ and inhibited by Gd3+ , a non-specific blocker of plasma membrane Ca2+ channels. Screening of numerous pharmacological agents revealed that a Ca2+ ionophore (A23187) was the only compound other than CDIAL to completely inhibit crop contractions via a tetanic paralysis. Taken together, our results suggest that CDIAL induces a tetanic paralysis of the crop by elevating intracellular Ca2+ through the activation of plasma membrane Ca2+ channels, which may explain the insecticidal effects of CDIAL against mosquitoes. Our pharmacological screening experiments also revealed the presence of two regulatory pathways in mosquito crop contractility not previously described: an inhibitory glutamatergic pathway and a stimulatory octopaminergic pathway. The latter pathway was also completely inhibited by CDIAL., (Copyright © 2020 Elsevier Inc. All rights reserved.)- Published
- 2021
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11. Dimeric and esterified sesquiterpenes from the liverwort Chiastocaulon caledonicum.
- Author
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Métoyer B, Benatrehina A, Rakotondraibe LH, Thouvenot L, Asakawa Y, Nour M, and Raharivelomanana P
- Subjects
- Molecular Structure, New Caledonia, Spectrum Analysis, Hepatophyta, Sesquiterpenes
- Abstract
This is the first chemical investigation of Chiastocaulon caledonicum, an endemic liverwort from New Caledonia. We herein present the isolation of thirteen compounds including seven undescribed sesquiterpenoids, namely four barbatane- and three myltaylane-type sesquiterpenes. The structures of these compounds were elucidated based on the interpretation of their chemical and spectroscopic/spectrometric data. Chiastocaulins A and B are the first examples of dimers based on two myltaylane units. The chemotaxonomic importance and the biosynthesis of the chiastocaulin structure are discussed. Terpenoid dimers formed via a Diels-Alder cyclization are thought to be specific to the Plagiochilaceae family., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Published
- 2020
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12. Tumor suppressor p53 independent apoptosis in HT-29 cells by auransterol from Penicillium aurantiacobrunneum.
- Author
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Anaya-Eugenio GD, Tan CY, Rakotondraibe LH, and Carcache de Blanco EC
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- Caspases, Effector biosynthesis, Cell Cycle Checkpoints physiology, Cell Death drug effects, Cell Line, Tumor, Cell Movement physiology, Cell Proliferation drug effects, Humans, Membrane Potential, Mitochondrial physiology, Proto-Oncogene Proteins c-bcl-2 metabolism, Reactive Oxygen Species metabolism, Apoptosis drug effects, Colonic Neoplasms prevention & control, Tumor Suppressor Protein p53 physiology
- Abstract
Colorectal cancer is the third leading cause of cancer related-death in the United States. Search for new alternatives to treat this type of cancer is necessary. In a previous report, auransterol from Penicillium aurantiacobrunneum showed cytotoxicity in HT-29 cancer cells. Thus, the goal of this study was to examine the potential cytotoxic mechanism of auransterol in HT-29 cells. Real-time cytotoxicity of auransterol was determined in HT-29 colon cancer cells, using the SRB assay. Loss of MTP, overproduction of ROS, cell cycle, cell migration, and caspase activity were analyzed. Western blot analysis was used to evaluate protein expression. Auransterol reduced cell proliferation rate in a time and concentration-dependent manner, with an IC
50 value > 100, 49.1 and 23.8 μM at 24, 48 and 72 h of treatment, respectively. After 24 h of treatment, 50 μM of auransterol induced loss of MTP, overproduction of ROS, increased caspase activity, induced cell cycle G1 phase accumulation and inhibition of migration in HT-29 cells compared to control. These results were supported by protein upregulation of Cyt c, BAX, PARP-1, p21 and procaspase-3, and downregulation of Bcl-2 with no modifications in procaspase-7 and p53. The cytotoxic effect of auransterol in HT-29 colon cancer cells is mediated by mitochondrial apoptosis independent of p53 activation, cell cycle G1 phase arrest, and inhibition of cell migration. This work encourages further preclinical and clinical studies of auransterol and suggests auransterol as a good candidate for colorectal cancer treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest., (Copyright © 2020. Published by Elsevier Masson SAS.)- Published
- 2020
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13. Insecticidal and Antifeedant Activities of Malagasy Medicinal Plant ( Cinnamosma sp.) Extracts and Drimane-Type Sesquiterpenes against Aedes aegypti Mosquitoes.
- Author
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Inocente EA, Nguyen B, Manwill PK, Benatrehina A, Kweka E, Wu S, Cheng X, Rakotondraibe LH, and Piermarini PM
- Abstract
The overuse of insecticides with limited modes of action has led to resistance in mosquito vectors. Thus, insecticides with novel modes of action are needed. Secondary metabolites in Madagascan plants of the genus Cinnamosma (Canellaceae) are commonly used in traditional remedies and known to elicit antifeedant and toxic effects in insect pests. Here we test the hypothesis that extracts of Cinnamosma sp. enriched in drimane sesquiterpenes are toxic and/or antifeedant to the yellow fever mosquito Aedes aegypti . We show that the bark and root extracts, which contain a higher abundance of drimane sesquiterpenes compared to leaves, were the most efficacious. Screening isolated compounds revealed cinnamodial to be the primary driver of adulticidal activity, whereas cinnamodial, polygodial, cinnafragrin A, and capsicodendrin contributed to the larvicidal activity. Moreover, an abundant lactone (cinnamosmolide) in the root extract synergized the larvicidal effects of cinnamodial. The antifeedant activity of the extracts was primarily contributed to cinnamodial, polygodial, and cinnamolide. Parallel experiments with warburganal isolated from Warburgia ugandensis (Canellaceae) revealed that aldehydes are critical for-and a hydroxyl modulates-insecticidal activity. Our results indicate that plant drimane sesquiterpenes provide valuable chemical platforms for developing insecticides and repellents to control mosquito vectors.
- Published
- 2019
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14. Structurally Modified Cyclopenta[ b ]benzofuran Analogues Isolated from Aglaia perviridis .
- Author
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Agarwal G, Wilson JR, Kurina SJ, Anaya-Eugenio GD, Ninh TN, Burdette JE, Soejarto DD, Cheng X, Carcache de Blanco EJ, Rakotondraibe LH, and Kinghorn AD
- Subjects
- Antineoplastic Agents, Phytogenic chemistry, Antineoplastic Agents, Phytogenic pharmacology, Benzofurans chemistry, Benzofurans pharmacology, HT29 Cells, Humans, Magnetic Resonance Spectroscopy, PC-3 Cells, Plant Extracts analysis, Plant Roots chemistry, Triterpenes isolation & purification, Aglaia chemistry, Antineoplastic Agents, Phytogenic isolation & purification, Benzofurans isolation & purification
- Abstract
Four new cyclopenta[ b ]benzofuran derivatives based on an unprecedented carbon skeleton ( 1 - 4 ), with a dihydrofuran ring fused to dioxanyl and aryl rings, along with a new structural analogue ( 5 ) of 5‴-episilvestrol (episilvestrol, 7 ), were isolated from an aqueous extract of a large-scale re-collection of the roots of Aglaia perviridis collected in Vietnam. Compound 5 demonstrated mutarotation in solution due to the presence of a hydroxy group at C-2‴, leading to the isolation of a racemic mixture, despite being purified on a chiral-phase HPLC column. Silvestrol ( 6 ) and episilvestrol ( 7 ) were isolated from the most potently cytotoxic chloroform subfraction of the roots. All new structures were elucidated using 1D and 2D NMR, HRESIMS, IR, UV, and ECD spectroscopic data. Of the five newly isolated compounds, only compound 5 exhibited cytotoxic activity against a human colon cancer (HT-29) and human prostate cancer cell line (PC-3), with IC
50 values of 2.3 μM in both cases. The isolated compounds ( 1 - 5 ) double the number of dioxanyl ring-containing rocaglate analogues reported to date from Aglaia species and present additional information on the structural requirements for cancer cell line cytotoxicity within this compound class.- Published
- 2019
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15. α-Pyrone and Sterol Constituents of Penicillium aurantiacobrunneum , a Fungal Associate of the Lichen Niebla homalea .
- Author
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Tan CY, Wang F, Anaya-Eugenio GD, Gallucci JC, Goughenour KD, Rappleye CA, Spjut RW, Carcache de Blanco EJ, Kinghorn AD, and Rakotondraibe LH
- Subjects
- Cell Line, Tumor, Crystallography, X-Ray, Drug Screening Assays, Antitumor, Humans, Molecular Structure, Pyrones pharmacology, Spectrum Analysis methods, Sterols pharmacology, Fungi isolation & purification, Lichens microbiology, Penicillium chemistry, Pyrones chemistry, Sterols chemistry
- Abstract
Four new metabolites, 4- epi -citreoviridin ( 1 ), auransterol ( 3 ), and two analogues ( 2 and 4 ) of paxisterol ( 6 ), together with two known metabolites (15 R *,20 S *)-dihydroxyepisterol ( 5 ) and ( 6 ), were isolated from cultures of the fungal associate, Penicillium aurantiacobrunneum , of the lichen Niebla homalea , endemic to California and Baja California. The structures of all compounds were determined by comprehensive spectroscopic and spectrometric methods, as well as single-crystal X-ray diffraction for the determination of the absolute configuration of 3 . Compound 1 showed selective cytotoxicity toward MCF-7 breast and A2780 ovarian cells with IC
50 values of 4.2 and 5.7 μM, respectively.- Published
- 2019
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16. Cytotoxic constituents from Penicillium concentricum, an endophytic fungus from Trichocolea tomentella.
- Author
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Anaya-Eugenio GD, Ali T, Rakotondraibe LH, and Carcache de Blanco E
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- Drug Screening Assays, Antitumor, Humans, Membrane Potential, Mitochondrial, NF-kappa B metabolism, Neoplasms drug therapy, Neoplasms metabolism, Tumor Cells, Cultured, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Apoptosis, Cell Cycle, Cell Proliferation, Neoplasms pathology, Penicillium chemistry, Streptophyta chemistry
- Abstract
In our continuing effort to identify bioactive secondary metabolites from natural sources, the antiproliferative activity of 23 compounds, previously isolated from Penicillium concentricum, was assessed using the sulforhodamine B assay. The cytotoxic effect was determined against HeLa cervical, HT-29 colon, MDA-MB-321 breast, PC-3, and DU-145 prostate cancer cell lines. Compounds were also tested in the mitochondrial transmembrane potential (MTP) and nuclear factor kappa B (NF-κB) target-based assays. The results showed that 2-bromogentisyl alcohol (2) and 3-hydroxy-benzenemethanol (8) exhibited the highest cytotoxic activity against different cancer cell lines. Epoxydon (14) showed selectivity against DU-145 prostate cancer cells [inhibitory concentration 50 (IC50)=1.2 μmol/l]. Compounds 2, 8, 14, 18, 21 also induced damage of MTP (IC50=0.1, 0.2, 7.0, 9.6, and 1.8 μmol/l, respectively). In the NF-κB assay, only compound 8 exhibited potent inhibition (IC50=0.3 μmol/l). Compounds 2 and 14 showed cytotoxic activity and induction of damage in mitochondrial membrane potential while compound 8 inhibited NF-κB and MTP damage. Additionally, compound 14 with selectivity against DU-145 prostate cancer cells induced cell cycle arrested in G2/M phase. Thus, compounds 2, 8, and 14 could be useful leads in the development of new anticancer agents from natural sources.
- Published
- 2019
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17. Bioactivity-Guided Isolation of Totarane-Derived Diterpenes from Podocarpus neriifolius and Structure Revision of 3-Deoxy-2α-hydroxynagilactone E.
- Author
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Benatrehina PA, Chen WL, Czarnecki AA, Kurina S, Chai HB, Lantvit DD, Ninh TN, Zhang X, Soejarto DD, Burdette JE, Kinghorn AD, and Rakotondraibe LH
- Abstract
Bioactivity-guided phytochemical investigation of Podocarpus neriifolius D. Don. (Podocarpaceae) has led to the isolation of one new (2) and three known (1, 3, and 4) B-type podolactones, along with three totarane-type diterpenes (5-7). Their structures were determined by interpretation of High Resolution ElectroSpray Ionization Mass Spectrometry (HRESIMS) and 1D and 2D NMR data, and comparison with the values reported in the literature. The structure of compound 1, previously identified as 3-deoxy-2α-hydroxynagilactone E (8), was revised as its 2β-epimer, which has been reported recently as a new compound. All of the isolates were evaluated for their antiproliferative activity against a panel of four human cancer cell lines, namely, ovarian (OVCAR3), breast (MDA-MB-231), colon (HT-29), and melanoma (MDA-MB-435), and compounds 1 and 3 were found to be cytotoxic with IC
50 values in the low micromolar range for most of the cell lines used. The major compound, inumakilactone A (3), was further tested in vivo using the HT-29, MDA-MB-435, and OVCAR3 cells in a murine hollow fiber model, for the first time.- Published
- 2019
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18. Capsicodendrin from Cinnamosma fragrans Exhibits Antiproliferative and Cytotoxic Activity in Human Leukemia Cells: Modulation by Glutathione.
- Author
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Karmahapatra S, Kientz C, Shetty S, Yalowich JC, and Rakotondraibe LH
- Subjects
- Antineoplastic Agents, Phytogenic chemistry, Antineoplastic Agents, Phytogenic pharmacology, Antioxidants chemistry, Antioxidants pharmacology, Apoptosis drug effects, Buthionine Sulfoximine pharmacology, Cell Line, Tumor, Cell Proliferation drug effects, DNA Damage, Glutathione antagonists & inhibitors, HL-60 Cells, Humans, K562 Cells, Leukemia, Myeloid metabolism, Leukemia, Myeloid pathology, Polycyclic Sesquiterpenes, Sesquiterpenes isolation & purification, Glutathione metabolism, Leukemia, Myeloid drug therapy, Magnoliopsida chemistry, Sesquiterpenes chemistry, Sesquiterpenes pharmacology
- Abstract
Capsicodendrin (CPCD, 1), an epimeric mixture of a dimeric drimane-type sesquiterpene, is one of the major compounds present in the three endemic species of Madagascan traditional chemopreventive plants: Cinnamosma species ( C. fragrans, C. macrocarpa, and C. madagascariensis). Despite the popular use of Cinnamosma in Madagascan traditional medicine and the reported antiproliferative properties of CPCD, elucidation of its mechanism(s) of action is still to be accomplished. In the present study, CPCD at low micromolar concentrations was cytotoxic and induced apoptosis in human myeloid leukemia cells in a time- and concentration-dependent manner. The activity of CPCD in HL-60 and K562 cells was modulated by glutathione (GSH), since depletion of this intracellular thiol-based antioxidant with buthionine sulfoximine resulted in significantly ( p < 0.05) greater potency in antiproliferation assays. GSH depletion also significantly potentiated the cytotoxic activity in CPCD-treated human HL-60 cells. Single-cell gel electrophoresis (Comet) assays revealed that GSH depletion in HL-60 cells enhanced the formation of DNA strand breaks in the presence of CPCD. Although CPCD does not contain an obvious Michael acceptor in its structure,
1 H NMR analyses indicated that cinnamodial (2), a monomer of CPCD, was formed within a few hours when dissolved in DMSO- d6 and interacts with GSH to form a covalent bond via Michael addition at the C-7 carbon. Together the results strongly suggest that 2 is responsible for the DNA-damaging, pro-apoptotic, and cytotoxic effects of CPCD and that depletion of GSH enhances overall activity by diminishing covalent interaction between GSH and this 2-alkenal decomposition product of CPCD.- Published
- 2018
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19. Total Synthesis of Scytonemide A Employing Weinreb AM Solid-Phase Resin.
- Author
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Wilson TA, Tokarski RJ 2nd, Sullivan P, Demoret RM, Orjala J, Rakotondraibe LH, and Fuchs JR
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- Amides chemistry, Cyclization drug effects, Humans, Proteasome Inhibitors chemistry, Solid-Phase Synthesis Techniques methods, Depsipeptides chemistry, Resins, Plant chemistry
- Abstract
The human 20S proteasome inhibitor scytonemide A (1), a macrocyclic imine originally isolated from the cyanobacterium Scytonema hofmanni, was synthesized via a biomimetic solid-phase peptide synthesis (SPPS) approach employing the Weinreb AM resin. Utilizing this approach, cyclization of the protected heptapeptide via formation of the imine bond occurred spontaneously upon cleavage from the resin in the presence of a reducing agent and subsequent aqueous workup. The final deprotection step necessary to produce the natural product was accomplished under slightly basic conditions, facilitating cleavage of the silyl ether group while leaving the macrocycle intact. Purification of the synthetic scytonemide A was accomplished via normal-phase flash column chromatography, potentially facilitating larger scale preparation of the compound necessary for future mechanistic and SAR studies. The structure of the target compound was confirmed by NMR spectroscopy, which also shed light on differences in the spectroscopic data obtained for the synthetic and natural scytonemide A samples for some of the amide and alcohol signals in the
1 H NMR spectrum.- Published
- 2018
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20. A natural agonist of mosquito TRPA1 from the medicinal plant Cinnamosma fragrans that is toxic, antifeedant, and repellent to the yellow fever mosquito Aedes aegypti.
- Author
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Inocente EA, Shaya M, Acosta N, Rakotondraibe LH, and Piermarini PM
- Subjects
- Aedes metabolism, Animals, Benzaldehydes chemistry, Benzaldehydes pharmacology, Larva drug effects, Mosquito Control, Mosquito Vectors metabolism, Plants, Medicinal chemistry, Sesquiterpenes isolation & purification, Sesquiterpenes pharmacology, TRPA1 Cation Channel genetics, Yellow Fever transmission, Yellow Fever virology, Aedes drug effects, Insect Repellents pharmacology, Insecticides pharmacology, Magnoliopsida chemistry, Mosquito Vectors drug effects, Plant Extracts pharmacology, TRPA1 Cation Channel agonists
- Abstract
Plants produce various secondary metabolites that offer a potential source of novel insecticides and repellents for the control of mosquito vectors. Plants of the genus Cinnamosma are endemic to, and widely-distributed throughout, the island of Madagascar. The barks of these species are commonly used in traditional medicines for treating a wide range of maladies. The therapeutic nature of the bark is thought to be associated with its enrichment of pungent drimane sesquiterpenes, which elicit antifeedant and toxic effects in some insects. Here we test the hypothesis that a bark extract of Cinnamosma fragrans (CINEX) and its major drimane sesquiterpenes are insecticidal, antifeedant, and repellent to Aedes aegypti, the principal mosquito vector of chikungunya, dengue, yellow fever, and Zika viruses. We demonstrate that CINEX is 1) toxic to larval and adult female mosquitoes, and 2) antifeedant and repellent to adult female mosquitoes. Moreover, we show that cinnamodial (CDIAL), a sesquiterpene dialdehyde isolated from CINEX, duplicates these bioactivities and exhibits similar toxic potency against pyrethroid-susceptible and -resistant strains of Ae. aegypti. Importantly, we show that CDIAL is an agonist of heterologously-expressed mosquito Transient Receptor Potential A1 (TRPA1) channels, and the antifeedant activity of CDIAL is dampened in a TRPA1-deficient strain of Ae. aegypti (TRPA1-/-). Intriguingly, TRPA1-/- mosquitoes do not exhibit toxic resistance to CDIAL. The data indicate that modulation of TRPA1 is required for the sensory detection and avoidance of CDIAL by mosquitoes, but not for inducing the molecule's toxicity. Our study suggests that CDIAL may serve as a novel chemical platform for the development of natural product-based insecticides and repellents for controlling mosquito vectors.
- Published
- 2018
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21. Novel Bioactive Natural Products Isolated from Madagascar Plants and Marine Organisms (2009-2017).
- Author
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Dai Y, Liu Y, and Rakotondraibe LH
- Subjects
- Biodiversity, Biological Products chemistry, Biological Products metabolism, Madagascar, Small Molecule Libraries chemistry, Small Molecule Libraries metabolism, Aquatic Organisms chemistry, Biological Products isolation & purification, Plants chemistry, Small Molecule Libraries isolation & purification
- Abstract
Madagascar's rain forests and tropical dry forests are home to numerous endemic plant species and the island is considered a biodiversity hotspot. About 80% of the Madagascan (Malagasy) population relies on traditional medicines that have been proven to contain a variety of biologically active compounds. In the search for bioactive compounds from Madagascan biodiversity, we accessed and collected most of the literature dealing with the isolation, structure elucidation, and biological activities of organic small molecules originating from Madagascan plants and marine organisms. Since we published the first review of this work in 2009 (Curr. Med. Chem., 17, 2010, Hou and Harinantenaina), the present paper covers the isolation, structures, and bioactivity of 182 new secondary metabolites isolated from Malagasy higher plants and marine organisms in the last seven years (2009-2017).
- Published
- 2018
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22. Halogenated Compounds from Directed Fermentation of Penicillium concentricum, an Endophytic Fungus of the Liverwort Trichocolea tomentella.
- Author
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Ali T, Inagaki M, Chai HB, Wieboldt T, Rapplye C, and Rakotondraibe LH
- Subjects
- Benzyl Alcohols chemistry, Colonic Neoplasms chemistry, Epoxy Compounds chemistry, Ethylene Glycols chemistry, Fermentation, HT29 Cells, Halogenation, Humans, Inhibitory Concentration 50, MCF-7 Cells, Molecular Structure, Xanthones chemistry, Benzyl Alcohols isolation & purification, Benzyl Alcohols pharmacology, Colonic Neoplasms drug therapy, Epoxy Compounds isolation & purification, Epoxy Compounds pharmacology, Ethylene Glycols isolation & purification, Ethylene Glycols pharmacology, Hepatophyta chemistry, Magnetic Resonance Spectroscopy methods, Penicillium chemistry, Xanthones pharmacology
- Abstract
One new chlorinated xanthone, 6-chloro-3,8-dihydroxy-1-methylxanthone (1), a new 2-bromo-gentisyl alcohol (2), and a mixture of 6-epimers of 6-dehydroxy-6-bromogabosine C (3a and 3b), together with 19 previously identified compounds, epoxydon (4), norlichexanthone (5), 2-chlorogentisyl alcohol (6), hydroxychlorogentisyl quinone (7), 6-dehydroxy-6α-chlorogabosine C (8a), 6-dehydroxy-6β-chlorogabosine C (8b), gentisyl alcohol (9), gentisyl quinone (10), (R,S)-1-phenyl-1,2-ethanediol (11), dehydrodechlorogriseofulvin (12), dechlorogriseofulvin (13), dehydrogriseofulvin (14), griseofulvin (15), ethylene glycol benzoate (16), alternariol (17), griseoxanthone C (18), drimiopsin H (19), griseophenone C (20), and griseophenone B (21), were isolated from cultures of Penicillium concentricum, a fungal endophyte of the liverwort Trichocolea tomentella. The structures of the new compounds (1, 2, 3a, and 3b) were elucidated by interpretation of spectroscopic data including one- and two-dimensional NMR techniques. Among these, compounds 2-4 displayed modest cytotoxicity to the MCF-7 hormone-dependent breast cancer cell line with IC
50 values of 8.4, 9.7, and 5.7 μM, respectively, whereas compound 9 exhibited selective cytotoxicity against the HT-29 colon cancer cell line with an IC50 value of 6.4 μM. During this study we confirmed that the brominated gentisyl alcohol (2) was formed by chemical conversion of 4 during bromide salt addition to culture media.- Published
- 2017
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23. Bioactive drimane sesquiterpenoids and aromatic glycosides from Cinnamosma fragrans.
- Author
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He D, Slebodnick C, and Rakotondraibe LH
- Subjects
- Antineoplastic Agents, Phytogenic isolation & purification, Breast Neoplasms drug therapy, Cell Proliferation drug effects, Female, Glycosides isolation & purification, Humans, MCF-7 Cells, Magnoliopsida chemistry, Models, Molecular, Plants, Medicinal chemistry, Polycyclic Sesquiterpenes, Sesquiterpenes isolation & purification, Antineoplastic Agents, Phytogenic chemistry, Antineoplastic Agents, Phytogenic pharmacology, Glycosides chemistry, Glycosides pharmacology, Sesquiterpenes chemistry, Sesquiterpenes pharmacology
- Abstract
Phytochemical investigation of the ethyl acetate and methanol extracts of the bark of Madagascan endemic and medicinal plant Cinnamosma fragrans led to the isolation of two drimane sesquiterpene derivatives: cinnafragroside A (1) and cinnafragrin E (2), two aromatic glycosides: 3,4,5-trimethoxyphenol 1-O-β-d-apiofuranosyl-(1→6)-β-d-glucopyranoside (3) and 3,4-dimethoxyphenyl-1-O-β-d-apiofuranosyl-(1→6)-β-d-glucopyranoside (4), together with 12 known compounds identified as: helicide (6), 1-(α-l-rhamnosyl(1→6)-β-d-glucopyranosyloxy)-3,4,5-trimethoxybenzene (7), vanilloloside (8), cinnamadin (9), ugandensolide (10), cinnamosmolide (11), cinnamolide (12), polygodial (13), cinnamodial (14), bemadienolide (15), 4-isopropyl-6-methyl-α-tetralone (16), and capsicodendrin (17). Another new compound, 11-norcinnafragrolide-9-one (5), was obtained during chemical derivatization of capsicodendrin and gave a hint to understanding the structure required for the antiproliferative activity of 17. The structures of the new compounds were elucidated based on the interpretation of their spectroscopic data including one and two dimensional nuclear magnetic resonance (1D- and 2D-NMR) and mass spectroscopic data. All isolated compounds were evaluated against the hormone dependent breast cancer cell line MCF-7. Compound 17 exhibited the most potent activity with an IC
50 value of 0.6μM. Our preliminary SAR study showed that the hydroxyl group at C-12' and the presence of conjugated carbonyl contribute to the antiproliferative activity., (Copyright © 2017 Elsevier Ltd. All rights reserved.)- Published
- 2017
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24. Angiostatic actions of capsicodendrin through selective inhibition of VEGFR2-mediated AKT signaling and disregulated autophagy.
- Author
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Pan CC, Shah N, Kumar S, Wheeler SE, Cinti J, Hoyt DG, Beattie CE, An M, Mythreye K, Rakotondraibe LH, and Lee NY
- Subjects
- Animals, Autophagy drug effects, Cell Line, Endothelial Cells drug effects, Fluorescent Antibody Technique, Humans, Magnoliaceae, Mice, Mice, Inbred C57BL, Signal Transduction drug effects, Zebrafish, Angiogenesis Inhibitors pharmacology, Neovascularization, Physiologic drug effects, Plant Extracts pharmacology, Proto-Oncogene Proteins c-akt antagonists & inhibitors, Vascular Endothelial Growth Factor Receptor-2 antagonists & inhibitors
- Abstract
Angiogenesis is the formation of new blood vessels from existing vasculature critical for embryonic development and vascular remodeling. Its dysregulation underlies numerous pathologic states ranging from ischemia to tumor growth and as such identifying new targeted- therapies is of significant interest for angiogenesis-based medicine. Here we evaluated the potential angiostatic properties of capsicodendrin (CPCD), a natural compound isolated from Cinnamosma macrocarpa, a plant belonging to the Malagasy Cinnamosma. CPCD potently inhibits endothelial proliferation, migration and capillary tube formation at nanomolar to low micromolar concentrations without inducing cytotoxic effects. We show that CPCD directly inactivates VEGFR2 and downstream AKT signaling, thereby strongly inducing autophagy as determined by increased expression of beclin1, autophagy-related gene (Atg) 3, Atg5 and LC3 cleavage. Ectopic AKT overexpression counteracts the inhibitory effects of CPCD on proliferation and capillary tubule formation. Importantly, CPCD treatment in vivo inhibits sprouting angiogenesis as evidenced by strongly reduced intersegmental vessel (ISV) sprouting and subintestinal vessel (SIV) formation during zebrafish embryonic development, and correlates with increased presence of LC3II along the ISVs despite overall reduced vasculature. These findings demonstrate CPCD as a potent inhibitor of the VEGFR2/AKT pathway at nanomolar concentrations and inducer of autophagy-related angiostatic effects.
- Published
- 2017
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- View/download PDF
25. Aerobic Decomposition of Trialkylquercetins: Structure Characterization and Antiproliferative Effect.
- Author
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Al-Jabban SM, Zhang X, Chen G, Rakotondraibe LH, and Chen QH
- Subjects
- Cell Line, Tumor, Drug Screening Assays, Antitumor, Humans, Antineoplastic Agents chemistry, Quercetin analogs & derivatives, Quercetin chemistry
- Abstract
The aerobic decomposition of 3,4',7-O-trialkylquercetins was first reported in this paper. The structures of four new decomposed products were characterized by analyzing the 1D and 2D NMR data, as well as their high resolution mass spectroscopic data. Their antiproliferative activity toward human prostate cancer cells has been assessed through WST-l cell proliferation assay. The decomposition mechanism was also proposed.
- Published
- 2016
26. Correction to Antiproliferative Trihydroxyalkylcyclohexenones from Pleiogynium timoriense.
- Author
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Eaton AL, Rakotondraibe LH, Brodie PJ, Goetz M, and Kingston DG
- Published
- 2016
- Full Text
- View/download PDF
27. Synthesis and Anti-Proliferative Effects of Quercetin Derivatives.
- Author
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Al-Jabban SM, Zhang X, Chen G, Mekuria EA, Rakotondraibe LH, and Chen QH
- Subjects
- Antineoplastic Agents, Phytogenic chemistry, Cell Line, Tumor, Cell Proliferation drug effects, Humans, Male, Molecular Structure, Prostatic Neoplasms drug therapy, Quercetin chemistry, Quercetin pharmacology, Antineoplastic Agents, Phytogenic pharmacology, Quercetin analogs & derivatives
- Abstract
Prostate cancer is the most common diagnosed invasive cancer in American men and is the second leading cause of cancer-related deaths. Although there are several therapies successful in treating early, localized stage prostate cancer, current treatment of advanced metastatic castration-resistant prostate cancer remains ineffective due to inevitable progression of resistance to first-line treatment with docetaxel. The natural product quercetin (3,3',4',5,7-pentahydroxyflavone), a flavonoid compound ubiquitous in dietary plants, possesses evidenced potential in treating advanced metastatic castration-resistant prostate cancer. However, its poor bioavailability and moderate potency hinder its advancement into clinical therapy. In order to engineer quercetin derivatives with improved potency and pharmacokinetic profiles for the treatment of advanced metastatic prostate cancer, we started this study with creating a small library of alkylated derivatives of quercetin for in vitro evaluation. The biological data and chemical reactivity of quercetin and its derivatives reported in literature directed us to design 3,4',7-O-trialkylquercetins as our first batch of targets. Consequently, nine 3,4',7-O-trialkylquercetins, together with four 3,7-O- dialkylquercetins, four 3,3',4',7-tetraalkylquercetins, and one 3,3',4'-O-trialkylquercetin, were prepared by one step O-alkylation of commercially available quercetin mediated by potassium carbonate. Their structures were determined by ID and 2D NMR data, and HRMS. Their anti-proliferative activities towards both androgen-refractory and androgen-sensitive prostate cancer cells were evaluated using WST-1 cell proliferation assay. The acquired structure-activity relationships indicate that 3,7-O-dialkylquercetins rather than 3,4',7-O-trialkylquercetins were much more potent than quercetin towards prostate cancer cells.
- Published
- 2015
28. A Synthetic Butenolide Diterpene is now a Natural Product Isolated from Metaporana sericosepala, a Plant from the Madagascar Dry Forest.
- Author
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Presley CC, Rakotondraibe LH, Brodie PJ, Callmander MW, Randrianaivo R, Rasamison VE, Rakotobe E, and Kingston DG
- Subjects
- 4-Butyrolactone chemistry, Climate, Madagascar, Molecular Structure, 4-Butyrolactone analogs & derivatives, Biological Products chemistry, Convolvulaceae chemistry, Diterpenes chemistry, Forests
- Abstract
Antiproliferative bioassay-guided fractionation of the ethanolic extract of the endemic Madagascan plant Metaporana sericosepala led to the first natural product isolation of a butenolide diterpene, which was synthesized during an anti-inflammatory study in 1988. The structure of the compound was elucidated as 3-homofarnesyl-4-hydroxybutenolide (1) by analysis of its spectroscopic data, including 1D- and 2D-NMR data and chemical evidence. The once synthetic compound can now also be considered as a natural product. Compound 1 had modest antiproliferative activity towards the A2780 ovarian cancer cell line,with an IC50 value of 8 µM.
- Published
- 2015
29. New Bioactive Lupane Triterpene Coumaroyl Esters Isolated from Buxus cochinchinensis.
- Author
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Pan L, Muñoz Acuña U, Chai H, Park HY, Ninh TN, Thanh BV, Merino EF, Cassera MB, Rakotondraibe LH, Carcache de Blanco EJ, Soejarto DD, and Kinghorn AD
- Subjects
- Alkaloids isolation & purification, Alkaloids pharmacology, Antimalarials isolation & purification, Antimalarials pharmacology, Esters chemistry, Esters isolation & purification, Esters pharmacology, HT29 Cells, Humans, Inhibitory Concentration 50, Molecular Structure, Plant Extracts isolation & purification, Plant Extracts pharmacology, Plasmodium falciparum drug effects, Triterpenes isolation & purification, Triterpenes pharmacology, Vietnam, Alkaloids chemistry, Antimalarials chemistry, Buxus chemistry, Plant Extracts chemistry, Triterpenes chemistry
- Abstract
Five new lupane triterpene coumaroyl esters (1-5), together with betulin (6) and a known Buxus alkaloid, N-3-benzoyldihydrocyclomicrophylline F (7), were isolated from a CHCl3-soluble partition of a methanol extract of Buxus cochinchinensis Pierre ex Gagnep. (Buxaceae) collected in Vietnam. Isolation work was monitored using human colon cancer cells (HT-29). The structures of the new compounds (1-5) were determined on the basis of spectroscopic data interpretation. In addition to their cytotoxicity against HT-29 cells and nuclear factor-kappa B (p65) inhibitory activity in an enzyme-linked immunosorbent assay, all isolates as well as two semisynthetic compounds derived from betulin and 5, respectively, were also evaluated for their in vitro antiplasmodial activities against the drug-resistant Dd2 strain of Plasmodium falciparum and antifungal effects on the growth of the pathogenic yeast Candida albicans. The new lupane triterpene coumaroyl esters (1-5), along with a betulin derivative and the known Buxus alkaloid, were found to show significant in vitro antimalarial activities, with IC50 values ranging from 0.26 to 2.07 µM., (Georg Thieme Verlag KG Stuttgart · New York.)
- Published
- 2015
- Full Text
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30. Antiproliferative Trihydroxyalkylcyclohexenones from Pleiogynium timoriense.
- Author
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Eaton AL, Rakotondraibe LH, Brodie PJ, Goetz M, and Kingston DG
- Subjects
- Antineoplastic Agents, Phytogenic chemistry, Cyclohexanones chemistry, Drug Screening Assays, Antitumor, Female, Humans, Inhibitory Concentration 50, Molecular Structure, Plant Bark chemistry, Tonga, Anacardiaceae chemistry, Antineoplastic Agents, Phytogenic isolation & purification, Antineoplastic Agents, Phytogenic pharmacology, Cyclohexanones isolation & purification, Cyclohexanones pharmacology
- Abstract
Investigation of a DCM extract of the bark of Pleiogynium timoriense from the former Merck collection of natural product extracts for antiproliferative activity indicated that it was active with an IC50 value of 1.3 μg/mL against the A2780 ovarian cancer cell line. Bioassay-directed fractionation of this extract yielded the three new bioactive trihydroxyalkylcyclohexenones 1-3. Their structures were determined by a combination of spectroscopic and chemical methods. Compounds 1-3 exhibited submicromolar antiproliferative activity against the A2780 human ovarian cancer cell line, with IC50 values of 0.8, 0.7, and 0.8 μM, respectively.
- Published
- 2015
- Full Text
- View/download PDF
31. Antiproliferative Compounds from Cleistanthus boivinianus from the Madagascar Dry Forest.
- Author
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Liu Y, Young K, Rakotondraibe LH, Brodie PJ, Wiley JD, Cassera MB, Callmander MW, Rakotondrajaona R, Rakotobe E, Rasamison VE, TenDyke K, Shen Y, and Kingston DG
- Subjects
- 4-Butyrolactone analogs & derivatives, 4-Butyrolactone chemistry, Antineoplastic Agents, Phytogenic chemistry, Cell Proliferation drug effects, Dioxoles chemistry, Drug Screening Assays, Antitumor, Forests, HCT116 Cells, Humans, Inhibitory Concentration 50, Lignans chemistry, Madagascar, Molecular Structure, Nuclear Magnetic Resonance, Biomolecular, Plant Leaves chemistry, Plasmodium falciparum drug effects, Stereoisomerism, Antineoplastic Agents, Phytogenic isolation & purification, Antineoplastic Agents, Phytogenic pharmacology, Lignans isolation & purification, Lignans pharmacology, Malpighiaceae chemistry
- Abstract
The two new lignans 3α-O-(β-D-glucopyranosyl)desoxypodophyllotoxin (1) and 4-O-(β-D-glucopyranosyl)dehydropodophyllotoxin (2) were isolated from Cleistanthus boivinianus, together with the known lignans deoxypicropodophyllotoxin (3), (±)-β-apopicropodophyllin (4), (-)-desoxypodophyllotoxin (5), (-)-yatein (6), and β-peltatin-5-O-β-D-glucopyranoside (7). The structures of all compounds were characterized by spectroscopic techniques. Compounds 1, 4, and 5 showed potent antiproliferative activities against the A2780 ovarian cancer cell line, with IC50 values of 33.0 ± 3.6, 63.1 ± 6.7, and 230 ± 1 nM, respectively. Compounds 2 and 7 showed only modest A2780 activities, with IC50 values of 2.1 ± 0.3 and 4.9 ± 0.1 μM, respectively, while compounds 3 and 6 had IC50 values of >10 μM. Compound 1 also had potent antiproliferative activity against the HCT-116 human colon carcinoma cell line, with an IC50 value of 20.5 nM, and compound 4 exhibited modest antiproliferative activity against the A2058 human caucasian metastatic melanoma and MES-SA human uterine sarcoma cell lines, with IC50 values of 4.6 and 4.0 μM, respectively.
- Published
- 2015
- Full Text
- View/download PDF
32. Antimalarial 5,6-Dihydro-α-pyrones from Cryptocarya rigidifolia: Related Bicyclic Tetrahydro-α-Pyrones Are Artifacts1.
- Author
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Liu Y, Rakotondraibe LH, Brodie PJ, Wiley JD, Cassera MB, Miller JS, Ratovoson F, Rakotobe E, Rasamison VE, and Kingston DG
- Subjects
- Antimalarials chemistry, Circular Dichroism, Crystallography, X-Ray, Molecular Structure, Nuclear Magnetic Resonance, Biomolecular, Pyrones chemistry, Structure-Activity Relationship, Antimalarials isolation & purification, Antimalarials pharmacology, Cryptocarya chemistry, Pyrones isolation & purification, Pyrones pharmacology
- Abstract
Antimalarial bioassay-guided fractionation of an EtOH extract of the root wood of Cryptocarya rigidifolia (Lauraceae) led to the isolation of the five new 5,6-dihydro-α-pyrones cryptorigidifoliols A-E (1-5) and the six bicyclic tetrahydro-α-pyrone derivatives cryptorigidifoliols F-K (6-11). The structure elucidations of all compounds were made on the basis of the interpretation of spectroscopic data and chemical derivatization, and the relative and absolute configurations were determined by NOESY, electronic circular dichroism (ECD), and (1)H NMR analysis of α-methoxyphenylacetyl (MPA) derivatives. The bicyclic tetrahydro-α-pyrone derivatives were identified as products of acid-catalyzed intramolecular Michael addition of the 5,6-dihydro-α-pyrones in the presence of silica gel. A structure-activity relationship study suggested that the presence of an α,β-unsaturated carbonyl moiety is not essential for potent antimalarial activity.
- Published
- 2015
- Full Text
- View/download PDF
33. Antiproliferative Compounds from Ocotea macrocarpa from the Madagascar Dry Forest 1 .
- Author
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Liu Y, Cheng E, Rakotondraibe LH, Brodie PJ, Applequist W, Randrianaivo R, Rakotondrafara A, Ratsimbason M, Rasamison VE, and Kingston DG
- Abstract
Bioassay-directed fractionation of an antiproliferative ethanol extract of the roots of Ocotea macrocarpa (Lauraceae) afforded the new butanolide macrocarpolide A ( 1 ), and the two new secobutanolides macrocarpolides B ( 2 ) and C ( 3 ), together with the known butanolides linderanolide B ( 4 ) and isolinderanolide ( 5 ). The structure elucidation of all compounds was carried out based on NMR and mass spectroscopic data analyses. The absolute configurations of all compounds isolated were determined by comparison of their optical rotation values with those found in literature. Compounds 1 - 5 showed good antiproliferative activities against the A2780 ovarian cell line, with IC
50 values of 2.57 ± 0.12 ( 1 ), 1.98 ± 0.23 ( 2 ), 1.67 ± 0.05 ( 3 ), 2.43 ± 0.41 ( 4 ), and 1.65 ± 0.44 µM ( 5 ), respectively.- Published
- 2015
- Full Text
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34. Antiproliferative Constituents of the Roots of Ethiopian Podocarpus falcatus and Structure Revision of 2α-Hydroxynagilactone F and Nagilactone I.
- Author
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Addo EM, Chai HB, Hymete A, Yeshak MY, Slebodnick C, Kingston DG, and Rakotondraibe LH
- Subjects
- Abietanes, Antineoplastic Agents, Phytogenic chemistry, Diterpenes chemistry, Drug Screening Assays, Antitumor, Ethiopia, HT29 Cells, Humans, Molecular Structure, Nuclear Magnetic Resonance, Biomolecular, Plant Roots chemistry, Antineoplastic Agents, Phytogenic isolation & purification, Antineoplastic Agents, Phytogenic pharmacology, Diterpenes isolation & purification, Diterpenes pharmacology, Pinaceae chemistry
- Abstract
Bioassay-guided fractionation using the human colorectal adenocarcinoma (HT-29) cell line of the methanol extract of dried roots of Podocarpus falcatus led to the isolation of two new type C nagilactones, 16-hydroxynagilactone F (1) and 2β,16-dihydroxynagilactone F (2), and the new totarane-type bisditerpenoid 7β-hydroxymacrophyllic acid (4), along with the seven known compounds 2β-hydroxynagilactone F (3), macrophyllic acid (5), nagilactone D (6), 15-hydroxynagilactone D (7), nagilactone I (8), inumakiol D (9), and ponasterone A (10). The structures of the new compounds were determined by 1D and 2D NMR, HRESIMS, UV, and IR and by comparison with the reported spectroscopic data of their congeners. The orientation of the C-2 hydroxy group of 3 and 8 was revised to be β based on evidence from detailed analysis of 1D and 2D NMR data and single-crystal X-ray diffraction studies. Among the isolated compounds, the nagilactones, including the new dilactones 16-hydroxynagilactone F (1) and 2β,16-dihydroxynagilactone F (2), were the most active (IC50 0.3-5.1 μM range) against the HT-29 cell line, whereas the bisditerpenoids (4 and 5) and the other known compounds 9 and 10 were inactive. The presence of the bioactive nagilactones in P. falcatus supports its traditional use.
- Published
- 2015
- Full Text
- View/download PDF
35. Neolignans and other metabolites from Ocotea cymosa from the Madagascar rain forest and their biological activities.
- Author
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Rakotondraibe LH, Graupner PR, Xiong Q, Olson M, Wiley JD, Krai P, Brodie PJ, Callmander MW, Rakotobe E, Ratovoson F, Rasamison VE, Cassera MB, Hahn DR, Kingston DG, and Fotso S
- Subjects
- Animals, Drug Screening Assays, Antitumor, Female, Forests, Humans, Insecticides chemistry, Lignans chemistry, Lignans pharmacology, Madagascar, Molecular Structure, Nuclear Magnetic Resonance, Biomolecular, Plasmodium falciparum drug effects, Spodoptera drug effects, Insecticides isolation & purification, Insecticides pharmacology, Lignans isolation & purification, Ocotea chemistry
- Abstract
Ten new neolignans including the 6'-oxo-8.1'-lignans cymosalignans A (1a), B (2), and C (3), an 8.O.6'-neolignan (4a), ococymosin (5a), didymochlaenone C (6a), and the bicyclo[3.2.1]octanoids 7-10 were isolated along with the known compounds 3,4,5,3',5'-pentamethoxy-1'-allyl-8.O.4'-neolignan, 3,4,5,3'-tetramethoxy-1'-allyl-8.O.4'-neolignan, didymochlaenone B, virologin B, ocobullenone, and the unusual 2'-oxo-8.1'-lignan sibyllenone from the stems or bark of the Madagascan plant Ocotea cymosa. The new 8.O.6'-neolignan 4a, dihydrobenzofuranoid 5a, and the bicyclo[3.2.1]octanoid 7a had in vitro activity against Aedes aegypti, while the new compounds 5a, 7a, 8, and 10a and the known virolongin B (4b) and ocobullenone (10b) had antiplasmodial activity. We report herein the structure elucidation of the new compounds on the basis of spectroscopic evidence, including 1D and 2D NMR spectra, electronic circular dichroism, and mass spectrometry, and the biological activities of the new and known compounds.
- Published
- 2015
- Full Text
- View/download PDF
36. In planta variation of volatile biosynthesis: an alternative biosynthetic route to the formation of the pathogen-induced volatile homoterpene DMNT via triterpene degradation in Arabidopsis roots.
- Author
-
Sohrabi R, Huh JH, Badieyan S, Rakotondraibe LH, Kliebenstein DJ, Sobrado P, and Tholl D
- Subjects
- Arabidopsis genetics, Chromatography, Gas, Gene Expression Regulation, Plant, Genes, Plant, Mass Spectrometry, Molecular Docking Simulation, Organ Specificity, Plant Roots genetics, Plant Roots microbiology, Pythium growth & development, Pythium physiology, Saccharomyces cerevisiae metabolism, Substrate Specificity, Triterpenes chemistry, Arabidopsis metabolism, Arabidopsis microbiology, Biosynthetic Pathways, Plant Roots metabolism, Terpenes metabolism, Triterpenes metabolism, Volatile Organic Compounds metabolism
- Abstract
Plant-derived volatile compounds such as terpenes exhibit substantial structural variation and serve multiple ecological functions. Despite their structural diversity, volatile terpenes are generally produced from a small number of core 5- to 20-carbon intermediates. Here, we present unexpected plasticity in volatile terpene biosynthesis by showing that irregular homo/norterpenes can arise from different biosynthetic routes in a tissue specific manner. While Arabidopsis thaliana and other angiosperms are known to produce the homoterpene (E)-4,8-dimethyl-1,3,7-nonatriene (DMNT) or its C16-analog (E,E)-4,8,12-trimethyl-1,3,7,11-tridecatetraene by the breakdown of sesquiterpene and diterpene tertiary alcohols in aboveground tissues, we demonstrate that Arabidopsis roots biosynthesize DMNT by the degradation of the C30 triterpene diol, arabidiol. The reaction is catalyzed by the Brassicaceae-specific cytochrome P450 monooxygenase CYP705A1 and is transiently induced in a jasmonate-dependent manner by infection with the root-rot pathogen Pythium irregulare. CYP705A1 clusters with the arabidiol synthase gene ABDS, and both genes are coexpressed constitutively in the root stele and meristematic tissue. We further provide in vitro and in vivo evidence for the role of the DMNT biosynthetic pathway in resistance against P. irregulare. Our results show biosynthetic plasticity in DMNT biosynthesis in land plants via the assembly of triterpene gene clusters and present biochemical and genetic evidence for volatile compound formation via triterpene degradation in plants., (© 2015 American Society of Plant Biologists. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
37. Nitrogen-containing dimeric nor-multiflorane triterpene from a Turraea sp.
- Author
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Rasamison VE, Rakotondraibe LH, Slebodnick C, Brodie PJ, Ratsimbason M, TenDyke K, Shen Y, Randrianjanaka LM, and Kingston DG
- Subjects
- Antimalarials chemistry, Antimalarials pharmacology, Antineoplastic Agents, Phytogenic chemistry, Antineoplastic Agents, Phytogenic pharmacology, Chloroquine pharmacology, Drug Screening Assays, Antitumor, Humans, Inhibitory Concentration 50, Molecular Structure, Plant Leaves chemistry, Plasmodium falciparum drug effects, Triterpenes chemistry, Triterpenes pharmacology, Antimalarials isolation & purification, Antineoplastic Agents, Phytogenic isolation & purification, Meliaceae chemistry, Nitrogen chemistry, Triterpenes isolation & purification
- Abstract
The new triterpene turranoic acid (1) and the new N-containing nor-triterpene turraenine (2), along with triptocallic acid B (3) and esculentoic acid (4) were isolated from leaves of a Turraea sp. Compounds 1-3 showed weak to moderate in vitro antiplasmodial activity against the chloroquine-resistant Plasmodium falciparum strain FCM29. Compound 1 also displayed weak cytotoxic activity against the nonsmall lung cancer cell line H522-T1 with an IC50 value of 16.4 μM.
- Published
- 2014
- Full Text
- View/download PDF
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