Publications by authors named "Djaja D Soejarto"

47 Publications

Spermidine alkaloid and glycosidic constituents of Vietnamese .

Phytochem Lett 2021 Jun 15;43:154-162. Epub 2021 Apr 15.

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.

Phytochemical investigation of the aerial parts of led to the isolation of secondary metabolites belonging to the spermidine alkaloid, glycoside, depsidone and phenol classes. Of the eleven secondary metabolites isolated in this study, two spermidine alkaloids, dovyalicins H () and I (), which belong to a rare group among this class, and six glycosides () are previously undescribed. The structures of all new isolates were determined by interpretation of spectroscopic and spectrometric data. In this report, the structural elucidation of these unprecedented secondary metabolites () is described.
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http://dx.doi.org/10.1016/j.phytol.2021.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078847PMC
June 2021

A pentamethoxylated flavone from Glycosmis ovoidea promotes apoptosis through the intrinsic pathway and inhibits migration of MCF-7 breast cancer cells.

Phytother Res 2021 Mar 30;35(3):1634-1645. Epub 2020 Oct 30.

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA.

The rare flavone 5,3'-dihydroxy-3,6,7,8,4'-pentamethoxyflavone (PMF) has been isolated from several plant species, and its cytotoxic activity has been reported against many types of cancer cells. In this study, PMF was purified from Glycomis ovoidea collected in Vietnam, and its antiproliferative effects and underlying mechanism of action were investigated against MCF-7 cells. PMF inhibited growth in MCF-7 > MCF-10A > MDA-MB-231 cells after 72 hr treatment, with IC values of 1.5, 1.9, and 8.6 μg/ml, respectively. Further experiments conducted with this compound in MCF-7 cells, showed the loss of mitochondrial membrane potential, reactive oxygen species overproduction, upregulation of BAX, cytochrome c, caspase-3 and PARP-1 and down-regulation of BCL-2 proteins as well as an increase in caspase-3/-7 activity, suggesting induction of the apoptotic intrinsic pathway. Furthermore, PMF increased cell cycle arrest in the G phase, which correlated with increments in the p53 and p21 levels. Additionally, MCF-7 cell migration was inhibited, which could be related to NF-κB p65 downregulation. Finally, PMF did not show toxicity in vivo in a zebrafish (Danio rerio) model. In conclusion, PMF induces cell death in MCF-7 cells through regulation of the BCL-2 protein family and may be proposed as a lead as a potential alternative for breast cancer therapy.
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http://dx.doi.org/10.1002/ptr.6930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005457PMC
March 2021

Cytotoxic and non-cytotoxic cardiac glycosides isolated from the combined flowers, leaves, and twigs of Streblus asper.

Bioorg Med Chem 2020 02 7;28(4):115301. Epub 2020 Jan 7.

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, United States. Electronic address:

A new non-cytotoxic [(+)-17β-hydroxystrebloside (1)] and two known cytotoxic [(+)-3'-de-O-methylkamaloside (2) and (+)-strebloside (3)] cardiac glycosides were isolated and identified from the combined flowers, leaves, and twigs of Streblus asper collected in Vietnam, with the absolute configuration of 1 established from analysis of its ECD and NMR spectroscopic data and confirmed by computational ECD calculations. A new 14,21-epoxycardanolide (3a) was synthesized from 3 that was treated with base. A preliminary structure-activity relationship study indicated that the C-14 hydroxy group and the C-17 lactone unit and the established conformation are important for the mediation of the cytotoxicity of 3. Molecular docking profiles showed that the cytotoxic 3 and its non-cytotoxic analogue 1 bind differentially to Na/K-ATPase. Compound 3 docks deeply in the Na/K-ATPase pocket with a sole pose, and its C-10 formyl and C-5, C-14, and C-4' hydroxy groups may form hydrogen bonds with the side-chains of Glu111, Glu117, Thr797, and Arg880 of Na/K-ATPase, respectively. However, 1 fits the cation binding sites with at least three different poses, which all depotentiate the binding between 1 and Na/K-ATPase. Thus, 3 was found to inhibit Na/K-ATPase, but 1 did not. In addition, the cytotoxic and Na/K-ATPase inhibitory 3 did not affect glucose uptake in human lung cancer cells, against which it showed potent activity, indicating that this cardiac glycoside mediates its cytotoxicity by targeting Na/K-ATPase but not by interacting with glucose transporters.
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http://dx.doi.org/10.1016/j.bmc.2019.115301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029422PMC
February 2020

Structurally Modified Cyclopenta[]benzofuran Analogues Isolated from .

J Nat Prod 2019 10 17;82(10):2870-2877. Epub 2019 Oct 17.

Institute of Ecology and Biological Resources , Vietnamese Academy of Science and Technology , Hanoi , Vietnam.

Four new cyclopenta[]benzofuran derivatives based on an unprecedented carbon skeleton (-), with a dihydrofuran ring fused to dioxanyl and aryl rings, along with a new structural analogue () of 5‴-episilvestrol (episilvestrol, ), were isolated from an aqueous extract of a large-scale re-collection of the roots of collected in Vietnam. Compound 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 () and episilvestrol () 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 exhibited cytotoxic activity against a human colon cancer (HT-29) and human prostate cancer cell line (PC-3), with IC values of 2.3 μM in both cases. The isolated compounds (-) double the number of dioxanyl ring-containing rocaglate analogues reported to date from species and present additional information on the structural requirements for cancer cell line cytotoxicity within this compound class.
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http://dx.doi.org/10.1021/acs.jnatprod.9b00631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819999PMC
October 2019

Highly sweet compounds of plant origin: From ethnobotanical observations to wide utilization.

J Ethnopharmacol 2019 Oct 3;243:112056. Epub 2019 Jul 3.

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, 43210, USA. Electronic address:

Ethnopharmacological Relevance: Ethnobotanical studies have been of very great importance in recognizing plants that contain substances that modulate the heterodimer T1R2-T1R3 sweet taste receptor, inclusive of Stevia rebaudiana (Asteraceae) and Siraitia grosvenorii (Cucurbitaceae).

Aim Of The Review: In addition to reviewing relevant ethnobotanical literature, inclusive of original field work conducted, the authors have provided a progress report on the ultimate regulatory acceptance of highly sweet ent-kaurane (steviol) diterpene glycosides from S. rebaudiana leaves ("stevia") and cucurbitane triterpene glycosides (mogrosides) from the fruits of S. grosvenorii (popularly known as "monk fruit"). Despite their relatively high prices relative to that of sucrose, the steviol glycosides and mogrosides are of current great interest for further more extensive utilization on the market as sweet-tasting non-caloric food additives, due to increases in the rates of obesity and diabetes all over the world. Recent phytochemical work on the sweet principles of these two species is highlighted, including the important "next-generation" sweetener, rebaudioside M, from S. rebaudiana.

Results: Initial observations on the ethnobotany of both S. rebaudiana and S. grosvenorii have proved crucial to indicating the presence of their sweet-tasting principles to the wider scientific community.

Conclusions: Ethnobotanical observations have been pivotal in enabling the discovery of many sweet-tasting plant constituents, with those of S. rebaudiana and S. grosvenorii both being examples. Extractives prepared from these species are now commercially used widely in the U.S. as additives for the sweetening of foods and beverages.
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http://dx.doi.org/10.1016/j.jep.2019.112056DOI Listing
October 2019

Caspase-Dependent Apoptosis in Prostate Cancer Cells and Zebrafish by Corchorusoside C from Streptocaulon juventas.

J Nat Prod 2019 06 23;82(6):1645-1655. Epub 2019 May 23.

Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy , University of Illinois at Chicago , Chicago , Illinois 60612 , United States.

Corchorusoside C (1), isolated from Streptocaulon juventas collected in Vietnam, was found to be nontoxic in a zebrafish ( Danio rerio) model and to induce cytotoxicity in several cancer cell lines with notable selective activity against prostate DU-145 cancer cells (IC 0.08 μM). Moreover, corchorusoside C induced DU-145 cell shrinkage and cell detachment. In CCD-112CoN colon normal cells, 1 showed significantly reduced cytotoxic activity (IC 2.3 μM). A preliminary mechanistic study indicated that 1 inhibits activity and protein expression of NF-κB (p50 and p65), IKK (α and β), and ICAM-1 in DU-145 cells. ROS concentrations increased at 5 h post-treatment, and MTP decreased in a dose-dependent manner. Moreover, decreased protein expression of Bcl-2 and increased expression of PARP-1 was observed. Furthermore, corchorusoside C increased both the activity and protein levels of caspases 3 and 7. Additionally, 1 induced sub-G1 population increase of DU-145 cells and modulated caspases in zebrafish with nondifferential morphological effects. Therefore, corchorusoside C (1) induces apoptosis in DU-145 cells and targets the same pathways both in vitro and in vivo in zebrafish. Thus, the use of zebrafish assays seems worthy of wider application than is currently employed for the evaluation of potential anticancer agents of natural origin.
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http://dx.doi.org/10.1021/acs.jnatprod.9b00140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615048PMC
June 2019

Potential Anticancer Agents Characterized from Selected Tropical Plants.

J Nat Prod 2019 03 4;82(3):657-679. Epub 2019 Mar 4.

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy , The Ohio State University , Columbus , Ohio 43210 , United States.

Higher plants are well known for their value in affording clinically useful anticancer agents, with such compounds acting against cancer cells by a range of mechanisms of action. There remains a strong interest in the discovery and development of plant secondary metabolites as additional cancer chemotherapeutic lead compounds. In the present review, progress on the discovery of plant-derived compounds of the biflavonoid, lignan, sesquiterpene, steroid, and xanthone structural types is presented. Several potential anticancer leads of these types have been characterized from tropical plants collected in three countries as part of our ongoing collaborative multi-institutional project. Preliminary structure-activity relationships and work on in vivo testing and cellular mechanisms of action are also discussed. In addition, the relevant work reported by other groups on the same compound classes is included herein.
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http://dx.doi.org/10.1021/acs.jnatprod.9b00018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441492PMC
March 2019

Bioactivity-Guided Isolation of Totarane-Derived Diterpenes from Podocarpus neriifolius and Structure Revision of 3-Deoxy-2α-hydroxynagilactone E.

Nat Prod Bioprospect 2019 Apr 19;9(2):157-163. Epub 2019 Feb 19.

Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University, College of Pharmacy, Columbus, OH, USA.

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 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.
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http://dx.doi.org/10.1007/s13659-019-0198-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426912PMC
April 2019

Cytotoxic and NF-κB and mitochondrial transmembrane potential inhibitory pentacyclic triterpenoids from Syzygium corticosum and their semi-synthetic derivatives.

Bioorg Med Chem 2018 08 17;26(15):4452-4460. Epub 2018 Jul 17.

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, United States. Electronic address:

Syzygium is a large genus of flowering plants, with several species, including the clove tree, used as important resources in the food and pharmaceutical industries. In our continuing search for anticancer agents from higher plants, a chloroform extract of the leaves and twigs of Syzygium corticosum collected in Vietnam was found to be active toward the HT-29 human colon cancer cell line. Separation of this extract guided by HT-29 cells and nuclear factor-kappa B (NF-κB) inhibition yielded 19 known natural products, including seven triterpenoids, three ellagic acid derivatives, two methylated flavonoids, a cyclohexanone, four megastigmanes, a small lactone, and an aromatic aldehyde. The full stereochemistry of (+)-fouquierol (2) was defined for the first time. Biological investigations showed that (+)-ursolic acid (1) is the major cytotoxic component of S. corticosum, which exhibited also potent activities in the NF-κB and mitochondrial transmembrane potential (MTP) inhibition assays conducted, with IC values of 31 nM and 3.5 µM, respectively. Several analogues of (+)-ursolic acid (1) were synthesized, and a preliminary structure-activity relationship (SAR) study indicated that the C-3 hydroxy and C-28 carboxylic acid groups and 19,20-dimethyl substitution are all essential in the mediation of the bioactivities observed for this triterpenoid.
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http://dx.doi.org/10.1016/j.bmc.2018.07.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6177235PMC
August 2018

Revisiting the linkage between ethnomedical use and development of new medicines: A novel plant collection strategy towards the discovery of anticancer agents.

J Med Plant Res 2017 Oct 25;11(40):621-634. Epub 2017 Oct 25.

Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 S. Wood St., Chicago, Illinois 60612, USA.

The Vietnam-Laos International Cooperative Biodiversity Group (ICBG) based at the University of Illinois at Chicago (UIC) catalyzed a country-wide network of medicinal plant preserves (MPP) and medicinal biodiversity preserves (MBP) now established in ten provinces of the Lao People's Democratic Republic (Lao PDR), which are relied upon as protected sources of ethnomedicines for local villagers and traditional healers. In collaboration with the Lao PDR's Institute of Traditional Medicine (ITM), our ongoing P01 Program Project (Ohio State University) examined the anticancer bioprospecting potential for two of the most exhaustively inventoried of these sites: the Bolikhamxay MPP and the Xiengkhouang MBP. Guided by prior voucher specimens sourced from these preserves with an overwhelming emphasis on plants employed in traditional medicine, 201 distinct samples from 96 species were collected along with proper herbarium documentation. Aliquots of these plant samples were extracted in azeotropic ethanol and evaporated to dryness for initial biological evaluation. In six samples from six different species (2.99% of the collected samples, 6.25% of taxa) it was observed that extracts exhibited notable cytotoxicity against HT-29 colon adenocarcinoma cells. The wisdom behind the utilization of HT-29 cells in this preliminary biological screen is discussed. Furthermore, comparison of screening results based on longstanding considerations and ideological underpinnings of ethnobotanical vs. "random" biodiversity-based collection approaches is detailed herein. The results of this interdisciplinary study support the hypothesis that, by privileging the initial sample set in terms of human safety and pharmacological activity, ethnobotanically driven collection for biological screening efforts can produce leads unprecedented by the strict traditional usages of plants.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5686776PMC
http://dx.doi.org/10.5897/jmpr2017.6485DOI Listing
October 2017

Potent Inhibitor of Drug-Resistant HIV-1 Strains Identified from the Medicinal Plant Justicia gendarussa.

J Nat Prod 2017 06 14;80(6):1798-1807. Epub 2017 Jun 14.

Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago , 835 South Wolcott Avenue, Chicago, Illinois 60612, United States.

Justicia gendarussa, a medicinal plant collected in Vietnam, was identified as a potent anti-HIV-1 active lead from the evaluation of over 4500 plant extracts. Bioassay-guided separation of the extracts of the stems and roots of this plant led to the isolation of an anti-HIV arylnaphthalene lignan (ANL) glycoside, patentiflorin A (1). Evaluation of the compound against both the M- and T-tropic HIV-1 isolates showed it to possess a significantly higher inhibition effect than the clinically used anti-HIV drug AZT. Patentiflorin A and two congeners were synthesized, de novo, as an efficient strategy for resupply as well as for further structural modification of the anti-HIV ANL glycosides in the search for drug leads. Subsequently, it was determined that the presence of a quinovopyranosyloxy group in the structure is likely essential to retain the high degree of anti-HIV activity of this type of compounds. Patentiflorin A was further investigated against the HIV-1 gene expression of the R/U5 and U5/gag transcripts, and the data showed that the compound acts as a potential inhibitor of HIV-1 reverse transcription. Importantly, the compound displayed potent inhibitory activity against drug-resistant HIV-1 isolates of both the nucleotide analogue (AZT) and non-nucleotide analogue (nevaripine). Thus, the ANL glycosides have the potential to be developed as novel anti-HIV drugs.
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http://dx.doi.org/10.1021/acs.jnatprod.7b00004DOI Listing
June 2017

Cardiac Glycoside Constituents of Streblus asper with Potential Antineoplastic Activity.

J Nat Prod 2017 03 16;80(3):648-658. Epub 2016 Dec 16.

Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago , Chicago, Illinois 60612, United States.

Three new (1-3) and two known (4 and 5) cytotoxic cardiac glycosides were isolated and characterized from a medicinal plant, Streblus asper Lour. (Moraceae), collected in Vietnam, with six new analogues and one known derivative (5a-g) synthesized from (+)-strebloside (5). A preliminary structure-activity relationship study indicated that the C-10 formyl and C-5 and C-14 hydroxy groups and C-3 sugar unit play important roles in the mediation of the cytotoxicity of (+)-strebloside (5) against HT-29 human colon cancer cells. When evaluated in NCr nu/nu mice implanted intraperitoneally with hollow fibers facilitated with either MDA-MB-231 human breast or OVCAR3 human ovarian cancer cells, (+)-strebloside (5) showed significant cell growth inhibitory activity in both cases, in the dose range 5-30 mg/kg.
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http://dx.doi.org/10.1021/acs.jnatprod.6b00924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5365359PMC
March 2017

Isolation of Bioactive Rotenoids and Isoflavonoids from the Fruits of Millettia caerulea.

Planta Med 2016 Jul 9;82(11-12):1096-104. Epub 2016 Jun 9.

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio, United States.

Three new rotenoids (1-3), two new isoflavonoids (4 and 5), and six known analogues (6-11) were isolated from an n-hexane partition of a methanol extract of the fruits of Millettia caerulea, with the structures of the new compounds elucidated by analysis of their spectroscopic data. The relative configurations of the rotenoids were determined by interpretation of their NMR spectroscopic data, and their absolute configurations were established using electronic circular dichroism spectra and specific rotation values. All compounds isolated were evaluated for their cell growth inhibitory activity against the HT-29 human colon cancer cell line, and the known compounds, (-)-3-hydroxyrotenone (6) and (-)-rotenone (7), were found to be potently active. When tested in an NF-κB inhibition assay, compound 6 showed activity. This compound, along with the new compound, (-)-caeruleanone D (1), and the known compound, ichthynone (8), exhibited K-Ras inhibitory potency. Further bioactivity studies showed that the new compounds, (-)-3-deoxycaeruleanone D (2) and (-)-3-hydroxycaeruleanone A (3), and the known compounds 8 and 11 induced quinone reductase in murine Hepa 1c1c7 cells.
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http://dx.doi.org/10.1055/s-0042-108059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4956498PMC
July 2016

New Bioactive Lupane Triterpene Coumaroyl Esters Isolated from Buxus cochinchinensis.

Planta Med 2015 Aug 1;81(12-13):1133-40. Epub 2015 Jul 1.

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, USA.

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.
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http://dx.doi.org/10.1055/s-0035-1546118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4545412PMC
August 2015

Species-specific Standardisation of Licorice by Metabolomic Profiling of Flavanones and Chalcones.

Phytochem Anal 2014 Jul-Aug;25(4):378-88. Epub 2013 Nov 13.

Introduction: Major phenolics from licorice roots (Glycyrrhiza sp.) are glycosides of the flavanone liquiritigenin (F) and its 2′-hydroxychalcone isomer, isoliquiritigenin (C). As the F and C contents fluctuate between batches of licorice, both quality control and standardisation of its preparations become complex tasks.

Objective: To characterise the F and C metabolome in extracts from Glycyrrhiza glabra L. and Glycyrrhiza uralensis Fisch. ex DC. by addressing their composition in major F–C pairs and defining the total F:C proportion.

Material And Methods: Three types of extracts from DNA-authenticated samples were analysed by a validated UHPLC/UV method to quantify major F and C glycosides. Each extract was characterised by the identity of major F–C pairs and the proportion of Fs among all quantified Fs:Cs.

Results: The F and C compositions and proportions were found to be constant for all extracts from a Glycyrrhiza species. All G. uralensis extracts contained up to 2.5 more Fs than G. glabra extracts. Major F–C pairs were B-ring glycosidated in G. uralensis, and A-/B-ring apiosyl-glucosidated in the G. glabra extracts. The F:C proportion was found to be linked to the glycosidation site: the more B-ring F-C glycosides were present, the higher was the final F:C proportion in the extract. These results enable the chemical differentiation of extracts from G. uralensis and G. glabra, which are characterised by total F:C proportions of 8.37:1.63 and 7.18:2.82, respectively.

Conclusion: Extracts from G. glabra and G. uralensis can be differentiated by their respective F and C compositions and proportions, which are both useful for further standardisation of licorice botanicals.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4391967PMC
http://dx.doi.org/10.1002/pca.2472DOI Listing
October 2015

Cytotoxic and natural killer cell stimulatory constituents of Phyllanthus songboiensis.

Phytochemistry 2015 Mar 14;111:132-40. Epub 2015 Jan 14.

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA. Electronic address:

A dichapetalin-type triterpenoid and a dibenzylbutyrolactone-type lignan, together with five known lignans, a known aromatic diterpenoid, and a known acylated phytosterol, were isolated from the aerial parts of Phyllanthus songboiensis, collected in Vietnam. Their structures were determined by interpretation of the spectroscopic data, and the inhibitory activity toward HT-29 human colon cancer cells of all isolates was evaluated by a cytotoxicity assay. The known arylnaphthalene lignan, (+)-acutissimalignan A, was highly cytotoxic toward HT-29 cells, with an IC50 value of 19 nM, but this compound was inactive as a DNA topoisomerase IIα (topo IIα) poison. The known phytosterol, (-)-β-sitosterol-3-O-β-D-(6-O-palmitoyl)glucopyranoside, was found to stimulate natural killer (NK) cells at a concentration of 10μM in the presence of interleukin 12 (IL-12).
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http://dx.doi.org/10.1016/j.phytochem.2014.12.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4333069PMC
March 2015

Bioactive indole alkaloids isolated from

Phytochem Lett 2014 Dec;10:54-59

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, OH 43210, United States.

Bioassay-guided fractionation was conducted on a CHCl-soluble extract of the stem bark of (Apocynaceae) collected in Vietnam using the HT-29 human colon cancer cell line, and led to the isolation of a new sarpagine-type indole alkaloid (), together with nine known alkaloids, including four macroline-derived alkaloids (), a sarpagine-type alkaloid (), and four macroline-pleiocarpamine bisindole alkaloids (). The structure of the new compound () was determined on the basis of spectroscopic data interpretation. Compounds were evaluated for their NF-κB (p65) inhibitory activity against the Hela cells in an ELISA assay. The new sarpagine alkaloid, (4)-methyltalpinine (), was found to show significant NF-κB inhibitory activity (ED = 1.2 µM). Furthermore, all the isolates () were evaluated for their antileishmanial activity, and compounds ( and ) exhibited leishmaniacidal activity against promastigotes of .
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http://dx.doi.org/10.1016/j.phytol.2014.06.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4287998PMC
December 2014

Investigation of Vietnamese plants for potential anticancer agents.

Phytochem Rev 2014 Dec;13(4):727-739

College of Pharmacy, The Ohio State University, 500 West 12 Avenue, Columbus, OH 43210, USA.

Higher plants continue to afford humankind with many new drugs, for a variety of disease types. In this review, recent phytochemical and biological progress is presented for part of a collaborative multi-institutional project directed towards the discovery of new antitumor agents. The specific focus is on bioactive natural products isolated and characterized structurally from tropical plants collected in Vietnam. The plant collection, identification, and processing steps are described, and the natural products isolated from these species are summarized with their biological activities.
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http://dx.doi.org/10.1007/s11101-014-9335-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4225705PMC
December 2014

Potent cytotoxic arylnaphthalene lignan lactones from Phyllanthus poilanei.

J Nat Prod 2014 Jun 12;77(6):1494-504. Epub 2014 Jun 12.

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University , Columbus, Ohio 43210, United States.

Two new (1 and 2) and four known arylnaphthalene lignan lactones (3-6) were isolated from different plant parts of Phyllanthus poilanei collected in Vietnam, with two further known analogues (7 and 8) being prepared from phyllanthusmin C (4). The structures of the new compounds were determined by interpretation of their spectroscopic data and by chemical methods, and the structure of phyllanthusmin D (1) was confirmed by single-crystal X-ray diffraction analysis. Several of these arylnaphthalene lignan lactones were cytotoxic toward HT-29 human colon cancer cells, with compounds 1 and 7-O-[(2,3,4-tri-O-acetyl)-α-L-arabinopyranosyl)]diphyllin (7) found to be the most potent, exhibiting IC50 values of 170 and 110 nM, respectively. Compound 1 showed activity when tested in an in vivo hollow fiber assay using HT-29 cells implanted in immunodeficient NCr nu/nu mice. Mechanistic studies showed that this compound mediated its cytotoxic effects by inducing tumor cell apoptosis through activation of caspase-3, but it did not inhibit DNA topoisomerase IIα activity.
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http://dx.doi.org/10.1021/np5002785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4073661PMC
June 2014

Caeruleanone A, a rotenoid with a new arrangement of the D-ring from the fruits of Millettia caerulea.

Org Lett 2014 Mar 19;16(5):1462-5. Epub 2014 Feb 19.

Division of Medicinal Chemistry and Pharmacognosy, ‡Division of Pharmacy Practice and Administration, College of Pharmacy, §Department of Chemistry and Biochemistry, The Ohio State University , Columbus, Ohio 43210, United States.

Caeruleanone A (1), a novel rotenoid with an unprecedented arrangement of the D-ring, was isolated with another two new analogues, caeruleanones B (2) and C (3), together with 11 known rotenoids from the fruits of Millettia caerulea. The structures of the new compounds were determined by spectroscopic data analysis, with that of 1 being confirmed by single-crystal X-ray diffraction. Compounds 2 and 3 displayed potent mitochondrial transmembrane potential inhibitory and quinone reductase induction activities.
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http://dx.doi.org/10.1021/ol500266zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3954433PMC
March 2014

A cytotoxic dimeric furanoheliangolide from

Tetrahedron Lett 2013 Oct;54(40):5457-5460

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, United States.

A new sesquiterpene lactone, rufescenolide C (), the first furanoheliangolide dimer, was isolated from the leaves of , collected in the Dominican Republic. Its structure was determined by analysis of its spectroscopic data, with the absolute configuration being established by analysis of the CD spectrum. A plausible biogenesis of this dimer is proposed. This compound showed potent cytotoxicity with an IC value of 150 nM, when tested against HT-29 human colon cancer cells.
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http://dx.doi.org/10.1016/j.tetlet.2013.07.128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3804354PMC
October 2013

Sphenostylisins A-K: bioactive modified isoflavonoid constituents of the root bark of Sphenostylis marginata ssp. erecta.

J Org Chem 2013 Oct 3;78(20):10166-77. Epub 2013 Oct 3.

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University , 500 West 12th Avenue, Columbus, Ohio 43210, United States.

Sphenostylisins A-C (1-3), three complex dimeric compounds representing two novel carbon skeletons, along with an additional eight new compounds, sphenostylisins D-K (4-11), were isolated from the active chloroform-soluble extract of the root bark of Sphenostylis marginata ssp. erecta using a bioactivity-guided isolation approach. The structures were elucidated by means of detailed spectroscopic analysis, including NMR and HRESIMS analysis, and tandem MS fragmentation was utilized to further support the structures of 1-3. The absolute configuration of sphenostylisin C (3) was established by electronic circular dichroism analysis. Plausible biogenetic relationships between the modified isoflavonoids 1-11 are proposed, and a cyclization reaction of 9 was conducted to support one of the biogenetic proposals made. All of these pure isolates were evaluated against a panel of in vitro bioassays, and among the results obtained, sphenostylisin A (1) was found to be a very potent NF-κB inhibitor (IC50 = 6 nM).
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http://dx.doi.org/10.1021/jo401573hDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3827909PMC
October 2013

Lipidated steroid saponins from Dioscorea villosa (wild yam).

Fitoterapia 2013 Dec 19;91:113-124. Epub 2013 Aug 19.

UIC/NIH Center for Botanical Dietary Supplements Research, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, United States. Electronic address:

Two groups of lipidated steroid saponins including seven new compounds (2, 3, 5, and 7-10) were isolated from the widely used botanical, wild yam (Dioscorea villosa), employing a fractionation protocol of metabolomic mining. This methodology recently led to the isolation of 14 diarylheptanoids from the same plant. Together with these lipidated steroid saponins, they establish additional new markers for D. villosa. The lipidation of steroids with analog long-chain fatty acids containing different degrees of unsaturation generates an entire series of compounds which are difficult to purify and analyze. The structures of the two series of lipidated steroid saponins (series A and B) were established by a combination of 1D and 2D NMR as well as GC-MS after chemical modification. Series A was determined to be a mixture of lipidated spirostanol glycosides (1-5), while series B (6-10) was proved to be a mixture of five lipidated clionasterol glucosides. The latter group represents the first derivatives of clionasterol to be found in D. villosa. The discovery of this specific structural type of aliphatic esters of steroid saponins expands the characterization of the secondary metabolome of D. villosa. It may also inspire biological studies which take into account the lipophilic character and significantly altered physiochemical characteristics of these otherwise relatively polar phytoconstituents.
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http://dx.doi.org/10.1016/j.fitote.2013.07.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3935402PMC
December 2013

Dynamic residual complexity of the isoliquiritigenin-liquiritigenin interconversion during bioassay.

J Agric Food Chem 2013 Mar 22;61(9):2146-57. Epub 2013 Feb 22.

UIC/NIH Center for Botanical Dietary Supplements Research, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago , 833 South Wood Street, Chicago, Illinois 60612, United States.

Bioactive components in food plants can undergo dynamic processes that involve multiple chemical species. For example, 2'-hydroxychalcones can readily isomerize into flavanones. Although chemically well documented, this reaction has barely been explored in the context of cell-based assays. The present time-resolved study fills this gap by investigating the isomerization of isoliquiritigenin (a 2'-hydroxychalcone) and liquiritigenin (a flavanone) in two culture media (Dulbecco's modified eagle medium and Roswell Park Memorial Institute medium) with and without MCF-7 cells, using high-performance liquid chromatography-diode array detector-electrospray ionization/atmospheric pressure chemical ionization-mass spectrometry for analysis. Both compounds were isomerized and epimerized under all investigated biological conditions, leading to mixtures of isoliquiritigenin and R/S-liquiritigenin, with 19.6% R enantiomeric excess. Consequently, all three species can potentially modulate the biological responses. This exemplifies dynamic residual complexity and demonstrates how both nonchiral reactions and enantiomeric discrimination can occur in bioassay media, with or without cells. The findings highlight the importance of controlling in situ chemical reactivity, influenced by biological systems when evaluating the mode of action of bioactives.
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http://dx.doi.org/10.1021/jf304445pDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3728173PMC
March 2013

Bioactive flavaglines and other constituents isolated from Aglaia perviridis.

J Nat Prod 2013 Mar 9;76(3):394-404. Epub 2013 Jan 9.

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, USA.

Eight new compounds, including two cyclopenta[b]benzopyran derivatives (1, 2), two cyclopenta[b]benzofuran derivatives (3, 4), three cycloartane triterpenoids (5-7), and an apocarotenoid (8), together with 16 known compounds, were isolated from the chloroform-soluble partitions of separate methanol extracts of a combination of the fruits, leaves, and twigs and of the roots of Aglaia perviridis collected in Vietnam. Isolation work was monitored using human colon cancer cells (HT-29) and facilitated with an LC/MS dereplication procedure. The structures of the new compounds (1-8) were determined on the basis of spectroscopic data interpretation. The Mosher ester method was employed to determine the absolute configurations of 5-7, and the absolute configuration of the 9,10-diol unit of compound 8 was established by a dimolybdenum tetraacetate [Mo2(AcO)4] induced circular dichroism procedure. Seven known rocaglate derivatives (9-15) exhibited significant cytotoxicity against the HT-29 cell line, with rocaglaol (9) being the most potent (ED50 0.0007 μM). The new compounds 2-4 were also active against this cell line, with ED50 values ranging from 0.46 to 4.7 μM. The cytotoxic compounds were evaluated against a normal colon cell line, CCD-112CoN. In addition, the new compound perviridicin B (2), three known rocaglate derivatives (9, 11, 12), and a known sesquiterpene, 2-oxaisodauc-5-en-12-al (17), showed significant NF-κB (p65) inhibitory activity in an ELISA assay.
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http://dx.doi.org/10.1021/np3007588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3606667PMC
March 2013

Diarylheptanoids from Dioscorea villosa (Wild Yam).

J Nat Prod 2012 Dec 17;75(12):2168-77. Epub 2012 Dec 17.

UIC/NIH Center for Botanical Dietary Supplements Research, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612, USA.

A fractionation methodology aimed at the metabolomic mining of new phytoconstituents for the widely used botanical, wild yam (Dioscorea villosa), makes use of 1D qHNMR and 2D NMR profiles along the preparative fractionation pathway. This quantifiable and structural guidance led to the isolation of 14 diarylheptanoids (1-14), including five new compounds (1-5) with a tetrahydropyrano core skeleton. The structures, including the absolute configurations of both new and previously known diarylheptanoids, were assigned by a combination of HRESIMS, 1D and 2D NMR, (1)H iterative full spin analysis (HiFSA), and Mosher's ester method. The isolation yields were consistent with yields predicted by qHNMR, which confirms the (semi)quantifiable capabilities of NMR-based preparative metabolomic mining. The qHNMR-aided approach enabled the identification of new and potentially significant chemical entities from a small fraction of the plant extract and, thereby, facilitated the characterization of the residual complexity of the D. villosa secondary metabolome. LC-MS profiling of different D. villosa accessions further confirmed that the diarylheptanoids represent genuine secondary metabolites, which can serve as a new class of markers for botanical integrity analysis of D. villosa.
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http://dx.doi.org/10.1021/np300603zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3710746PMC
December 2012

Use of the hollow fiber assay for the discovery of novel anticancer agents from fungi.

Methods Mol Biol 2012 ;944:267-77

College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA.

The hollow fiber assay (HFA) is a drug discovery tool to aid investigators in the prioritization of lead compounds identified by in vitro testing for further development in animal models of disease. In the HFA, cells are cultured in hollow fibers containing pores of a diameter (500 kDa) large enough for proteins and other macromolecules to enter, but too small for the cells to escape. The fibers are filled with cells, sealed and placed in the peritoneal cavity of immunodeficient mice. The mice undergo a predetermined treatment regimen after which the fibers are retrieved and the cells evaluated for activity of a target relevant to the disease modeled. The HFA combines advantages of both in vitro and in vivo assay systems. It uses the same cell lines used in culture systems, is a rapid assay, and requires fewer animals and less test substance than conventional xenograft systems. Like traditional in vivo assays, the test substance is evaluated in a live animal, which affords an initial assessment of associated toxicity and pharmacokinetic properties of the test substance.
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http://dx.doi.org/10.1007/978-1-62703-122-6_20DOI Listing
March 2013

Cytotoxic and NF-κB inhibitory sesquiterpene lactones from Piptocoma rufescens.

Tetrahedron 2012 Mar 26;68(12):2671-2678. Epub 2012 Jan 26.

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.

Six new (1-6) and eight known germacranolide-type sesquiterpene lactones, along with several known phenylpropanol coumarates and methylated flavonoids, were isolated from the leaves of Piptocoma rufescens, collected in the Dominican Republic. The new compounds were identified by analysis of their spectroscopic data, with the molecular structure of 3 being established by single-crystal X-ray diffraction. The absolute configurations of the sesquiterpene lactones isolated were determined from their CD and NOESY NMR spectra, together with the analysis of Mosher ester reactions. Bioassay screening results showed the majority of the sesquiterpene lactones isolated (1-13) to be highly cytotoxic toward the HT-29 human colon cancer cell line, with the most potent compound being 15-deoxygoyazensolide (10, IC(50), 0.26 µM). In addition, several of the sesquiterpene lactones exhibited NF-κB (p65) inhibitory activity.
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http://dx.doi.org/10.1016/j.tet.2012.01.061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369275PMC
March 2012

Isolation, structure elucidation, and biological evaluation of 16,23-epoxycucurbitacin constituents from Eleaocarpus chinensis.

J Nat Prod 2012 Mar 12;75(3):444-52. Epub 2012 Jan 12.

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, United States.

Eight new 16,23-epoxycucurbitacin derivatives, designated as elaeocarpucins A-H (1-8), and five known cucurbitacins (9-13) were isolated from the chloroform-soluble partitions of separate methanol extracts of the fruits and stem bark of Elaeocarpus chinensis collected in Vietnam. Isolation work was facilitated using a LC/MS dereplication procedure, and bioassay-guided fractionation was monitored using HT-29 human cancer cells. The structures of compounds 1-8 were determined on the basis of spectroscopic data interpretation, with the absolute configurations of isomers 1 and 2 established by the Mosher ester method. Compounds 1-13 were evaluated in vitro against the HT-29 cell line and using a mitochondrial transmembrane potential assay. Elaeocarpucin C (3), produced by partial synthesis from 16α,23α-epoxy-3β,20β-dihydroxy-10αH,23βH-cucurbit-5,24-dien-11-one (13), was found to be inactive when evaluated in an in vivo hollow fiber assay using three different cancer cell types (dose range 0.5-10 mg/kg/day, i.p.).
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http://dx.doi.org/10.1021/np200879pDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3311738PMC
March 2012