Publications by authors named "Jiangnan Peng"

46 Publications

Recognizing pioneering Black plant scientists in our schools and society.

Trends Plant Sci 2021 10 7;26(10):989-992. Epub 2021 Sep 7.

Department of Plant Biology, Carnegie Institution for Science, Stanford, CA, USA. Electronic address:

We highlight the achievements of four pioneering Black plant scientists to raise awareness of the importance of diversity, equity, and inclusion in science. Their stories come alive at Historically Black Colleges and Universities through exhibits of science and art and classroom activities (https://www.plantcellatlas.org/pca-art-exhibit.html).
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http://dx.doi.org/10.1016/j.tplants.2021.07.021DOI Listing
October 2021

Phytochemical Analysis of Leaves: Identification of Garcinamines F-H and Their Antiproliferative Activities.

Plants (Basel) 2021 Jun 2;10(6). Epub 2021 Jun 2.

Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Montesano 49, 80131 Naples, Italy.

is a medicinal plant used in the Arab region for intestinal diseases, lung and liver diseases, digestive problems, and as an antidiabetic agent. Repeated chromatographic purifications of leaves led to the isolation of three undescribed guaiane sesquiterpene derivatives, named garcinamines F-H, characterized by the presence of an amino acid unit, along with five known sesquiterpene lactones (garcinamines B-E and 9β-hydroxyparthenolide). The structures of the new compounds were established using spectroscopic (1D and 2D NMR) and spectrometric methods (ESIMS). Garcinamine H possesses a double bond at the Δ position, a structural feature rarely reported in guaianolide-type sesquiterpenes. The antiproliferative activity of the isolated sesquiterpenes was screened against three different cancer cell lines, and 9β-hydroxyparthenolide and garcinamines C and D displayed significant effects against lung carcinoma (A549), colon carcinoma (LoVo), and breast carcinoma (MCF7) cell lines.
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http://dx.doi.org/10.3390/plants10061130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8229242PMC
June 2021

Microwave-Assisted Synthesis of Organometallic Rhenium (I) Pentylcarbonato Complexes: New Synthon for Carboxylato, Sulfonato and Chlorido Complexes.

J Organomet Chem 2021 Mar 27;936. Epub 2021 Jan 27.

Morgan State University, Department of Chemistry, Baltimore, MD 21251.

Tricarbonylrhenium(I)(α-diimine) complexes are of importance because of their strong cytotoxic and fluorescence properties. Syntheses of such complexes were achieved through a two-step process. First, the pentylcarbonato complexes, -(CO)(α-diimine)ReOC(O)OCH were synthesized through a microwave-assisted reaction of Re(CO), α-diimine, 1-pentanol and CO in a few hours. Second, the pentylcarbonato complexes are treated with carboxylic, sulfonic and halo acids to obtain the corresponding carboxylato, sulfonato and halido complexes. This is the first example of conversion of Re(CO) into a rhenium carbonyl complex through microwave-assisted reaction.
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http://dx.doi.org/10.1016/j.jorganchem.2021.121718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8095682PMC
March 2021

rs12785878 T>C Polymorphism Is Associated With an Increased Risk of Early Onset of Alzheimer's Disease in Chinese Population.

Front Genet 2021 22;12:583695. Epub 2021 Feb 22.

Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, China.

Vitamin D insufficiency has been considered a risk factor for Alzheimer's disease (AD) in several studies. Recently, four single-nucleotide polymorphisms (SNPs) to be genome-wide significant for 25-hydroxyvitamin D [25(OH)D] were identified to have an association with the risk of AD. These include rs2282679 A>C, rs10741657 T>C, rs12785878 T>C, and rs6013897 T>A. However, the association between these polymorphisms and AD susceptibility in the Chinese population remains unclear. A case-control cohort study was conducted in 676 AD patients (mean age at onset was 69.52 ± 10.90 years, male: 39.2%) and 551 healthy controls (mean age was 67.73 ± 6.02 years, male: 44.8%). Genotyping was determined by PCR and SNaPshot sequencing. To determine whether the four SNPs account for risks in AD in Chinese population, multivariate logistic regression models were performed. Stratified analysis was performed based on gender and age of onset of AD, separately. Statistical significance was set at 0.0125 (0.05/4) based on Bonferroni correction. rs12785878 T>C was found to be significantly associated with an increased risk of early-onset Alzheimer's disease (EOAD) ( = 300, risk allele C, adjusted OR = 1.542, adjusted 95% CI = 1.176-2.023, = 0.002). There was no statistical significance of the other three SNPs between the two groups. Our results suggested that rs12785878 T>C might be associated with an increased risk of EOAD in the Chinese population, while other polymorphisms related to vitamin D insufficiency might not be. However, due to the limited data in this study, replication studies in a larger sample are required.
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http://dx.doi.org/10.3389/fgene.2021.583695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938861PMC
February 2021

Construction and efficiency analysis of prediction model for venous thromboembolism risk in the elderly after hip fracture.

Zhong Nan Da Xue Xue Bao Yi Xue Ban 2021 Feb;46(2):142-148

Department of Orthopaedic Trauma, Xiangya Hospital, Central South University, Changsha 410008, China.

Objectives: To screen the risk factors for predicting venous thromboembolism (VTE) risk after hip fracture in the elderly, to establish a prediction model based on these factors, and to analyze its prediction efficacy.

Methods: A total of 52 hip fracture patients over 60 years old with VTE admitted to the Department of Orthopaedic Trauma, Xiangya Hospital, Central South University from March 2017 to April 2019 were selected as a thrombus group, and another 52 hip fracture patients over 60 years old without VTE were selected as a control group. The differences of hospitalization data and examination results between the 2 groups were compared. Logistic regression model was used to explore the influence of risk factors on VTE risk after hip fracture in the elderly and construct the prediction model based on these factors. The receiver operating characteristic curve was used to analyze the predictive effectiveness of model, Hosmer-lemeshow goodness of fit test was used to evaluate the fitting degree of prediction model.

Results: Univariate analysis showed that injury-admission interval, Caprini score, WBC count, platelet count, neutrophil count, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, systemic immune-inflammatory index (SII), and fibrinogen in the thrombus group were higher than those in the control group (all <0.05). Logistic regression analysis showed that injury-admission interval, Caprini score, and SII were independent predictors of VTE risk after hip fracture in the elderly. The AUC was 0.949 (95% CI 0.901 to 0.996) when the sensitivity and specificity were 82.70% and 96.20%, respectively, which were significantly higher than each single index, and the prediction model had perfect fitting degree (Hosmer-lemeshow =14.078, >0.05).

Conclusions: SII, Caprini score, and injury-admission interval are independent predictors of VTE after hip fracture in the elderly. The prediction model based on these 3 factors has a good efficacy on the prediction of VTE risk, and could provide important reference for the prevention, management, and treatment of VTE after hip fracture in the elderly.
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http://dx.doi.org/10.11817/j.issn.1672-7347.2021.190722DOI Listing
February 2021

Taccalonolides: A Novel Class of Microtubule-Stabilizing Anticancer Agents.

Cancers (Basel) 2021 Feb 22;13(4). Epub 2021 Feb 22.

Department of Chemistry, Morgan State University, Baltimore, MD 21251, USA.

Microtubule stabilizing agents, such as paclitaxel, docetaxel, and cabazitaxel have been among the most used chemotherapeutic agents in the last decades for the treatment of a wide range of cancers in the clinic. One of the concerns that limit their use in clinical practice is their intrinsic and acquired drug resistance, which is common to most anti-cancer chemotherapeutics. Taccalonolides are a new class of microtubule stabilizers isolated from the roots of a few species in the genus of . In early studies, taccalonolides demonstrated different effects on interphase and mitotic microtubules from those of paclitaxel and laulimalide suggesting a unique mechanism of action. This prompts the exploration of new taccalonolides with various functionalities through the identification of minor constituents of natural origin and semi-synthesis. The experiments on the new highly potent taccalonolides indicated that taccalonolides possessed a unique mechanism of covalently binding to the microtubule. An X-ray diffraction analysis of a crystal of taccalonolides AJ binding to tubulin indicated that the covalent binding site is at β-tubulin D226. Taccalonolides circumvent all three mechanisms of taxane drug resistance both in vitro and in vivo. To improve the activity, the structure modification through semi-synthesis was conducted and the structure-activity relationships (SARs) was analyzed based on natural and semi-synthetical taccalonolides. The C22-C23 epoxide can significantly increase the antiproliferation potency of taccalonolides due to the covalent link of C22 and the carboxylic group of D226. Great progress has been seen in the last few years in the understanding of the mechanism of this class of microtube-stabilizing agents. This review summarizes the structure diversity, structure-activity relationships (SARs), mechanism of action, and in vivo activities of taccalonolides.
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http://dx.doi.org/10.3390/cancers13040920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926778PMC
February 2021

Polycyclic aromatic hydrocarbons as a potential source of carcinogenicity of mate.

J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 2019 30;37(1):26-41. Epub 2018 Dec 30.

a ASCEND Center for Biomedical Research , Morgan State University , Baltimore , MD , USA.

Drinking mate, an infusion of the herb ilex paraguariensis, is very common in several South American countries, and has been associated with an increased risk of esophageal cancer. This increased risk may be attributed to drinking mate very hot, or to mate's potentially carcinogenic contaminants, such as polycyclic aromatic hydrocarbons (PAHs). Mate leaves are often dried via smoking, and therefore commercial samples may have high amounts of PAHs. We found 10 original articles that had measured PAHs in commercial dry samples, and nearly all found very high mass fractions. Most studies found benzo[a]pyrene mass fractions to be over 25 ng/g, and some found levels up to 600 ng/g. However, carcinogenic PAHs are often hydrophobic, and may not readily transfer into infusions. Seven articles studied transfer rates, and these rates varied from 1 to 50%, depending on the methods employed. Further careful studies of transfer rates in situations that mimic real life drinking of mate are recommended. Also, further studies of biological indicators of PAH exposure, particularly in randomized experiments, and analyzing DNA from tumor samples of mate drinkers are recommended.
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http://dx.doi.org/10.1080/10590501.2019.1555323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6443446PMC
February 2020

A Simple and Noninvasive DOSY NMR Method for Droplet Size Measurement of Intact Oil-In-Water Emulsion Drug Products.

J Pharm Sci 2019 02 3;108(2):815-820. Epub 2018 Oct 3.

Division of Pharmaceutical Analysis, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland 20993. Electronic address:

In a typical oil-in-water emulsion drug product, oil droplets with varied sizes are dispersed in a water phase and stabilized by surfactant molecules. The size and polydispersity of oil droplets are critical quality attributes of the emulsion drug product that can potentially affect drug bioavailability. More critically, to ensure accuracy in characterization of the finished drug product, analytical methods should introduce minimal physical perturbation (e.g., temperature variation or dilution) before the analysis. The classical methods of dynamic light scattering or electron microscopy can be used but they generally require sample dilution or harsh preparation conditions, respectively. By contrast, the size distribution of emulsion formulations can be assessed with a simple and noninvasive solution nuclear magnetic resonance method, namely, two-dimensional Diffusion Ordered SpectroscopY. The two-dimensional Diffusion Ordered SpectroscopY method probed signal decay of methyl resonances from oil and sorbate molecules and was applied to 3 types of U.S.-marketed emulsion drug products, that is, difluprednate, cyclosporine, and propofol, yielding measured droplet sizes of 40-280 nm in diameter. The high precision of ±6 nm of the new nuclear magnetic resonance method allows analytical differentiation of lot-to-lot and brand-to-brand droplet size differences in emulsion drug products, critical for drug-quality development, control, and surveillance.
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http://dx.doi.org/10.1016/j.xphs.2018.09.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995278PMC
February 2019

Chemical Structure and Composition of Major Glycans Covalently Linked to Therapeutic Monoclonal Antibodies by Middle-Down Nuclear Magnetic Resonance.

Anal Chem 2018 09 27;90(18):11016-11024. Epub 2018 Aug 27.

Glycosylation of monoclonal antibodies (mAbs) is a critical quality attribute that can impact mAb drug efficacy and safety. The mAb glycans are inherently heterogeneous in chemical structure and composition of monosaccharides. The established fluorescence or mass-spectrometry (MS) detection methods for glycosylation evaluation may require multiple steps of glycan cleavage or extensive digestion of the mAb, chemical labeling of the glycans, column separation and report the chemical identity of glycans indirectly through retention time and molecular weight values. In demonstrating chemical structure similarity and comparability among mAb drugs, orthogonal analytical methods for measuring glycan chemistry are needed to ensure the quality of drug products. Here, a "middle-down" NMR method is developed as a proof-of-concept approach to measure the domain-specific glycosylation of marketed mAb drugs without cleavage of the glycan moieties. Complete glycan H/C chemical shift assignments were obtained at C natural abundance from commercial standard glycans that allowed unambiguous determination of the chemical structure, glycosidic linkage position, and anomeric configuration of each monosaccharide in the major N-glycan scaffolds found in mAb molecules. The analysis of glycan anomeric peaks in two-dimensional (2D) H-C NMR spectra yielded metrics for clinically important mAb quality attributes (i.e., galactosylation (Gal%) and fucosylation (Fuc%)), consistent with literature results using a standard glycan-mapping method. Therefore, the middle-down NMR method provided a facile orthogonal measurement for mAb glycosylation characterization with improved chemical information content on glycan structure determination and quantification, compared to standard approaches.
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http://dx.doi.org/10.1021/acs.analchem.8b02637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7040853PMC
September 2018

Taccalonolide Microtubule Stabilizers Generated Using Semisynthesis Define the Effects of Mono Acyloxy Moieties at C-7 or C-15 and Disubstitutions at C-7 and C-25.

J Nat Prod 2018 03 23;81(3):579-593. Epub 2018 Jan 23.

The taccalonolides are a unique class of microtubule stabilizers isolated from Tacca spp. that have efficacy against drug-resistant tumors. Our previous studies have demonstrated that a C-15 acetoxy taccalonolide, AF, has superior in vivo antitumor efficacy compared to AJ, which bears a C-15 hydroxy group. With the goal of further improving the in vivo efficacy of this class of compounds, we semisynthesized and tested the biological activities of 28 new taccalonolides with monosubstitutions at C-7 or C-15 or disubstitutions at C-7 and C-25, covering a comprehensive range of substituents from formic acid to anthraquinone-2-carbonyl chloride. The resulting taccalonolide analogues with diverse C-7/C-15/C-25 modifications exhibited IC values from 2.4 nM to >20 μM, allowing for extensive in vitro structure-activity evaluations. This semisynthetic strategy was unable to provide a taccalonolide with improved therapeutic window due to hydrolysis of substituents at C-7 or C-15 regardless of size or steric bulk. However, two of the most potent new taccalonolides, bearing isovalerate modifications at C-7 or C-15, demonstrated potent and highly persistent antitumor activity in a drug-resistant xenograft model when administered intratumorally. This study demonstrates that targeted delivery of the taccalonolides to the tumor could be an effective, long-lasting approach to treat drug-resistant tumors.
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http://dx.doi.org/10.1021/acs.jnatprod.7b00967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866228PMC
March 2018

Phenolic constituents from Rheum nobile and their antioxidant activity.

Nat Prod Res 2017 Dec 17;31(24):2842-2849. Epub 2017 Mar 17.

d School of Basic Medical Science , Beijing University of Chinese Medicine , Beijing , China.

Although the rhizomes of Rheum nobile Hook. f. et Thoms (Polygonaceae) are widely used in Tibetan medicine, no previous investigations regarding the biological activities and rarely chemical constituents of this plant have been reported. As part of an ongoing search for novel bioactive agents, a phytochemical investigation of R. nobile led to the isolation of two new compounds Rheumone B (1) and piceatannol-4'-O-β-D-(6″-O-acetyl)-glucoside (2), together with 15 known compounds by gel filtration over Sephadex LH-20 and preparative HPLC. Their structures were determined by combined spectroscopic methods. Compounds 1-10 were evaluated for their ability to scavenge 2,2-diphenyl-1-picrylhydzyl (DPPH) radical and compounds 7-10 showed relatively strong scavenging abilities with IC values from 2.76 μM to 11.80 μM. In conclusion, naphthalene glycosides, stilbene glycosides, flavanols, especially anthraquinones are main chemical constituents of this plant. The ability to scavenge DPPH radical of compound 8 was the highest among compounds 1-10.
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http://dx.doi.org/10.1080/14786419.2017.1303691DOI Listing
December 2017

New cytotoxic trichothecene macrolide epimers from endophytic Myrothecium roridum IFB-E012.

J Antibiot (Tokyo) 2016 08 13;69(8):652-5. Epub 2016 Jul 13.

Department of Chemistry and Biochemistry, University of North Carolina at Wilmington, Wilmington, NC, USA.

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http://dx.doi.org/10.1038/ja.2016.86DOI Listing
August 2016

Dual activities of the anti-cancer drug candidate PBI-05204 provide neuroprotection in brain slice models for neurodegenerative diseases and stroke.

Sci Rep 2016 05 12;6:25626. Epub 2016 May 12.

Center for Drug Discovery and Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, US.

We previously reported neuroprotective activity of the botanical anti-cancer drug candidate PBI-05204, a supercritical CO2 extract of Nerium oleander, in brain slice and in vivo models of ischemic stroke. We showed that one component of this neuroprotective activity is mediated through its principal cardiac glycoside constituent, oleandrin, via induction of the potent neurotrophic factor brain-derived neurotrophic factor (BDNF). However, we also noted that the concentration-relation for PBI-05204 in the brain slice oxygen-glucose deprivation (OGD) model is considerably broader than that for oleandrin as a single agent. We thus surmised that PBI-05204 contains an additional neuroprotective component(s), distinct from oleandrin. We report here that neuroprotective activity is also provided by the triterpenoid constituents of PBI-05204, notably oleanolic acid. We demonstrate that a sub-fraction of PBI-05204 (Fraction 0-4) containing oleanolic and other triterpenoids, but without cardiac glycosides, induces the expression of cellular antioxidant gene transcription programs regulated through antioxidant transcriptional response elements (AREs). Finally, we show that Fraction 0-4 provides broad neuroprotection in organotypic brain slice models for neurodegeneration driven by amyloid precursor protein (APP) and tau implicated in Alzheimer's disease and frontotemporal dementias, respectively, in addition to ischemic injury modeled by OGD.
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http://dx.doi.org/10.1038/srep25626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4865873PMC
May 2016

Texas Native Plants Yield Compounds with Cytotoxic Activities against Prostate Cancer Cells.

J Nat Prod 2016 Mar 19;79(3):531-40. Epub 2016 Jan 19.

Department of Pharmacology and ‡Cancer Therapy & Research Center, The University of Texas Health Science Center at San Antonio , San Antonio, Texas 78229, United States.

There remains a critical need for more effective therapies for the treatment of late-stage and metastatic prostate cancers. Three Texas native plants yielded three new and three known compounds with antiproliferative and cytotoxic activities against prostate cancer cells with IC50 values in the range of 1.7-35.0 μM. A new sesquiterpene named espadalide (1), isolated from Gochnatia hypoleuca, had low micromolar potency and was highly effective in clonogenic assays. Two known bioactive germacranolides (2 and 3) were additionally isolated from G. hypoleuca. Dalea frutescens yielded two new isoprenylated chalcones, named sanjuanolide (4) and sanjoseolide (5), and the known sesquiterpenediol verbesindiol (6) was isolated from Verbesina virginica. Mechanistic studies showed that 1-4 caused G2/M accumulation and the formation of abnormal mitotic spindles. Tubulin polymerization assays revealed that 4 increased the initial rate of tubulin polymerization, but did not change total tubulin polymer levels, and 1-3 had no effects on tubulin polymerization. Despite its cytotoxic activity, compound 6 did not initiate changes in cell cycle distribution and has a mechanism of action different from the other compounds. This study demonstrates that new compounds with significant biological activities germane to unmet oncological needs can be isolated from Texas native plants.
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http://dx.doi.org/10.1021/acs.jnatprod.5b00908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4860899PMC
March 2016

Identification of Compounds with Efficacy against Malaria Parasites from Common North American Plants.

J Nat Prod 2016 Mar 21;79(3):490-8. Epub 2015 Dec 21.

Department of Genetics, Texas Biomedical Research Institute , San Antonio, Texas 78227, United States.

Some of the most valuable antimalarial compounds, including quinine and artemisinin, originated from plants. While these drugs have served important roles over many years for the treatment of malaria, drug resistance has become a widespread problem. Therefore, a critical need exists to identify new compounds that have efficacy against drug-resistant malaria strains. In the current study, extracts prepared from plants readily obtained from local sources were screened for activity against Plasmodium falciparum. Bioassay-guided fractionation was used to identify 18 compounds from five plant species. These compounds included eight lupane triterpenes (1-8), four kaempferol 3-O-rhamnosides (10-13), four kaempferol 3-O-glucosides (14-17), and the known compounds amentoflavone and knipholone. These compounds were tested for their efficacy against multi-drug-resistant malaria parasites and counterscreened against HeLa cells to measure their antimalarial selectivity. Most notably, one of the new lupane triterpenes (3) isolated from the supercritical extract of Buxus sempervirens, the common boxwood, showed activity against both drug-sensitive and -resistant malaria strains at a concentration that was 75-fold more selective for the drug-resistant malaria parasites as compared to HeLa cells. This study demonstrates that new antimalarial compounds with efficacy against drug-resistant strains can be identified from native and introduced plant species in the United States, which traditionally have received scant investigation compared to more heavily explored tropical and semitropical botanical resources from around the world.
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http://dx.doi.org/10.1021/acs.jnatprod.5b00874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5558429PMC
March 2016

Melampodium leucanthum, a source of cytotoxic sesquiterpenes with antimitotic activities.

J Nat Prod 2015 Mar 16;78(3):388-95. Epub 2015 Feb 16.

A new tricyclic sesquiterpene, named meleucanthin (1), was isolated from an extract of the leaves and branches of Melampodium leucanthum, along with four known germacranolide sesquiterpene lactones, leucanthin-A (2), leucanthin-B (3), melampodin-A acetate (4), and 3α-hydroxyenhydrin (5). The chemical structure of 1 was elucidated by analysis of 1D and 2D NMR and mass spectrometric data. All compounds exhibited antiproliferative and cytotoxic efficacy against PC-3 and DU 145 prostate cancer cells, as well as HeLa cervical cancer cells, with IC50 values ranging from 0.18 to 9 μM. These compounds were effective in clonogenic assays and displayed high cellular persistence. They were also found to be capable of circumventing P-glycoprotein-mediated drug resistance. Mechanism of action studies showed that 4 caused an accumulation of cells in the G2/M phase of the cell cycle, and 2-5 caused the formation of abnormal mitotic spindles. These results suggest the cytotoxic effects of these germacranolides involve inhibition of mitotic spindle function, and it is likely that other mechanisms additionally contribute to cell death. These studies also demonstrate the possibility of isolating new, biologically active compounds from indigenous Texas plants.
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http://dx.doi.org/10.1021/np500768sDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4749154PMC
March 2015

An iridoid glucoside and the related aglycones from Cornus florida.

J Nat Prod 2014 Sep 21;77(9):2138-43. Epub 2014 Aug 21.

Department of Applied Chemistry, College of Science, Xi'an University of Technology , Xi'an 710054, People's Republic of China.

A new iridoid glucoside, cornusoside A (1), and four new natural product iridoid aglycones, cornolactones A-D (2-5), together with 10 known compounds were isolated from the leaves of Cornus florida. The structures of compounds 1-5 were established by interpretation of their spectroscopic data. Cornolactone B (3) is the first natural cis-fused tricyclic dilactone iridoid containing both a five- and a six-membered lactone ring. A biosynthesis pathway is proposed for cornolactones C (4) and D (5), the C-6 epimers of compounds 1-3.
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http://dx.doi.org/10.1021/np5002362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4176392PMC
September 2014

Synthetic reactions with rare taccalonolides reveal the value of C-22,23 epoxidation for microtubule stabilizing potency.

J Med Chem 2014 Jul 2;57(14):6141-9. Epub 2014 Jul 2.

Department of Pharmacology, ‡Cancer Therapy & Research Center, and §Department of Medicine, University of Texas Health Science Center at San Antonio , San Antonio, Texas 78229, United States.

The taccalonolides are microtubule stabilizers isolated from plants of the genus Tacca. Taccalonolide AF is 231 times more potent than the major metabolite taccalonolide A and differs only by the oxidation of the C-22,23 double bond in A to an epoxy group in AF. In the current study, 10 other rare natural taccalonolides were epoxidized and in each case epoxidation improved potency. The epoxidation products of taccalonolide T and AI were the most potent, with IC50 values of 0.43 and 0.88 nM, respectively. These potent taccalonolides retained microtubule stabilizing effects, and T-epoxide demonstrated antitumor effects in a xenograft model of breast cancer. Additional reactions demonstrated that reduction of the C-6 ketone resulted in an inactive taccalonolide and that C-22,23 epoxidation restored its activity. These studies confirm the value of C-22,23 epoxidation as an effective strategy for increasing the potency of a wide range of structurally diverse taccalonolide microtubule stabilizers.
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http://dx.doi.org/10.1021/jm500619jDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4216226PMC
July 2014

Structure-activity relationships of retro-dihydrochalcones isolated from Tacca sp.

J Nat Prod 2013 Dec 4;76(12):2189-94. Epub 2013 Dec 4.

Department of Pharmacology, ‡Cancer Therapy & Research Center, University of Texas Health Science Center at San Antonio , San Antonio, Texas 78229, United States.

Several biologically active compounds have been identified from Tacca species, including glycosides, diarylheptanoids, saponins, withanolides, and the taccalonolide class of microtubule stabilizers. More recently, two cytotoxic retro-dihydrochalcones named evelynin A (7) and taccabulin A (6) were isolated and their biological activities characterized, including the finding that taccabulin has microtubule destabilizing effects. Here we describe the identification and characterization of five new retro-chalcones, named taccabulins B-E (1-4) and evelynin B (5) from Tacca sp. extracts. Their structures were determined using 1D and 2D NMR as well as mass spectroscopic data and modeled into the colchicine binding site of tubulin. The antiproliferative and microtubule effects of each compound were determined experimentally and found to be well correlated with modeling studies. The isolation and biological characterization of several retro-dihydrochalcones facilitated preliminary structure-activity relationships for this compound class concerning its antiproliferative and microtubule depolymerizing activities.
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http://dx.doi.org/10.1021/np4005085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4012383PMC
December 2013

The bat flower: a source of microtubule-destabilizing and -stabilizing compounds with synergistic antiproliferative actions.

J Nat Prod 2013 Oct 2;76(10):1923-9. Epub 2013 Oct 2.

Department of Pharmacology, The University of Texas Health Science Center at San Antonio , San Antonio, Texas 78229, United States.

The biosynthesis of secondary metabolites provides higher plants with mechanisms of defense against microbes, insects, and herbivores. One common cellular target of these molecules is the highly conserved microtubule cytoskeleton, and microtubule-targeting compounds with insecticidal, antifungal, nematicidal, and anticancer activities have been identified from plants. A new retro-dihydrochalcone, taccabulin A, with microtubule-destabilizing activity has been identified from the roots and rhizomes of Tacca species. This finding is notable because the microtubule-stabilizing taccalonolides are also isolated from these sources. This is the first report of an organism producing compounds with both microtubule-stabilizing and -destabilizing activities. A two-step chemical synthesis of taccabulin A was performed. Mechanistic studies showed that taccabulin A binds within the colchicine site on tubulin and has synergistic antiproliferative effects against cancer cells when combined with a taccalonolide, which binds to a different site on tubulin. Taccabulin A is effective in cells that are resistant to many other plant-derived compounds. The discovery of a natural source that contains both microtubule-stabilizing and -destabilizing small molecules is unprecedented and suggests that the synergistic action of these compounds was exploited by nature long before it was discovered in the laboratory.
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http://dx.doi.org/10.1021/np4005079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3922119PMC
October 2013

Hydrolysis reactions of the taccalonolides reveal structure-activity relationships.

J Nat Prod 2013 Jul 15;76(7):1369-75. Epub 2013 Jul 15.

Department of Pharmacology, University of Texas Health Science Center at San Antonio, Texas 78229, United States.

The taccalonolides are microtubule stabilizers isolated from plants of the genus Tacca that show potent in vivo antitumor activity and the ability to overcome multiple mechanisms of drug resistance. The most potent taccalonolide identified to date, AJ, is a semisynthetic product generated from the major plant metabolite taccalonolide A in a two-step reaction. The first step involves hydrolysis of taccalonolide A to generate taccalonolide B, and then this product is oxidized to generate an epoxide group at C-22-C-23. To generate sufficient taccalonolide AJ for in vivo antitumor efficacy studies, the hydrolysis conditions for the conversion of taccalonolide A to B were optimized. During purification of the hydrolysis products, we identified the new taccalonolide AO (1) along with taccalonolide I. When the same hydrolysis reaction was performed on a taccalonolide E-enriched fraction, four new taccalonolides, assigned as AK, AL, AM, and AN (2-5), were obtained in addition to the expected product taccalonolide N. Biological assays were performed on each of the purified taccalonolides, which allowed for increased refinement of the structure-activity relationship of this class of compounds.
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http://dx.doi.org/10.1021/np400435tDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3761391PMC
July 2013

Chemically diverse microtubule stabilizing agents initiate distinct mitotic defects and dysregulated expression of key mitotic kinases.

Biochem Pharmacol 2013 Apr 8;85(8):1104-14. Epub 2013 Feb 8.

Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.

Microtubule stabilizers are some of the most successful drugs used in the treatment of adult solid tumors and yet the molecular events responsible for their antimitotic actions are not well defined. The mitotic events initiated by three structurally and biologically diverse microtubule stabilizers; taccalonolide AJ, laulimalide/fijianolide B and paclitaxel were studied. These microtubule stabilizers cause the formation of aberrant, but structurally distinct mitotic spindles leading to the hypothesis that they differentially affect mitotic signaling. Each microtubule stabilizer initiated different patterns of expression of key mitotic signaling proteins. Taccalonolide AJ causes centrosome separation and disjunction failure to a much greater extent than paclitaxel or laulimalide, which is consistent with the distinct defects in expression and activation of Plk1 and Eg5 caused by each stabilizer. Localization studies revealed that TPX2 and Aurora A are associated with each spindle aster formed by each stabilizer. This suggests a common mechanism of aster formation. However, taccalonolide AJ also causes pericentrin accumulation on every spindle aster. The presence of pericentrin at every spindle aster initiated by taccalonolide AJ might facilitate the maintenance and stability of the highly focused asters formed by this stabilizer. Laulimalide and paclitaxel cause completely different patterns of expression and activation of these proteins, as well as phenotypically different spindle phenotypes. Delineating how diverse microtubule stabilizers affect mitotic signaling pathways could identify key proteins involved in modulating sensitivity and resistance to the antimitotic actions of these compounds.
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http://dx.doi.org/10.1016/j.bcp.2013.01.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3661198PMC
April 2013

Amyrisins A-C, O-prenylated flavonoids from Amyris madrensis.

J Nat Prod 2012 Mar 19;75(3):494-6. Epub 2012 Jan 19.

Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, United States.

Three new O-prenylated flavonoids, amyrisins A-C (1-3), were isolated from the leaves and twigs of Amyris madrensis, along with the known compound polygamain (4). The structures of 1-3 were elucidated on the basis of the analysis of spectroscopic data interpretation. Amyrisins B (2) and C (3) showed moderate cytotoxicity against PC-3 and DU 145 prostate cancer cells with IC(50) values of 17.5 and 23 μM, respectively, while amyrisin A (1) did not show any cytotoxicity at the highest concentration tested, 50 μM. Polygamain (4) exhibited potent antiproliferative and microtubule-depolymerizing activities.
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http://dx.doi.org/10.1021/np200796eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3311741PMC
March 2012

Potent taccalonolides, AF and AJ, inform significant structure-activity relationships and tubulin as the binding site of these microtubule stabilizers.

J Am Chem Soc 2011 Nov 8;133(47):19064-7. Epub 2011 Nov 8.

Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.

The taccalonolides are a class of microtubule stabilizing agents isolated from plants of the genus Tacca. In efforts to define their structure-activity relationships, we isolated five new taccalonolides, AC-AF and H2, from one fraction of an ethanol extract of Tacca plantaginea. The structures were elucidated using a combination of spectroscopic methods, including 1D and 2D NMR and HR-ESI-MS. Taccalonolide AJ, an epoxidation product of taccalonolide B, was generated by semisynthesis. Five of these taccalonolides demonstrated cellular microtubule-stabilizing activities and antiproliferative actions against cancer cells, with taccalonolide AJ exhibiting the highest potency with an IC(50) value of 4.2 nM. The range of potencies of these compounds, from 4.2 nM to >50 μM, for the first time provides the opportunity to identify specific structural moieties crucial for potent biological activities as well as those that impede optimal cellular effects. In mechanistic assays, taccalonolides AF and AJ stimulated the polymerization of purified tubulin, an activity that had not previously been observed for taccalonolides A and B, providing the first evidence that this class of microtubule stabilizers can interact directly with tubulin/microtubules. Taccalonolides AF and AJ were able to enhance tubulin polymerization to the same extent as paclitaxel but exhibited a distinct kinetic profile, suggesting a distinct binding mode or the possibility of a new binding site. The potencies of taccalonolides AF and AJ and their direct interaction with tubulin, together with the previous excellent in vivo antitumor activity of this class, reveal the potential of the taccalonolides as new anticancer agents.
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http://dx.doi.org/10.1021/ja209045kDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3234588PMC
November 2011

Identification and biological activities of new taccalonolide microtubule stabilizers.

J Med Chem 2011 Sep 11;54(17):6117-24. Epub 2011 Aug 11.

Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.

The taccalonolides are a unique class of microtubule stabilizers that do not bind directly to tubulin. Three new taccalonolides, Z, AA, and AB, along with two known compounds, taccalonolides R and T, were isolated from Tacca chantrieri and Tacca integrifolia. Taccalonolide structures were determined by 1D and 2D NMR methods. The biological activities of the new taccalonolides, as well as taccalonolides A, B, E, N, R, and T, were evaluated. All nine taccalonolides display microtubule stabilizing activity, but profound differences in antiproliferative potencies were noted, with IC(50) values ranging from the low nanomolar range for taccalonolide AA (32 nM) to the low micromolar range for taccalonolide R (13 μM). These studies demonstrate that diverse taccalonolides possess microtubule stabilizing properties and that significant structure-activity relationships exist. In vivo antitumor evaluations of taccalonolides A, E, and N show that each of these molecules has in vivo antitumor activity.
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http://dx.doi.org/10.1021/jm200757gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3180930PMC
September 2011

Evelynin, a cytotoxic benzoquinone-type Retro-dihydrochalcone from Tacca chantrieri.

J Nat Prod 2010 Sep;73(9):1590-2

Department of Pharmacology and Cancer Therapy & Research Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.

A new benzoquinone-type retro-dihydrochalcone, named evelynin, was isolated from the roots and rhizomes of Tacca chantrieri. The structure was elucidated on the basis of the analysis of spectroscopic data and confirmed by a simple one-step total synthesis. Evelynin exhibited cytotoxicity against four human cancer cell lines, MDA-MB-435 melanoma, MDA-MB-231 breast, PC-3 prostate, and HeLa cervical carcinoma cells, with IC(50) values of 4.1, 3.9, 4.7, and 6.3 μM, respectively.
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http://dx.doi.org/10.1021/np100350sDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2945413PMC
September 2010

Antiproliferative effects of curcuphenol, a sesquiterpene phenol.

Fitoterapia 2010 Oct 10;81(7):762-6. Epub 2010 Apr 10.

Molecular Biology and Biotechnology Institute, University Major of San Andres, La Paz, Bolivia.

Curcuphenol is a sesquiterpene isolated from sponges and plants having several significant biological activities. The present study explored its effect on cell proliferation and apoptosis in Caco-2 human colon cancer cells. It was demonstrated that curcuphenol in concentrations in the range of 29-116 µg/ml inhibited cell proliferation and DNA replication and induced cell death in a dose-dependent manner. The induction of apoptosis was associated with a stimulation of the activity of caspase-3. The findings presented here suggest that curcuphenol has antiproliferative and pro-apoptotic properties.
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http://dx.doi.org/10.1016/j.fitote.2010.04.001DOI Listing
October 2010

Structure and absolute configuration of karlotoxin-2, an ichthyotoxin from the marine dinoflagellate Karlodinium veneficum.

J Am Chem Soc 2010 Mar;132(10):3277-9

Department of Pharmacognosy and National Center for Natural Products Research, University of Mississippi, University, Mississippi 38677, USA.

In an attempt to determine the cause of repeated fish kills in an estuarine aquaculture facility in Maryland, a toxin with hemolytic, cytotoxic, and ichthyotoxic properties, designated as karlotoxin-2 (KmTx2), was isolated from Karlodinium veneficum. The structure of KmTx2 was elucidated by means of detailed ID and 2D NMR spectra, including 2D INADEQUATE. The relative and absolute configurations of KmTx2 were determined using J-based configuration analysis and comparison of its degradation products with synthetic controls.
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http://dx.doi.org/10.1021/ja9091853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2836391PMC
March 2010

Metabonomics study of urine from Sprague-Dawley rats exposed to Huang-yao-zi using (1)H NMR spectroscopy.

J Pharm Biomed Anal 2010 May 29;52(1):136-41. Epub 2009 Dec 29.

Institute of Radiation Medicine, Academy of Military Medical Sciences, No. 27, Taiping Rd., Haidian District, Beijing 100850, PR China.

Urinary metabolic perturbations associated with liver toxicity induced by Huang-yao-zi (root of Dioscorea bulifera L.) were studied using nuclear magnetic resonance spectroscopy ((1)H NMR) to determine the correlations between metabonomic profiling and histopathologic/biochemical observations and to discover biomarkers for liver toxicity. Huang-yao-zi with a maximal tolerance dose (MTD) was given to male Sprague-Dawley rats for 72h followed by metabonomic analysis of urine samples collected at 24 and 72h. The results revealed that the levels of taurine, creatine, betaine, dimethylglycine (DMG), acetate, glycine were elevated, whereas, the levels of succinate, 2-oxoglutarate, citrate, hippurate and urea were reduced. Partial least square (PLS)-discrimination analysis (DA) of NMR spectra revealed two apparent clusters between control groups and treatment groups, indicating metabolic changes observed in urine samples in response to Huang-yao-zi treatment. In addition, mechanism associated with oxidative injury of hepatic mitochondria was investigated. These results indicated that (1)H NMR-based metabonomics analysis in urine samples may be useful for predicting hepatotoxicity induced by Huang-yao-zi.
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http://dx.doi.org/10.1016/j.jpba.2009.12.026DOI Listing
May 2010

Reducing oyster-associated bacteria levels using supercritical fluid CO2 as an agent of warm pasteurization.

Int J Food Microbiol 2010 Mar 20;138(1-2):63-70. Epub 2009 Nov 20.

Department of Pharmacognosy, School of Pharmacy, The University of Mississippi, University, MS 38677-1848, USA.

An innovative approach to Post-Harvest Processing (PHP) of oysters is introduced focusing on the effects of supercritical carbon dioxide (scCO(2)) on bacterial contaminants trapped in the digestive system of oysters. Oysters were exposed to scCO(2) under two conditions: (1) 100 bar and 37 degrees C for 30 min and (2) 172 bar and 60 degrees C for 60 min. Using FDA standard guidelines for food analysis, variations in the Aerobic Plate Count (APC) were assessed. It was established that exposing oysters to CO(2) at 100 bar and 37 degrees C for 30 min and at 172 bar and 60 degrees C for 60 min induced 2-log and 3-log reductions in the APC respectively. The decrease in the microbial load as a result of treatment with scCO(2) was found to be significant (P=0.002). A release of adductor muscles from the shell was noted in oysters treated at 172 bar and 60 degrees C for 60 min; this was not the case for oysters treated at 100 bar and 37 degrees C for 30 min. A blind study allowing sensory analysis of treated vs. untreated oysters was also completed and no significant change in the physical appearance, smell, or texture was recorded. In this paper, we also report the effect of scCO(2) on several bacterial isolates, including a referenced ATCC strain of a non-pathogenic Vibrio (Vibrio fischeri) as well as several other bacterial isolates cultured from oyster' tissues and found to share biochemical features common to pathogenic Vibrio strains. A complete inactivation (minimum 7-log reduction) was achieved with these latter bacterial isolates. A 6-log reduction was observed with V. fischeri.
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http://dx.doi.org/10.1016/j.ijfoodmicro.2009.11.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2830373PMC
March 2010
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