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IntroductionWe have evaluated two approaches of monitoring schools and colleges of pharmacy based on North American Pharmacist Licensure Examination® (NAPLEX®) passage rates. Historically, the Accreditation Council for Pharmacy Education (ACPE) has cited programs based on achieving a passage rate ≥2 SD standard deviations (SD) below the national average. Since the National Association of Boards of Pharmacy (NABP) no longer reports scores, this procedure is currently being reconsidered. Our supposition is that the failure rate of ≥2 SD below the average passage rate should be retained, but now, based on the national average passage rate. However, we further suggest this is not adequate, due to major variations in class size.CommentaryWe suggest the establishment of a ‘maximum acceptable failure count’, likely in the range of 20-25 failing graduates per class. Analyses of data from 2017-2019 indicate that this approach would lead to monitoring approximately 15% of existing programs that graduate approximately 40% of individuals failing NAPLEX, versus monitoring approximately 5% of programs that graduate approximately 9% of individuals failing NAPLEX.ImplicationsThe historical method of monitoring pharmacy programs with NAPLEX passage based on the national average ≥2 SD is not adequate, primarily due large variations in class size. In that accreditation standards are currently being revised (“Standards 2025”), this would be an ideal time to reconsider methods for selecting programs that warrant monitoring based on inadequate NAPLEX passage rates. We suggest the concept of ‘maximum acceptable failure count’ should be taken into account when identifying programs to be cited.

On the basis of copious preclinical data supporting the preventive efficacy of small fruits such as berries and grapes, Chen and colleagues conducted a randomized (noncomparative) phase II trial evaluating two doses of strawberry powder (60 g/d or 30 g/d for six months) to prevent esophageal cancer in China (reported in this issue of the journal, beginning on page 41); 60 g/d reduced the histologic grade of dysplastic lesions and reduced localized biomarkers, whereas 30 g/d was not effective. Fundamental questions remain such as the best formulation of strawberry powder, the active components associated with powder, and the actual mechanism of action, and standardized preparations will be required to permit the widespread use of strawberry powder with a predicable outcome. Clearly, however, this work is a good example of proof-of-principle and highlights the important role of diet, nutrition, and natural products in cancer prevention. Cancer Prev Res; 5(1); 30–33. ©2012 AACR.

Supplementary Materials from Induction of Retinoid X Receptor Activity and Consequent Upregulation of p21WAF1/CIP1 by Indenoisoquinolines in MCF7 Cells

Related Article from Strawberry Fields Forever?

The benefits of fruit and vegetable dietary consumption are largely defined in epidemiological terms. Relatively little is known about the discrete effects on metabolic pathways elicited by individual dietary fruits and vegetables. To address this, grape powder was added to both a standard and a high-fat Western pattern diet given to 10-week-old female C57BL/6J mice for a period of 91 days, whereupon 24 h urines were collected and the mice euthanized after a 12 h fast for the collection of liver tissue. Alterations in hepatic and urinary metabolite patterns were determined by gas chromatography-mass spectrometry-based metabolomics. Urinary excretion of the gut microbiota metabolites 4-hydroxyphenylacetic acid, 5-hydroxyindole, glyceric acid, gluconic acid and

Datura innoxia Mill., Solanaceae, an underexplored ethnomedicinal plant, has been empirically evaluated in the current study for the isolation of bioactive agents. A crude extract of D. innoxia leaves was subjected to normal-phase medium pressure and vacuum liquid chromatography which led to the purification of a withanolide, isowithametelin. The chemical structure was established based on single-crystal X-ray diffraction. Isowithametelin exhibited substantial cytotoxicity against tested human cancer cell lines (breast cancer MCF-7 (ATCC® HTB-22), lung carcinoma LU-1 (human lung carcinoma established in the Department of Surgical Oncology, University of Illinois at Chicago), and prostate adenocarcinoma PC-3 (ATCC® CRL-1435)) with IC50 values of 4.3 ± 0.93, 6.9 ± 1.3, and 0.01 ± 0.001 μg/ml, respectively. It also inhibited nitric oxide production in lipopolysaccharide-activated murine macrophage RAW 264.7 cells (IC50 value of 18.5 ± 1.8 μg/ml) and demonstrated moderate protein kinase inhibition. This work suggests a possible anticancer role of isowithametelin; in vivo studies remain necessary to corroborate in vitro efficacy.

Two new helvolic acid analogues (1 and 2) and one new fumagillin derivative containing an octahydroisobenzofuran moiety (3), together with four known compounds (4-7), were isolated from an Aspergillus terreus, isolated from soil collected from Mauna Kea, the highest mountain in Hawaii. Compound 4 was recorded in SciFinder with a CAS Registry Number of 1379525-35-5, but it was not documented in the cited reference (ACS Chem. Biol. 2012, 7, 137). The structures of compounds 1-4 were elucidated by NMR spectroscopy and HRMS and ECD analysis. Compounds 5 and 6 showed significant inhibitory activity against NF-κB with IC50 values of 2.7 ± 2.6 and 6.5 ± 0.8 μM, respectively. Compounds 1 and 2 were active against S. aureus with MICs of 6.25 and 6.25 μg/mL, respectively, while compound 5 inhibited E. coli with an MIC of 3.12 μg/mL.

Main conclusion Metabolites in Rafflesia-infected and non-infected Tetrastigma were compared which may have applications in Rafflesia propagation. Benzylisoquinoline alkaloids, here reported for the first time in Vitaceae, were abundant in non-infected shoots and may be a form of defense. In Rafflesia-infected shoots, oxylipins, which mediate immune response, were elevated. Abstract Endemic to the forests of Southeast Asia, Rafflesia (Rafflesiaceae) is a genus of holoparasitic plants producing the largest flowers in the world, yet completely dependent on its host, the tropical grape vine, Tetrastigma. Rafflesia species are threatened with extinction, making them an iconic symbol of plant conservation. Thus far, propagation has proved challenging, greatly decreasing efficacy of conservation efforts. This study compared the metabolites in the shoots of Rafflesia-infected and non-infected Tetrastigma loheri to examine how Rafflesia infection affects host metabolomics and elucidate the Rafflesia infection process. Results from LC–MS-based untargeted metabolomics analysis showed benzylisoquinoline alkaloids were naturally more abundant in non-infected shoots and are here reported for the first time in the genus Tetrastigma, and in the grape family, Vitaceae. These metabolites have been implicated in plant defense mechanisms and may prevent a Rafflesia infection. In Rafflesia-infected shoots, oxygenated fatty acids, or oxylipins, and a flavonoid, previously shown involved in plant immune response, were significantly elevated. This study provides a preliminary assessment of metabolites that differ between Rafflesia-infected and non-infected Tetrastigma hosts and may have applications in Rafflesia propagation to meet conservation goals.

Solvent fractions from leaf and bark extracts of Vaccinium leschenaultii were screened for their antioxidant, cell viability, and nitric oxide (NO) inhibitory potential. Antioxidant activit...

Two new helvolic acid analogues (

Throughout this book the power of combination chemoprevention is highlighted. Even individual agents that function by virtue of pleiotropic mechanisms of action portray a combination effect. In this final chapter, we offer a brief perspective on the concept of combining numerous (e.g., 10–25) dietary agents for the creation of a cocktail capable of mediating a broad-based cancer chemopreventive response. The challenges of logically and systematically founding a cocktail comprised of 10–25 dietary chemopreventive components functioning in an additive or synergistic manner are addressed. Obviously, this is no mean task. Some technological advances are necessary, such as creating in vitro systems engineered to encompass several hallmarks of cancer, and animal models that generically correlate with the genesis of human cancer. Nonetheless, as illustrated by the cogent, on point contributions presented in this book, over the past several decades, we have already acquired the knowledge and skill necessary for accomplishing this vast undertaking. Given the current day morbidity and mortality associated with malignant metastatic cancer, and future projections of even greater devastation, all of humanity would benefit by a holistic approach utilizing the tools provided to us by Nature.

Background/aim There is an unmet clinical need to develop new anticancer and chemopreventive agents. The aim of the present study was to identify β-carboline derivatives with cancer chemopreventive and therapeutic potential. Materials and methods Forty-eight tetrahydro-β-carboline derivatives were synthesized and evaluated for their anticancer and chemopreventive activities, through induction of quinone reductase 1 (QR1), aromatase inhibition, as well as inhibition of nitric oxide (NO) production. Results 2-((1-Bromonaphthalen-2-yl)methyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole demonstrated the most potent activity in the QR1 induction assay with an induction ratio value of 3.2 (CD=1.3 μM). The R-isomer of the amide derivative (2-((1-bromonaphthalen-2-yl)methyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-3-yl)(4-methylpiperazin-1-yl)methanone was the most potent inhibitor of NO production with a 50% inhibitory concentration, IC50=6.54 μM and had a low cytotoxic effect (IC50=17.98 μM) on RAW 264.7 cells. Subsequent computational docking study revealed that this compound binds to the active site of inducible nitric oxide synthase with favorable interactions. Conclusion our results provided promising β-carboline leads for further optimization and development with therapeutic potential as new chemopreventive and chemotherapy agents.

Toranja 'Burarama', Citrus maxima (Burm.) Merr. (Citrus grandis), is a new citrus discovered in the State of Espirito Santo, Brazil. As several varieties of citrus are known to possess antioxidant and cancer chemopreventive properties, the aim of the study was to evaluate in vitro if this Toranja possess these properties. The antioxidant activity, the potential to induce quinone reductase 1, and the influence on cell viability were measured. ESI(-)FT-ICR MS analysis was also performed and identified flavonoids, coumarins, and fatty acids in the extract. The ethyl acetate and methanolic extracts of the peels presented the highest antioxidant activity in vitro by DPPH (IC50 = 298.3 ± 2.6 μg/ml and 303.8 ± 0.4 μg/ml), ABTS assay (IC50 = 298.2 ± 6.4 μg/ml and 296.4 ± 2.5 μg/ml), and FRAP (IC50 = 234.6 ± 1.8 μg/ml and 398.1 ± 3.8 μg/ml). The ethyl acetate extract of the peel induced quinone reductase 1 activity in Hepa1c1c7 cells, indicating that C. maxima exhibited cancer chemopreventive properties.

In our ongoing effort of discovering anticancer and chemopreventive agents, a series of 2-arylindole derivatives were synthesized and evaluated toward aromatase and quinone reductase 1 (QR1). Biological evaluation revealed that several compounds (e.g., 2d, IC50 = 1.61 μM; 21, IC50 = 3.05 μM; and 27, IC50 = 3.34 μM) showed aromatase inhibitory activity with half maximal inhibitory concentration (IC50) values in the low micromolar concentrations. With regard to the QR1 induction activity, 11 exhibited the highest QR1 induction ratio (IR) with a low concentration to double activity (CD) value (IR = 8.34, CD = 2.75 μM), while 7 showed the most potent CD value of 1.12 μM. A dual acting compound 24 showed aromatase inhibition (IC50 = 9.00 μM) as well as QR1 induction (CD = 5.76 μM) activities. Computational docking studies using CDOCKER (Discovery Studio 3.5) provided insight in regard to the potential binding modes of 2-arylindoles within the aromatase active site. Predominantly, the 2-arylindoles preferred binding with the 2-aryl group toward a small hydrophobic pocket within the active site. The C-5 electron withdrawing group on indole was predicted to have an important role and formed a hydrogen bond with Ser478 (OH). Alternatively, meta-pyridyl analogs may orient with the pyridyl 3′-nitrogen coordinating with the heme group.

In previous studies, withanolides isolated from Physalis peruviana were found to exhibit anti-inflammatory potential by suppressing nitrite production induced by lipopolysaccharide (LPS) treatment. Currently, we selected two of the most potent compounds, 4β-hydroxywithanolide E (1) and physalactone (2), to examine the underlying mechanism of action. With LPS-stimulated RAW 264.7 cells in culture, the compounds inhibited the mRNA and protein expression of iNOS and COX-2. To determine which upstream signaling proteins were involved in these effects, phosphorylation levels of three mitogen-activated protein kinases (MAPKs) including ERK1/2, JNK1/2, and p38, were examined, but found unaffected. Similarly, the degradation of IκBα was not attenuated by the compounds. However, phosphorylation of Akt at the Ser-473 residue was inhibited, as was the phosphorylation of STAT1. Interestingly, the compounds also reduced the protein level of total STAT1, possibly by ubiquitin-dependent protein degradation. In sum, these results indicate the potential of 1 and 2 to mediate anti-inflammatory effects through the unexpected mechanism of inhibiting the transcription of iNOS and COX-2 via Akt- and STAT1-related signaling pathways.

In this article we have comprehensively reported the synthesis, complete chemical characterization (FTIR, multinuclear NMR, single crystal XRD, CHNS, AAS) and biological applications of seventeen ferrocene incorporated selenoureas. Biological applications include comparative DNA binding studies (with, cyclic voltammetry), antioxidant activities (DPPH (2,2-diphenyl-1-picrylhydrazyl) scavenging), anti-inflammatory activities (nitrite inhibition), phase I enzyme inhibition activities (aromatase inhibition), phase II enzyme induction studies (quinone reductase induction) and cytotoxic studies against neuroblastoma (MYCN2 and SK-N-SH), liver cancer (Hepa 1c1c7) breast cancer (MCF-7) and human cervical carcinoma HeLa cells (ATCC® CCL-2). All the compounds showed decent structure dependent biological applications. We are thankful to Higher Education Commission Islamabad, Pakistan and Pakistan Academy of Sciences for financial support. Appendix A Scopus

Bioassay-guided fractionation of the dichloromethane extract from the apical bud of Gardenia sootepenesis Hutch. (Rubiaceae) led to the isolation of four new cycloartane triterpenes, sootepins F-I (1-4), along with four known derivatives (5-8). The structures of the new compounds were determined by 1D and 2D NMR experiments and by comparison of the physicochemical data with published values. The isolates were evaluated for cancer chemopreventive potential based on their ability to inhibit nitric oxide (NO) production and tumor necrosis factor-alpha (TNF-α)-induced nuclear factor kappa (NF-κB) activity. Compounds 6-8 inhibited TNF-α-induced NF-κB activity with half maximal inhibitory concentration (IC50) values of 8.3, 5.6, and 6.0μM, respectively; compounds 7 and 8 showed significant NO-inhibitory activity with IC50 values of 3.2 and 2.0μM, respectively.

Multiple myeloma (MM) continues to claim the lives of a majority of patients. MM cancer stem cells (CSCs) have been demonstrated to sustain tumor growth. Due to their ability to self-renew and to express detoxifying enzymes and efflux transporters, MM-CSCs are rendered highly resistant to conventional therapies. Therefore, managing MM-CSCs characteristics could have profound clinical implications. Bruceantin (BCT) is a natural product previously demonstrated to inhibit the growth of MM in RPMI 8226 cells-inoculated mouse xenograft models, and to cause regression in already established tumors. The objectives of the present study were to test the inhibitory effects of BCT on MM-CSCs growth derived from a human primary tumor, and to explore a mechanism of action underlying these effects. BCT exhibited potent antiproliferative activity in MM-CSCs starting at 25 nM. BCT induced cell cycle arrest, cell death and apoptosis in MM-CSCs as well as inhibited cell migration and angiogenesis in vitro. Using a qPCR screen, it was found that the gene expression of a number of Notch pathway members was altered. Pretreatment of MM-CSCs with the γ-secretase inhibitor RO4929097, a Notch pathway inhibitor, reversed BCT-induced effects on MM-CSCs proliferation. In this study, BCT was shown to be an effective agent in controlling the proliferation, viability and migration of MM-CSCs as well as angiogenesis in vitro. The effect on MM-CSCs proliferation may be mediated by the Notch pathway. These results warrant further investigation of BCT in a broader set of human-derived MM-CSCs and with in vivo models representative of MM.

Scope Physalis peruviana (Solanaceae) is used for culinary and medicinal purposes. We currently report withanolides, isolated from P. peruviana, inhibit the growth of colon cancer monolayer and spheroid cultures. A detailed mechanistic evaluation was performed with 4β-hydroxywithanolide E (4HWE). Methods and results Treatment of HT-29 cells with low concentrations of 4HWE inhibited growth while enhancing levels of p21(Waf1/Cip1) and reducing levels of several cell cycle-related proteins. Apoptosis was induced at higher concentrations. In addition, 4HWE treatment downregulated the levels of Hsp90 client proteins. Nuclear sirtuin 1 (SIRT1) was increased and histone H3 acetylated at lysine 9 was decreased. An additional consequence of SIRT1 elevation in the nucleus may be inhibition of c-Jun activity. The expression of 21 genes was altered, including downregulation of PTGS2, and this correlated with reduced protein levels of cyclooxygenase-2 (COX-2). Overall, efficacious induction of G0/G1 cell cycle arrest at low concentrations, and induction of apoptosis at higher concentrations are interesting 4HWE-mediated phenomena that are accompanied by a complex array of molecular events. Conclusion Considering the worldwide prevalence of colon cancer, and the unique mode of action mediated by 4HWE, it is reasonable to investigate additional mechanistic details and the potential utility of this compound.

Two new heteroleptic palladium(II) complexes have been synthesized by reacting equimolar quantities of palladium(II) chloride, sodium 4-(2-methoxyphenyl)piperazine-1-carbodithioate and diphenyl-p-tolylphosphine (1) or tri-p-tolylphosphine (2). Complexes 1 and 2 have been characterized using elemental analysis, Fourier transform infrared spectroscopy, multinuclear NMR (1H, 13C and 31P) spectroscopy and single-crystal X-ray analysis. The latter technique confirms a pseudo square-planar geometry in which two adjacent positions are occupied by bidentate dithiocarbamate while chloro and substituted triphenylphosphine are present at the remaining two positions. The anticancer activity of both complexes against five different cancer cell lines (LU – human lung carcinoma, established at UIC, Department of Surgical Oncology; MCF7 – human breast adenocarcinoma, ATCC number HTB-22™; MDA-MB-231 – human breast adenocarcinoma, ATCC number HTB-26™; Hepa-1c1c7 – mouse liver hepatoma, ATCC number CRL-2026™; PC-3 – human prostate adenocarcinoma, ATCC number CRL-1435™) was determined by MTT assay, revealing 2 has higher activity than 1. A drug–calf thymus DNA binding study with UV–visible spectroscopy reveals a higher DNA binding affinity of 2 (3.511 × 104 M−1) than 1 (4.213 × 103 M−1). Density functional theory studies confirm the relatively more stable nature of 2 than 1. Copyright © 2016 John Wiley & Sons, Ltd.

Heteroleptic platinum(II) dithiocarbamates, of general formula [Pt(DTC)LCl], where DTC = 4-(4-methoxyphenyl)piperazine-1-carbodithioate (1 and 2) and 4-(furan-2-carbonyl)piperazine-1-carbodithioate (3) and L = tri(4-flourophenylphosphine) (1 and 3) and tri(4-chlorophenylphosphine) (2) have been synthesized and characterized by different analytical techniques. These complexes are square planar with picoplatin or phenanthriplatin type steric hindrance from aromatic C–H groups of the phosphine ligand as shown by single-crystal analysis. In 1, the Pt square plane is hindered by two axially oriented hydrogens, whereas by only one in 2 and 3. DNA-binding studies by UV/visible spectroscopy revealed a stronger electrostatic interaction of 1 compared to 2 and 3, and the results are further supported by viscometry and cyclic voltammetric measurements. Their in vitro anticancer activity against five different cancer cell lines using a MTT assay revealed high potency of the complexes. The higher activity of 1 than both 2 and 3 is consistent with DNA binding strength and we speculate that it may be due to the relatively inert nature of platinum towards off-target biomolecules ensured by the hindrance caused by the two axially oriented hydrogens.

Litsea verticillata Hance (Lauraceae), a Chinese medicine used to treat swelling caused by injury or by snake bites, was the first plant identified by our National Institutes of Health (NIH)-funded International Cooperative Biodiversity Group (ICBG) project to exhibit anti-HIV activities. From this plant, we discovered a class of 8 novel litseane compounds, prototypic sesquiterpenes, all of which demonstrated anti-HIV activities. In subsequent studies, 26 additional compounds of different structural types were identified. During our continuing investigation of this plant species, we identified two new litseanes, litseaverticillols L and M, and a new sesquiterpene butenolide, litseasesquibutenolide. Litseaverticillols L and M were found to inhibit HIV-1 replication, with an IC[Formula: see text] value of 49.6[Formula: see text][Formula: see text]M. To further determine the antiviral properties of this plant, several relatively abundant isolates, including a litseane compound, two eudesmane sesquiterpenes and three lignans, were evaluated against an additional 21 viral targets. Lignans 8 and 9 were shown to be active against the Epstein–Barr Virus (EBV), with EC[Formula: see text] values of 22.0[Formula: see text][Formula: see text]M ([Formula: see text]) and 16.2[Formula: see text][Formula: see text]M ([Formula: see text]), respectively. Since many antiviral compounds have been discovered in L. verticillata, we further prepared 38 plant extracts made from the different plant parts of 9 additional Litsea species. These extracts were evaluated for their anti-HIV and cytotoxic activities, and four of the extracts, which ranged across three different species, displayed 97–100% inhibitory effects against HIV replication without showing cytotoxicity to a panel of human cell lines at a concentration of 20[Formula: see text][Formula: see text]g/mL.

Background The pharmacology, toxicology and pharmacokinetics of bioactive preparations derived from natural sources has become a flourishing field of research. However, researching complex extracts and natural products faces numerous challenges. More broadly in recent years the critique of pharmacological research, and specifically its design, the methods used and reporting has intensified. Aims This consensus document provides a perspective on what constitutes best practice in pharmacological research on bioactive preparations derived from natural sources, providing a perspective of what the leading specialist journals in the field consider as the core characteristics of good research. Approach (‘methods’) The editors-in-chief of seven journals developed this best practice statement in an iterative process. A first draft of the guidelines (prepared by MH) was then discussed and amended by the other editors. Outcomes Core to this contribution is a table which provides detailed advice including simple points like a use of appropriate controls and the full taxonomic validity of the material under investigation (see also below), to the relevance of the model for the question being researched (e.g., can specific in silico or in vitro models really address the species anti-inflammatory activity?). Therefore, obviously, researchers must pay detailed attention to reporting and discussing such studies. This information must be discussed critically (as much as it is possible based on the published papers) in terms of their scientific quality and validity. While these points are obvious, as editors, we are aware that they are often not properly implemented. Conclusion We call for an approach which incorporates a careful design, meticulous execution and a detailed reporting of studies focusing on the pharmacology/bioactivity of bioactive preparations. Clearly testable research questions must be developed and investigated experimentally. As the founder of pharmacology Claude Bernard put it already in 1865: ‘…. either the experimenter's hypothesis will be disproved or it will be proved by experiment. When experiment disproves its preconceived ideas, the experimenter must discard or modify it.‘

Resveratrol was first isolated in 1939 by Takaoka from Veratrum grandiflorum O. Loes. Following this discovery, sporadic descriptive reports appeared in the literature. However, spurred by our seminal paper published nearly 60 years later, resveratrol became a household word and the subject of extensive investigation. Now, in addition to appearing in over 20,000 research papers, resveratrol has inspired monographs, conferences, symposia, patents, chemical derivatives, etc. In addition, dietary supplements are marketed under various tradenames. Once resveratrol was brought to the limelight, early research tended to focus on pharmacological activities related to the cardiovascular system, inflammation, and cancer but, over the years, the horizon greatly expanded. Around 130 human clinical trials have been (or are being) conducted with varying results. This may be due to factors such as disparate doses (ca. 5 to 5,000 mg/day) and variable experimental settings. Further, molecular targets are numerous and a dominant mechanism is elusive or nonexistent. In this context, the compound is overtly promiscuous. Nonetheless, since the safety profile is pristine, and use as a dietary supplement is prevalent, these features are not viewed as detrimental. Given the ongoing history of resveratrol, it is reasonable to advocate for additional development and further clinical investigation. Topical preparations seem especially promising, as do conditions that can respond to anti-inflammatory action and/or direct exposure, such as colon cancer prevention. Although the ultimate fate of resveratrol remains an open question, thus far, the compound has inspired innovative scientific concepts and enhanced public awareness of preventative health care.

Toranja 'Burarama', Citrus maxima (Burm.) Merr. (Citrus grandis), is a new citrus discovered in the State of Espírito Santo, Brazil. As several varieties of citrus are known to possess antioxidant and cancer chemopreventive properties, the aim of the study was to evaluate in vitro if this Toranja possess these properties. The antioxidant activity, the potential to induce quinone reductase 1, and the influence on cell viability were measured. ESI(-)FT-ICR MS analysis was also performed and identified flavonoids, coumarins, and fatty acids in the extract. The ethyl acetate and methanolic extracts of the peels presented the highest antioxidant activity in vitro by DPPH (IC

Traditional medicinal plants are often used for both the prevention and the treatment of local diseases. Taking into consideration the medicinal importance of Hedera nepalensis within local Pakistani traditions, the present study was undertaken to analyze the in vitro cancer chemopreventive and cytotoxic properties of the plant. The in vitro cancer chemopreventive testing was performed using nitrite assay, NFκB assay, aromatase assay, and quinone reductase 1 (QR1) assay. The cytotoxic potential was evaluated on three cancer-cell lines: MCF-7, MDA-MB-231, and HeLa using sulforhodamine B (SRB) assay. The results of cancer chemopreventive assays show that n-hexane and ethyl acetate fractions of tested plant have promising cancer chemopreventive potential. Lupeol isolated from n-hexane as well as ethyl acetate fraction showed lowest IC50 (0.20 ± 1.9 μM) in NFκB assay. Crude extract and its fractions inhibited the growth of three cancer cell lines by more than 60%, IC50 value of lupeol varied from 2.32 to 10.2 μM. HPLC-DAD-based quantification of lupeol in different plant tissues demonstrated that leaves of H. nepalensis are a rich source of lupeol (0.196 mg/100 mg dry weight). Our data have shown that H. nepalensis harbors cancer chemopreventive and cytotoxic agents.

Chiral peptides and iso-peptides were synthesized in excellent yield by using benzotriazole mediated solution phase synthesis. Benzotriazole acted both as activating and leaving group, eliminating frequent use of protection and subsequent deprotection. The procedure was based on the hypothesis that epimerization should be suppressed in solution due to a faster coupling rate than SPPS. All the synthesized peptides complied with Lipinski's Ro5 except for the rotatable bonds. Inhibition of cell proliferation of cancer cell lines is one of the most commonly used methods to study the effectiveness of any anticancer agents. Synthesized peptides and iso-peptides were tested against three cancer cell lines (MCF-7, MDA-MB 231) to determine their anti-proliferative potential. NFkB was also determined. Molecular docking studies were also carried out to complement the experimental results.

(E)-4-(3,5-dimethoxystyryl)phenyl acetate (Cmpd1) is a resveratrol analog that preferentially inhibits glioma, breast, and pancreatic cancer cell growth, with IC50 values of 6-19 μM. Notably, the human U251MG glioblastoma tumor line is the most sensitive, with an IC50 of 6.7 μM, compared with normal fibroblasts, which have an IC5020 μM. Treatment of U251MG cells that harbor aberrantly active signal transducer and activator of transcription (Stat) 3 with Cmpd1 suppresses Stat3 tyrosine705 phosphorylation in a dose-dependent manner in parallel with the induction of pserine727 Stat3 and extracellular signal-regulated kinase/mitogen-activated protein kinase 1/2 (pErk1/2(MAPK)). Inhibition of pErk1/2(MAPK) induction by the mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor PD98059 [2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one] blocked both the pserine727 Stat3 induction and ptyrosine705 Stat3 suppression by Cmpd1, indicating dependency on the mitogen-activated protein/extracellular signal-regulated kinase kinase-Erk1/2(MAPK) pathway for Cmpd1-induced modulation of Stat3 signaling. Cmpd1 also blocked epidermal growth factor-stimulated pStat1 induction, whereas upregulating pSrc, pAkt, p-p38, pHeat shock protein 27, and pmammalian target of rapamycin levels. However, pJanus kinase 2 and pEpidermal growth factor receptor levels were not significantly altered. Treatment of U251MG cells with Cmpd1 reduced in vitro colony formation, induced cell cycle arrest in the G2/M phase and cleavage of caspases 3, 8, and 9 and poly(ADP ribose) polymerase, and suppressed survivin, myeloid cell leukemia 1, Bcl-xL, cyclin D1, and cyclin B1 expression. Taken together, these data identify a novel mechanism for the inhibition of Stat3 signaling by a resveratrol analog and suggest that the preferential growth inhibitory effects of Cmp1 occur in part by Erk1/2(MAPK)-dependent modulation of constitutively active Stat3.

LC-UV/MS-based metabolomic analysis of the Hawaiian endophytic fungus Paraphaeosphaeria neglecta FT462 led to the identification of four unique mercaptolactated γ-pyranol-γ-lactams, paraphaeosphaerides E-H (1-4) together with one γ-lactone (5) and the methyl ester of compound 2 (11). The structures of the new compounds (1-5 and 11) were elucidated through the analysis of HRMS and NMR spectroscopic data. The absolute configuration was determined by chemical reactions with sodium borohydride, hydrogen peroxide, α-methoxy-α-(trifluoromethyl)phenylacetyl chlorides (Mosher reagents), and DP4 + NMR calculations. All the compounds were tested against STAT3, A2780 and A2780cisR cancer cell lines, E. coli JW2496, and NF-κB. Compounds 1 and 3 strongly inhibited NF-κB with IC50 values of 7.1 and 1.5 μM, respectively. Fil: Li, Chun Shun. University of Hawai'i at Hilo; Estados Unidos Fil: Sarotti, Ariel Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; Argentina Fil: Huang, Peng. University of Hawai'i at Hilo; Estados Unidos. Anhui University of Chinese Medicine; China Fil: Dang, Uyen T.. Texas A&M University; Estados Unidos Fil: Hurdle, Julian G.. Texas A&M University; Estados Unidos Fil: Kondratyuk, Tamara P.. University of Hawai'i at Hilo; Estados Unidos Fil: Pezzuto, J. M.. University of Hawai'i at Hilo; Estados Unidos. Arnold & Marie Schwartz College of Pharmacy and Health Sciences; Estados Unidos Fil: Turkson, James Turkson. University of Hawai'i; Estados Unidos Fil: Cao, Shugeng. University of Hawai'i at Hilo; Estados Unidos

Two new compounds heliotropiumides A (1) and B (2), phenolamides each with an uncommon carbamoyl putrescine moiety, were isolated from the seeds of a naturalized Hawaiian higher plant, Heliotropium foertherianum Diane & Hilger in the borage family, which is widely used for the treatment of ciguatera fish poisoning. The structures of compounds 1 and 2 were characterized based on MS spectroscopic and NMR analysis, and DP4+ calculations. The absolute configuration (AC) of compound 1 was determined by comparison of its optical rotation with those reported in literature. Compound 2 showed inhibition against NF-κB with an IC50 value of 36 μM. Fil: Cai, You-Sheng. University of Hawaii at Hilo; Estados Unidos. Wuhan University; China Fil: Sarotti, Ariel Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; Argentina Fil: Gündisch, Daniela. University of Hawaii at Hilo; Estados Unidos Fil: Kondratyuk, Tamara P.. University of Hawaii at Hilo; Estados Unidos Fil: Pezzuto, John. Long Island University; Estados Unidos. University of Hawaii Cancer Center; Estados Unidos Fil: Turkson, James. University of Hawaii Cancer Center; Estados Unidos Fil: Cao, Shugeng. University of Hawaii at Hilo; Estados Unidos

New compounds 18-nor-3,17-dihydroxyspongia-3,13(16),14-trien-2-one (1), 18-nor-3,5,17-trihydroxyspongia-3,13(16),14-trien-2-one (2), and spongiapyridine (3) and the known compound 17-hydroxy-4-epi-spongialactone A (4) were isolated from an Indonesian sponge of the genus Spongia. The structures of 1-3 were deduced by analyses of physical and spectroscopic data. Diterpene 3 is unusual, as the D-ring is a pyridyl ring system rather than the standard δ-lactone. The structure elucidation of this compound was complicated by facile exchange of the axial proton at the C-11 methylene with deuterium from methanol-d4. The isolated compounds were tested for biological activity in a battery of in vitro assays (TNF-α-induced NFκB, LPS-induced iNOS, RXR stimulation, quinone reductase 1 induction, aromatase inhibition, TRPM7 ion channels, and aspartic protease BACE1 inhibition). Norditerpene 2 modestly inhibited aromatase with an IC50 of 34 μM and induced quinone reductase 1 activity with a CD (the concentration needed to double the enzymatic response) of 11.2 μM. The remaining isolates were inactive.

Hedychium coronarium J. Koenig, Zingiberaceae, is a medicinal plant popularly used to treat inflammatory conditions in different countries. Three labdane diterpenes [isocoronarin D (1), methoxycoronarin D (2), ethoxycoronarin D (3)] and benzoyl eugenol (4) were isolated from rhizomes and their chemopreventive potential was evaluated using in vitro assays, namely the inhibition of NF-κB, COX-1 and -2, the induction of antioxidant response element (ARE), and the inhibition of cell proliferation. Diterpene 1 activated ARE (EC50 57.6 ± 2.4 μM), while 2, 3 and 4 significantly inhibited NF-κB (IC50 of 7.3 ± 0.3, 3.2 ± 0.3 and 32.5 ± 4.9 μM, respectively). In addition, 2 and 3 selectively inhibited COX-1 (IC50 values of 0.9 ± 0.0 and 3.8 ± 0.0 μM, respectively). These data support the potential chemopreventive activity of constituents from H. coronarium rhizomes. Keywords: Hedychium coronarium, Zingiberaceae, COX-1 and -2, NF-κB, Labdane diterpenes