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Natural Product Communications

EDITOR-IN-CHIEF DR. PAWAN K AGRAWAL Natural Product Inc. 7963, Anderson Park Lane, Westerville, Ohio 43081, USA

[email protected] EDITORS PROFESSOR ALEJANDRO F. BARRERO Department of Organic Chemistry, University of Granada, Campus de Fuente Nueva, s/n, 18071, Granada, Spain [email protected] PROFESSOR ALESSANDRA BRACA Dipartimento di Chimica Bioorganicae Biofarmacia, Universita di Pisa, via Bonanno 33, 56126 Pisa, Italy [email protected] PROFESSOR DEAN GUO State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100083, China [email protected] PROFESSOR YOSHIHIRO MIMAKI School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Horinouchi 1432-1, Hachioji, Tokyo 192-0392, Japan [email protected] PROFESSOR STEPHEN G. PYNE Department of Chemistry University of Wollongong Wollongong, New South Wales, 2522, Australia [email protected] PROFESSOR MANFRED G. REINECKE Department of Chemistry, Texas Christian University, Forts Worth, TX 76129, USA [email protected] PROFESSOR WILLIAM N. SETZER Department of Chemistry The University of Alabama in Huntsville Huntsville, AL 35809, USA [email protected] PROFESSOR YASUHIRO TEZUKA Institute of Natural Medicine Institute of Natural Medicine, University of Toyama, 2630-Sugitani, Toyama 930-0194, Japan [email protected] PROFESSOR DAVID E. THURSTON Department of Pharmaceutical and Biological Chemistry, The School of Pharmacy, University of London, 29-39 Brunswick Square, London WC1N 1AX, UK [email protected]

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Prof. Karsten Krohn Paderborn, Germany Prof. Chiaki Kuroda Tokyo, Japan Prof. Hartmut Laatsch Gottingen, Germany Prof. Marie Lacaille-Dubois Dijon, France Prof. Shoei-Sheng Lee Taipei, Taiwan Prof. Francisco Macias Cadiz, Spain Prof. Imre Mathe Szeged, Hungary Prof. Ermino Murano Trieste, Italy Prof. M. Soledade C. Pedras Saskatoon, Canada Prof. Luc Pieters Antwerp, Belgium Prof. Peter Proksch Düsseldorf, Germany Prof. Phila Raharivelomanana Tahiti, French Polynesia Prof. Luca Rastrelli Fisciano, Italy Prof. Monique Simmonds Richmond, UK Dr. Bikram Singh Palampur, India Prof. John L. Sorensen Manitoba, Canada Prof. Valentin Stonik Vladivostok, Russia Prof. Winston F. Tinto Barbados, West Indies Prof. Sylvia Urban Melbourne, Australia Prof. Karen Valant-Vetschera Vienna, Austria

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NPC

2013 Vol. 8 No. 8 1089 - 1092

Natural Product Communications

In vitro Anti-proliferative Effect of Naturally Occurring Oxyprenylated Chalcones Serena Fioritoa, Francesco Epifano*a, Celine Bruyèreb, Robert Kissb and Salvatore Genovesea a

Dipartimento di Farmacia, Università “G. D’Annunzio” Chieti-Pescara, Via dei Vestini 31, 66100 Chieti Scalo (CH), Italy b Laboratoire de Toxicologie, Faculté de Pharmacie, Université Libre de Bruxelles (ULB), Brussels, Belgium [email protected]

Received: March 28th, 2013; Accepted: May 20th, 2013

As a continuation of our ongoing studies aimed to depict the effects and mechanism of action of naturally occurring oxyprenylated phenylpropanoids and polyketides, in this paper we describe the synthesis and in vitro anti-proliferative effects of selected compounds belonging to the above cited classes of secondary metabolites on six cancer cell lines using the MTT colorimetric assay. Our study revealed that among the natural products tested, only oxyprenylated chalcones exhibited an appreciable effect (mean IC50 = 32 - 64 M), while substituted alcohols, phenylpropenes, naphthoquinones, and aminoacid derivatives were by far less active or inactive. Keywords: Anti-proliferative activity, Chalcones, Glycyrrhiza spp., Oxyprenylated secondary metabolites, Phenylpropanoids, Polyketides.

Prenylation is the chemical or enzymatic addition of a terpenyl moiety to an accepting molecule (for example, another terpenoid, an aromatic compound, a protein). This biochemical reaction occurs in nature in plant families like Rutaceae, Compositae, Apiaceae, Guttiferae, Leguminosae, and others, comprising several edible fruits and vegetables [1,2]. Thus oxyprenylated natural products represent compounds of mixed origin for which the final step of the biosynthetic process is the prenylation of an alkaloid or a phenylpropanoid / polyketide core. Considering the length of the carbon chain, three types of prenyloxy skeletons can be classified: C5 (isopentenyl), C10 (geranyl) and C15 (farnesyl). To date about 350 oxyprenylated derivatives have been isolated and/or synthesized and were shown to possess a wide range of valuable and promising pharmacological activities [1,2]. Every year, approximately seven million people die from cancer, which makes this disease responsible for at least 12% of deaths worldwide [3]. A number of important new commercialized anticancer drugs have been obtained from natural sources [4], including vinblastine, vincristine, vinorelbine, etoposide, teniposide, taxol, taxotere, topotecan and irinotecan from plants [5]. In fact, as emphasized by Tan et al. [6], natural products have been the most significant sources of drugs, accounting for approximately 74% of anticancer drugs. Thus, as claimed both by Coseri [3] and Gordaliza [4], natural products represent the most valuable potential source of novel anticancer agents. In this context we have already recently reported that some oxyprenylated secondary metabolites exert an effective in vitro growth inhibitory effect against a wide panel of human cancer cell lines [7]. Thus the search of novel oxyprenylated phenylpropanoids and polyketides as alternative anticancer agents is a field of current and growing interest. In this work, we characterized the in vitro growth inhibitory activity of 15 selected oxyprenylated phenylpropanoids, polyketides, napthtoquinones, and aminoacid derivatives. The in vitro IC50 growth inhibitory concentrations of each phytochemical were determined in six human cancer cell lines using the MTT colorimetric assay. The compounds under investigation in the present paper are illustrated below.

R2

R1

COOH R4 O

NHAc R3

O

1

2 R1 = CH2CH2OH, R2 = R3 = R4 = H 3 R1 = CH2CH2OAc, R2 = R3 = R4 = H 1 4 R = CH2CH2OH, R2 = R3 = H, R4 = isopentenyl 5 R1 = CHO, R2 = R3 = R4 = H 6 R1 = CH2OH, R2 = R3 = OMe, R4 = H 1 2 7 R = CHO, R = R3 = OCH3, R4 = isopentenyl 8 R1 = CH2CH2CH2OH, R2 = R3 = R4 = H 9 R1 = CH2CH=CH2, R2 = R4 = H,R3 = OMe 10 R1 = CH=CH-CH3, R2 = R4 = H,R3 = OMe 11 R1 = CH2CH=CH2, R2 = R3 = OMe, R4 = H

O O

R 1O

R2

R3

O

12

1

2

3

R5

R4

O

4

5

13 R = R = R = H, R = OMe, R = isopentenyl 14 R1 = isopentenyl, R2 = R3 = OH, R4 = H, R5 = OH 15 R1 = isopentenyl, R2 = R3 = OH, R4 = R5 =H

N-acetyl-O-isopentenyl-L-tyrosine (1) has been extracted from the fungus Pithomyces ellis [8], etrogol (2) and its acetate (3) from Citrus spp. (Rutaceae) [9], 3-(4-geranyloxyphenyl)-1-ethanol (4), a juvenile hormone of several insect species [10], and p-isopentenyloxybenzaldehyde (5) from the essential oil of leaves of Clausena anisata Hook f. (Rutaceae) [11], 3,5-dimethoxy-4isopentenyloxybenzyl alcohol (6), as an angelic acid ester, from the roots of Erechtites hieracifolia (L.) Raf ex DC.(Asteraceae) [12], geranyloxyvanillin (7) from the apolar extracts of Crithmum maritimum L. (Apiaceae) [13], 3-(4-isopentenyloxyphenyl)-1propanol (8) from the roots of Fagara zanthoxyloides Lam. [14] and Zanthoxylum wutaiense Chen (Rutaceae) [15], 4-isopentenyloxyeugenol (9) and 2,6-dimethoxy-4-isopentenyloxyallylbenzene (11) from Illicium anisatum L. (Illiciaceae) [16], 4-isopentenyloxyisoeugenol (10) from Illicium verum Hook. f. [17], lawsone 2-isopentenyl ether (12) from the fungus Streptocarpus dunnii [18], xinjiachalcone A (13) from roots of Glycyrrhiza inflata

1090 Natural Product Communications Vol. 8 (8) 2013 O

O

(a)

HO

O

OCH3

OCH3

(b), (c)

O

O

OCH3

OH

Scheme 1: Reagents and conditions: a) K2CO3, 3,3-dimethylallyl bromide, acetone, 80°C, 1 h; b) 4-OH-C6H4COCH3, KOH 60% (H2O/EtOH), reflux, 3 h; c) crystallization

Batalin [19], and finally chalcones (2E)-1-{2,6-dihydroxy-4-[(3methylbut-2-enyl)oxy]phenyl}-3-(4-hydroxyphenyl)prop-2-en-1-one (14) and (2E)-1-{2,6-dihydroxy-4-[(3-methylbut-2-enyl)oxy] phenyl}-3-phenylprop-2-en-1-one (15) from Helichrysum [20], Pleiotaxis [21], and Metalasia spp. [22]. The synthesis of compounds 1-8 and 12 was accomplished following the already reported methodology [23]. Compounds 9-11 were obtained from commercially available eugenol, isoeugenol, and 4-allyl-2,6-dimethoxyphenol in 99%, 97%, and 61% yields, respectively using the described Williamson reaction of isopentenylation of phenols [23]. As outlined in Scheme 1, xinjiachalcone A (13) was synthesized by a two-step process starting from commercially available 4-hydroxy-2methoxybenzaldehyde that was first alkylated by the usual methodology, as depicted above, with 3,3-dimethylallyl bromide and K2CO3 in acetone at 80°C for 2 h; the corresponding adduct was then subjected to an aldol condensation by reaction with 4-hydroxyacetophenone in a 60% hydroalcoholic solution of KOH at reflux for 3 h to provide, after acid-base work-up, the desired product 13 in 53% overall yield. (2E)-1-{2,6-Dihydroxy-4-[(3methylbut-2-enyl)oxy]phenyl}-3-(4-hydroxyphenyl)prop-2-en-1-one (14) and (2E)-1-{2,6-dihydroxy-4-[(3-methylbut-2-enyl)oxy] phenyl}-3-phenylprop-2-en-1-one (15) were both synthesized starting from commercially available 2,4,6-trihydroxyacetophenone that was first selectively alkylated in position 4 with 3,3dimethylallylbromide in the presence of the sterically hindered base 1,5-diazabicylo[5.4.0]-undecene (commonly known as DBU) in acetone at room temperature for 3 h, and then the obtained adduct was made to react with either 4-hydroxybenzaldehyde or benzaldehyde under the same aldol condensation experimental conditions as described above providing 14 and 15 in 25% and 30% yields, respectively after crystallization with n-hexane (Scheme 2). OH

OH

O

Fiorito et al.

All the synthesized oxyprenylated products were then assessed for their in vitro anti-proliferative effects on a panel of six cancer cell lines exhibiting different levels of resistance to pro-apoptotic stimuli using the MTT colorimetric assay. Results are reported in Table 1. The lack of a reference drug is justified by the fact that practically all the cancer cell lines, except PC3 cells, have been selected to be resistant to the most common therapeutically used chemotherapeutic agents. From data reported in Table1 it is evident that, among the compounds tested, only chalcones and the benzyl alcohol 6 displayed an appreciable level of activity, while the tyrosine derivative 1, benzaldehydes, phenylethanols or phenylpropanols, and all phenylpropenes displayed either a weak or no activity (IC50 > 100 µM). Among the chalcones, xinjiachalcone A (13) was found to be the most effective agent, revealing more uniform growth inhibitory values on all six cancer cell lines ranging from a minimum of 27 µM against the LoVo line to a maximum of 38 µM against the PC3 one. The two other chalcones, 14 and 15, were by far less effective, especially against U373, Hs683, and SKMEL-28 lines. However, the recorded pattern of results is in line with the current knowledge about natural and semi-synthetic chalcones as anti-proliferative agents [24]. 3,5-Dimethoxy-4isopentenyloxybenzyl alcohol (6) was finally the only one phytochemical, not belonging to the chalcone group, for which IC50 values were < 100 µM for all six cancer cell lines, although recorded parameters revealed only a weak effect. In general, LoVo cells were seen to be the most sensitive lines among the ones under investigation. In fact 12 out of 15 compounds recorded an IC50 value < 100 µM. These cells are widely used as a model of colorectal cancer, which in turn is known to be one of the main causes of death for cancer worldwide. Being oxyprenylated secondary metabolites well spread in several edible fruits and vegetables, such a higher sensitivity of adenocarcinoma cells might be of great interest in the near future for the development of cancer chemopreventive strategies as well as to properly address the synthesis of semisynthetic analogues of the title compounds with enhanced growth inhibitory activities. Such studies are now ongoing in our laboratories. O

O

(a)

HO

O

OCH3

OCH3

(b), (c)

O

O

(a)

HO

O

OH

O

OH

OCH3

OH

Scheme 1: Reagents and conditions: a) K2CO3, 3,3-dimethylallyl bromide, acetone, 80°C, 1 h; b) 4-OH-C6H4COCH3, KOH 60% (H2O/EtOH), reflux, 3 h; c) crystallization (b), (c)

OH

O

Experimental

O

OH

R

Scheme 2: Reagents and conditions: a) DBU, 3,3-dimethylallyl bromide, acetone, r.t., 3 h; b) 4-OH-C6H4CHO, R = OH (PhCHO, R = H), KOH 60% (H2O/EtOH), reflux, 3 h; c) crystallization.

Chemicals: Compounds 1-8 and 12 were synthesized following the already methodology [23]. 4-Isopentenyloxyeugenol (9), 4isopentenyloxyisoeugenol (10), and 2,6-dimethoxy-4isopentenyloxy-allylbenzene (11) were obtained starting from commercially available eugenol, isoeugenol, and 4-allyl-2,6dimethoxyphenol in 99%, 97%, and 61% yields, respectively using the described methodology of isopentenylation of phenols [23]. Analytical data for each adduct were in full agreement with those reported in the literature for the same compound [20-22].

Anti-proliferative activity of oxyprenylated chalcones

Natural Product Communications Vol. 8 (8) 2013 1091

Table 1: In vitro growth inhibitory activity in six human cancer cell lines induced by treatment with the 15 compounds. Compound U373 > 100 > 100 > 100 > 100 > 100 87 > 100 85 > 100 > 100 > 100 > 100 30 76 81

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

A549 > 100 > 100 > 100 > 100 34 73 95 > 100 > 100 95 > 100 56 33 48 50

Hs683 > 100 > 100 > 100 > 100 > 100 90 > 100 > 100 > 100 > 100 > 100 95 28 63 54

MTT colorimetric assay IC50 (µM) SKMEL-28 > 100 > 100 > 100 > 100 > 100 91 > 100 > 100 > 100 > 100 > 100 > 100 35 79 81

Xinjiachalcone A (13): To a stirred solution of 4-hydroxy-2methoxybenzaldehyde (3.3 mmol) in acetone (15 mL) dry K2CO3 (3.3 mmol) was added and the resulting suspension was kept at 80°C for 5 min. 3,3-Dimethylallyl bromide was then poured into the reaction mixture that was made to react at the same temperature for 1 h. The resulting solution was diluted with H2O (150 mL) and extracted with n-hexane (3 x 30 mL). The collected organic phases were dried over Na2SO4 and evaporated to dryness under vacuum yielding a white solid structurally characterized as 4-isopentenyl-2methoxybenzaldehyde by NMR, IR, and GC-MS. This compound (1.0 mmol) and 4-hydroxyacetophenone (1.5 mmol) were dissolved in EtOH (6 mL) and to the resulting mixture a 60% solution of KOH in water (6 mL) was added and reacted at 100°C for 3 h. The resulting suspension was cooled and poured into water (300 mL) and extracted with n-hexane (3 x 20 mL). The aqueous solution was acidified with HCl 10% and extracted with CH2Cl2 (2 x 50 mL). The collected organic phases were dried over Na2SO4 and evaporated to dryness under vacuum and the desired product was obtained after crystallization with n-hexane. Analytical data were in full agreement with those reported in the literature for the same compound [19]. Synthesis of chalcones 14 and 15. General procdure: To a stirred solution of 2,4,6-trihydroxyacetophenone (10.7 mmol) in acetone (50 mL) DBU (10.7 mmol) was added and the resulting mixture made to react for 5 min. 3,3-Dimethylallyl bromide was then poured into the reaction medium, and the resulting solution was kept for 3 h at room temperature, then diluted with a 10% solution of HCl (300 mL), and finally extracted with n-hexane (3 x 50 mL). The collected organic phases were dried over Na2SO4 and evaporated to dryness under vacuum yielding a white solid structurally characterized as 2,6-dihydroxy-4-isopentenyloxyacetophenone by NMR, IR, and GC-MS. The same procedure described previously for the synthesis of xinjiachalcone A provided (2E)-1-{2,6-dihydroxy-4-[(3-methylbut-2-enyl)oxy]phenyl}-3-(4-hydroxyphenyl)prop-2-en-1-one (14) and (2E)-1-{2,6-dihydroxy-4-[(3-methylbut-2-enyl)oxy]phenyl}-3phenylprop-2-en-1-one (15) in 25% and 30% yields, respectively, after crystallization from n-hexane. Analytical data were in full

PC3 > 100 > 100 > 100 > 100 > 100 71 > 100 > 100 > 100 89 > 100 > 100 38 67 63

LoVo > 100 77 > 100 93 94 64 48 67 86 73 73 > 100 27 44 54

Mean + SEM >100 >96 >100 >99 >88 79 + 5 >91 >92 >98 >93 >96 >92 32 + 2 63 + 6 64 + 6

agreement with those reported in the literature for the same compounds [20-23]. Biological assays: Human cancer cell lines were obtained from the American Type Culture Collection (ATCC, Manassas, VA, USA), the European Collection of Cell Culture (ECACC, Salisbury, UK) and the Deutsche Sammlung von Mikroorganismen und Zellkulturen (DSMZ, Braunschweig, Germany). The code number and histological type of each of the cell lines used in the current study are as follows. Glioma model lines included the Hs683 oligodendroglioma (ATCC code HTB-138) and the U373 (ECACC code 89081403) glioblastoma cell lines. Melanoma model included the SKMEL-28 (ATCC code HTB-72) cell line. Carcinoma models included the A549 non-small-cell-lung cancer (NSCLC) (DSMZ code ACC107), the PC-3 prostate (DSMZ code ACC465) and the LoVo colon (DSMZ code ACC350) cancer cell lines. The determination of the IC50 growth inhibitory concentrations in vitro was carried out by means of the MTT colorimetric assay, as detailed previously [25-27]. Briefly, this test measures the number of metabolically active (thus living) cells that are able to transform the yellow substrate 3-(4,5-dimethylthazol-2-yl)-2,5diphenyltetrazolium bromide (MTT) into the blue formazan dye via a mitochondrial reduction involving succinate dehydrogenase. The amount of formazan obtained at the end of the experiment (measured by spectrophotometry) is directly proportional to the number of living cells. The determination of the optical density in the control compared with the treated cells therefore enables quantitative measurements of the effects of compounds on the growth of normal as well as cancer cells in vitro. Each experimental condition was assessed in 6 replicates. Acknowledgments – Financial support for this study from the University “G. D’Annunzio” of Chieti-Pescara is gratefully acknowledged by Authors from Italy. R.K. is a Director of Research with the Fonds National de la Recherche Scientifique (FRS-FNRS, Brussels, Belgium).

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Natural Product Communications Vol. 8 (8) 2013 Published online (www.naturalproduct.us)

A New Macrolide from a Marine-derived Fungus Aspergillus sp. Jie Bao, Xin-Ya Xu, Xiao-Yong Zhang and Shu-Hua Qi HPLC-MS and GC-MS Analyses Combined with Orthogonal Partial Least Squares to Identify Cytotoxic Constituents from Turmeric (Curcuma longa L.) Jianlan Jiang, Huan Zhang, Zidan Li, Xiaohang Zhang, Xin Su, Yan Li, Bin Qiao and Yingjin Yuan Determination of Antiplasmodial Activity and Binding Affinity of Selected Natural Products towards PfTrxR and PfGR Ranjith Munigunti, Katja Becker, Reto Brun and Angela I. Calderón In vitro Anti-inflammatory and Antioxidant Potential of Si-Miao-San, its Modifications and Pure Compounds Agnieszka D. Lower-Nedza, Carmen Kuess, Haiyu Zhao, Baolin Bian and Adelheid H. Brantner Smooth Muscle Relaxation Activity of an Aqueous Extract of Dried Immature Fruit of Poncirus trifoliata (PF-W) on an Isolated Strip of Rat Ileum Kyu-Sang Kim, Won-Sik Shim, Ike Campomayor dela Peña, Eun-Kyung Seo, Woo-Young Kim, Hyo-Eon Jin, Dae-Duk Kim, Suk-Jae Chung, Jae-Hoon Cheong and Chang-Koo Shim Invertebrate Water Extracts as Biocompatible Reducing Agents for the Green Synthesis of Gold and Silver Nanoparticles Lina Han, Yeong Shik Kim, Seonho Cho, and Youmie Park Elemental Analysis of Ginkgo biloba Leaf Samples Collected during One Vegetation Period Szilvia Czigle, Erzsébet Háznagy-Radnai, Klára Pintye-Hódi, Jaroslav Tóth, Daniela Tekeľová and Imre Máthé Wild Thymbra capitata from Western Rif (Morocco): Essential Oil Composition, Chemical Homogeneity and Yield Variability Khadija Bakhy, Ouafae Benlhabib, Chaouki Al Faiz, Ange Bighelli, Joseph Casanova and Felix Tomi Essential Oils of Chiliadenus lopadusanus (Asteraceae) Pietro Zito, Maurizio Sajeva, Elena Scirica, Maurizio Bruno, Sergio Rosselli, Antonella Maggio and Felice Senatore Chemical Composition of the Essential Oil of Lepidagathis fasciculata from Bondla Forest of Goa, India Rajesh K. Joshi Leaf Oil from Vepris madagascarica (Rutaceae), Source of (E)-Anethole Delphin J. R. Rabehaja, Harilala Ihandriharison, Panja A. R. Ramanoelina, Suzanne Ratsimamanga-Urverg, Ange Bighelli, Joseph Casanova and Félix Tomi Cardiovascular Effects of the Essential Oil of Croton zehntneri Leaves in DOCA-salt Hypertensive, Conscious Rats Rodrigo José Bezerra de Siqueira, Gloria Pinto Duarte, Pedro Jorge Caldas Magalhães and Saad Lahlou Chemical Composition and Antioxidant Activity of the Essential Oil and Fatty Acids of the Flowers of Rhanterium adpressum Chahrazed Hamia, Nadhir Gourine, Hadjer Boussoussa, Mokhtar Saidi, Emile M. Gaydou and Mohamed Yousfi Chemical Composition and Biological Activity of Conyza bonariensis Essential Oil Collected in Mérida, Venezuela Liliana Araujo, Laila M. Moujir, Janne Rojas, Luis Rojas, Juan Carmona and María Rondón Chemical Compositions, Phytotoxicity, and Biological Activities of Acorus calamus Essential Oils from Nepal Prabodh Satyal, Prajwal Paudel, Ambika Poudel, Noura S. Dosoky, Debra M. Moriarity, Bernhard Vogler and William N. Setzer

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Review/Account Review on Research of Suppression Male Fertility and Male Contraceptive Drug Development by Natural Products Vijay Kumar Bajaj and Radhey S Gupta

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Natural Product Communications 2013 Volume 8, Number 8 Contents Original Paper

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Natural Clovanes from the Gorgonian Coral Rumphella antipathies Hsu-Ming Chung, Wei-Hsien Wang, Tsong-Long Hwang, Yang-Chang Wu and Ping-Jyun Sung Microbial Biotransformation of 16α,17-Epoxy-ent-kaurane-19-oic acid by Beauveria sulfurescens ATCC 7159-F Ricardo A. Furtado, G. M. Kamal B. Gunaherath, Jairo K. Bastos and A. A. Leslie Gunatilaka Establishment of In vitro Adventitious Root Cultures and Analysis of Andrographolide in Andrographis paniculata Shiv Narayan Sharma, Zenu Jha and Rakesh Kumar Sinha New Cycloartane-type Triterpenes from Marcetia latifolia (Melastomataceae) and in silico Studies on Candida parapsilosis Protease Tonny C. C. Leite, Franco H. A. Leite, Ivo J. C. Vieira, Raimundo Braz Filho and Alexsandro Branco Triterpene Glycosides from the Sea Cucumber Eupentacta fraudatrix. Structure and Biological Action of Cucumariosides I1, I3, I4, Three New Minor Disulfated Pentaosides Alexandra S. Silchenko, Anatoly I. Kalinovsky, Sergey A. Avilov, Pelageya V. Andryjaschenko, Pavel S. Dmitrenok, Ekaterina A. Martyyas and Vladimir I. Kalinin Improved Extraction and Complete Mass Spectral Characterization of Steroidal Alkaloids from Veratrum californicum Christopher M. Chandler, Jeffrey W. Habig, Ashley A. Fisher, Katherine V. Ambrose, Susana T. Jiménez and Owen M. McDougal TLC-Image Analysis of Non-Chromophoric Tuberostemonine Alkaloid Derivatives in Stemona Species Sumet Kongkiatpaiboon, Vichien Keeratinijakal and Wandee Gritsanapan Two New Compounds from Gorgonian-associated Fungus Aspergillus sp. Xin-Ya Xu, Xiao-Yong Zhang, Fei He, Jiang Peng, Xu-Hua Nong and Shu-Hua Qi New Metabolites from the Algal Associated Marine-derived Fungus Aspergillus carneus Olesya I. Zhuravleva, Shamil Sh. Afiyatullov, Ekaterina A. Yurchenko, Vladimir A. Denisenko, Natalya N. Kirichuk and Pavel S. Dmitrenok Chiroptical Studies of Flavanone Marcelo A. Muñoz, María A. Bucio and Pedro Joseph-Nathan Flavonoids with Anti-HSV Activity from the Root Bark of Artocarpus lakoocha Boonchoo Sritularak, Kullasap Tantrakarnsakul, Vimolmas Lipipun and Kittisak Likhitwitayawuid Orphan Flavonoids and Dihydrochalcones from Primula Exudates Tshering Doma Bhutia, Karin M. Valant-Vetschera and Lothar Brecker First Identification of -Glucosidase Inhibitors from Okra (Abelmoschus esculentus) Seeds Wannisa Thanakosai and Preecha Phuwapraisirisan In vitro Anti-proliferative Effect of Naturally Occurring Oxyprenylated Chalcones Serena Fiorito, Francesco Epifano, Celine Bruyère, Robert Kiss and Salvatore Genovese Kaempferol 3,7,4´-glycosides from the Flowers of Clematis Cultivars Keisuke Sakaguchi, Junichi Kitajima and Tsukasa Iwashina 7-O-Methylpelargonidin Glycosides from the Pale Red Flowers of Catharanthus roseus Fumi Tatsuzawa Pyranocoumarin and Triterpene from Millettia richardiana Manitriniaina Rajemiarimiraho, Jean Théophile Banzouzi, Stéphane Richard Rakotonandrasana, Pierre Chalard, Françoise Benoit-Vical, Léa Herilala Rasoanaivo, Amélie Raharisololalao and Roger Randrianja A Concise and Efficient Total Synthesis of α-Mangostin and β-Mangostin from Garcinia mangostana Dandan Xu, Ying Nie, Xizhou Liang, Ling Ji, Songyuan Hu, Qidong You, Fan Wang, Hongchun Ye and Jinxin Wang Variation in the Contents of Neochlorogenic Acid, Chlorogenic Acid and Three Quercetin Glycosides in Leaves and Fruits of Rowan (Sorbus) Species and Varieties from Collections in Lithuania Kristina Gaivelyte, Valdas Jakstas, Almantas Razukas and Valdimaras Janulis A New Cytotoxic Phenolic Derivative from the Roots of Antidesma acidum Sutin Kaennakam, Jirapast Sichaem, Pongpun Siripong and Santi Tip-pyang A New Nervogenic Acid Glycoside with Pro-coagulant Activity from Liparis nervosa Qin Song, Qingyao Shou, Xiaojun Gou, Fengzhen Chen, Jing Leng and Weifeng Yang Biologically Active Secondary Metabolites from Asphodelus microcarpus Mohammed M. Ghoneim, Guoyi Ma, Atef A. El-Hela, Abd-Elsalam I. Mohammad, Saeid Kottob, Sayed El-Ghaly, Stephen J. Cutler and Samir A. Ross Dibenzylbutane Lignans from the Stems of Schisandra bicolor Yinning Chen, Na Li, Yuehui Zhu, Cuilan Zhang, Xiaofei Jiang, Jianxiang Yang, Zhifang Xu, Samuel X. Qiu and Riming Huang Absolute Configuration of Falcarinol (9Z-heptadeca-1,9-diene-4,6-diyn-3-ol) from Pastinaca sativa Mireia Corell, Emile Sheehy, Paul Evans, Nigel Brunton and Juan Valverde Continued inside backcover

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