Elsevier The Boulevard, Langford Lane, Kidlington, Oxford, OX5 1GB, UK Radarweg 29, PO Box 211, 1000 AE Amsterdam, The Netherlands First edition 2014 Copyright © 2014 Elsevier B.V All rights reserved No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means electronic, mechanical, photocopying, recording or otherwise without the prior written permission of the publisher Permissions may be sought directly from Elsevier’s Science & Technology Rights Department in Oxford, UK: phone (ỵ44) (0) 1865 843830; fax (ỵ44) (0) 1865 853333; email: permissions@elsevier.com Alternatively you can submit your request online by visiting the Elsevier web site at http://elsevier.com/locate/permissions, and selecting Obtaining permission to use Elsevier material Notice No responsibility is assumed by the publisher for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the material herein Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress ISBN: 978-0-444-63294-4 ISSN: 1572-5995 For information on all Elsevier publications visit our web site at store.elsevier.com Printed and bound in Great Britain 14 15 16 17 18 11 10 This book has been manufactured using Print On Demand technology Each copy is produced to order and is limited to black ink The online version of this book will show color figures where appropriate Contributors Numbers in Parentheses indicate the pages on which the author’s contributions begin Daniela P.S Alho (33), Grupo de Quı´mica Farmaceˆutica, Faculdade de Farma´cia, Universidade de Coimbra, Po´lo das Cieˆncias da Sau´de, Azinhaga de Santa Comba, and Centro Neurocieˆncias e Biologia Celular, Universidade de Coimbra, Coimbra, Portugal Dmitry L Aminin (73), G.B Elyakov Pacific Institute of Bioorganic Chemistry, Far East Division, Russian Academy of Sciences, Vladivostok, Russia Atta-ur-Rahman (257), International Center for Chemical and Biological Sciences, H.E.J Research Institute of Chemistry, University of Karachi, Karachi, Pakistan Sergey A Avilov (73), G.B Elyakov Pacific Institute of Bioorganic Chemistry, Far East Division, Russian Academy of Sciences, Vladivostok, Russia Francisco J Barba (317), Department of Nutrition and Food Chemistry, Universitat de Vale`ncia, Burjassot, Spain Joa˜o M Batista Jr (379), Nucleus for Bioassays, Biosynthesis and Ecophysiology of Natural Products (NuBBE), Institute of Chemistry, Sa˜o Paulo State University— UNESP, Araraquara, Sa˜o Paulo, Brazil Rachid Benhida (191), Institut de Chimie de Nice, UMR 7272 CNRS, Universite´ de Nice-Sophia Antipolis, Nice Cedex 2, France Khalid Bougrin (191), Laboratoire de Chimie des Plantes et de Synthe`se Organique et Bioorganique, URAC23, Faculte´ des Sciences, Universite´ Mohammed V-Agdal, Rabat, Morocco Vanderlan da Silva Bolzani (379), Nucleus for Bioassays, Biosynthesis and Ecophysiology of Natural Products (NuBBE), Institute of Chemistry, Sa˜o Paulo State University—UNESP, Araraquara, Sa˜o Paulo, Brazil Koen Dewettinck (343), Department of Food Safety and Food Quality, Ghent University, Ghent, Belgium Marı´a J Esteve (317), Department of Nutrition and Food Chemistry, Universitat de Vale`ncia, Burjassot, Spain Ana Frı´gola (317), Department of Nutrition and Food Chemistry, Universitat de Vale`ncia, Burjassot, Spain Takahiko Fujikawa (219), Laboratory of Molecular Prophylaxis and Pharmacology, Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, and Department of Biochemistry and Proteomics, Mie University Graduate School of Medicine, Mie, Japan xiii xiv Contributors Bruno M.F Gonc¸alves (33), Grupo de Quı´mica Farmaceˆutica, Faculdade de Farma´cia, Universidade de Coimbra, Po´lo das Cieˆncias da Sau´de, Azinhaga de Santa Comba, and Centro Neurocieˆncias e Biologia Celular, Universidade de Coimbra, Coimbra, Portugal Rajinder K Gupta (415), School of Biotechnology, Guru Gobind Singh Indraprastha University, Delhi, India Tetsuya Hirata (219), R&D Center, Kobayashi Pharmaceutical Co., Ltd., Osaka, Japan Ingrid Hook (115), School of Pharmacy and Pharmaceutical Sciences, Trinity Biosciences Institute (TBSI), Trinity College Dublin, Dublin, Ireland Tsuyoshi Ikeda (219), Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan Shabnam Javed (257), Center for Undergraduate Studies, University of Punjab, Quaid-e-Azam Campus, Lahore-54590, Pakistan Yongkui Jing (33), Department of Medicine, Mount Sinai School of Medicine, New York, USA Vladimir I Kalinin (73), G.B Elyakov Pacific Institute of Bioorganic Chemistry, Far East Division, Russian Academy of Sciences, Vladivostok, Russia Thien Trung Le (343), Faculty of Food Science and Technology, Nong Lam University, Ho Chi Minh City, Viet Nam Ana S Leal (33), Grupo de Quı´mica Farmaceˆutica, Faculdade de Farma´cia, Universidade de Coimbra, Po´lo das Cieˆncias da Sau´de, Azinhaga de Santa Comba, and Centro Neurocieˆncias e Biologia Celular, Universidade de Coimbra, Coimbra, Portugal Monica Rosa Loizzo (1), Department of Pharmacy, Health Sciences and Nutrition, University of Calabria, Rende (CS), Italy Nadine Martinet (191), Institut de Chimie de Nice, UMR 7272 CNRS, Universite´ de Nice-Sophia Antipolis, Nice Cedex 2, France Hamid Marzag (191), Institut de Chimie de Nice, UMR 7272 CNRS, Universite´ de Nice-Sophia Antipolis, Nice Cedex 2, France, and Laboratoire de Chimie des Plantes et de Synthe`se Organique et Bioorganique, URAC23, Faculte´ des Sciences, Universite´ Mohammed V-Agdal, Rabat, Morocco Ekaterina S Menchinskaya (73), G.B Elyakov Pacific Institute of Bioorganic Chemistry, Far East Division, Russian Academy of Sciences, Vladivostok, Russia Vanessa I.S Mendes (33), Grupo de Quı´mica Farmaceˆutica, Faculdade de Farma´cia, Universidade de Coimbra, Po´lo das Cieˆncias da Sau´de, Azinhaga de Santa Comba, and Centro Neurocieˆncias e Biologia Celular, Universidade de Coimbra, Coimbra, Portugal Francesco Menichini (1), Department of Pharmacy, Health Sciences and Nutrition, University of Calabria, Rende (CS), Italy Clive Mills (115), School of Pharmacy and Pharmaceutical Sciences, Trinity Biosciences Institute (TBSI), Trinity College Dublin, Dublin, Ireland Contributors xv Sansei Nishibe (219), Department of Pharmacognosy, Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Kanazawa, Japan Evgeny A Pislyagin (73), G.B Elyakov Pacific Institute of Bioorganic Chemistry, Far East Division, Russian Academy of Sciences, Vladivostok, Russia Kristy M Richards (93), U.S FDA, Lenexa, Kansas, USA Jorge A.R Salvador (33), Grupo de Quı´mica Farmaceˆutica, Faculdade de Farma´cia, Universidade de Coimbra, Po´lo das Cieˆncias da Sau´de, Azinhaga de Santa Comba, and Centro Neurocieˆncias e Biologia Celular, Universidade de Coimbra, Coimbra, Portugal Helen Sheridan (115), School of Pharmacy and Pharmaceutical Sciences, Trinity Biosciences Institute (TBSI), Trinity College Dublin, Dublin, Ireland Alexandra S Silchenko (73), G.B Elyakov Pacific Institute of Bioorganic Chemistry, Far East Division, Russian Academy of Sciences, Vladivostok, Russia Robert E Smith (93), U.S FDA, Lenexa, Kansas, and Department of Science, Park University, Parkville, Missouri, USA Kavita Tiwari (415), School of Biotechnology, Guru Gobind Singh Indraprastha University, Delhi, India Joel D.W Toh (157), Department of Pharmacy, National University of Singapore, Singapore, Singapore Kevin Tran (93), U.S FDA, Lenexa, Kansas, USA Rosa Tundis (1), Department of Pharmacy, Health Sciences and Nutrition, University of Calabria, Rende (CS), Italy Yoshihide Usami (283), Laboratory of Pharmaceutical Organic Chemistry, Osaka University of Pharmaceutical Sciences, Takatsuki, Osaka, Japan Ana S Valdeira (33), Grupo de Quı´mica Farmaceˆutica, Faculdade de Farma´cia, Universidade de Coimbra, Po´lo das Cieˆncias da Sau´de, Azinhaga de Santa Comba, and Centro Neurocieˆncias e Biologia Celular, Universidade de Coimbra, Coimbra, Portugal John Van Camp (343), Department of Food Safety and Food Quality, Ghent University, Ghent, Belgium Pierre Warnault (191), Institut de Chimie de Nice, UMR 7272 CNRS, Universite´ de Nice-Sophia Antipolis, Nice Cedex 2, France Esther C.Y Woon (157), Department of Pharmacy, National University of Singapore, Singapore, Singapore Preface Natural products continue to provide a treasure of novel materials with potential applications in a variety of different fields This volume of Studies in Natural Product Chemistry presents a number of exciting articles on a wide range of bioactive natural products In Chapter by Tundis et al., the potential role of natural triterpenoids with cycloartane, cucurbitane, friedelane, tirucallane, and lupane skeleton in tumor chemoprevention and treatment is discussed Their structures and mechanisms of action are presented In Chapter 2, Salvador et al discuss the effects of natural pentacyclic triterpenoids and their semisynthetic derivatives, highlighting their potential in anticancer drug discovery Chapter by Aminin et al describes the medicinal chemistry of sea cucumber triterpene glycosides Some of these were found to be against cancer while others showed immunomodulatory activity Annonaceous acetogenins constitute a large class of natural polyketides, with over 400 representatives They show pesticidal, anti-infective, and cytotoxic properties In Chapter 4, Smith et al discuss their properties, including neurotoxicity exhibited by them In Chapter 5, the various classes of naphthoquinones and their biological activities are discussed by Hook et al Their production, biosynthesis, and synthesis are also discussed Obesity has become a common health problem Woon and Toh, in Chapter 6, review the applications of several natural compounds to cure obesity from an epigenetic perspective They describe their bioactivity, clinical data, and mechanisms of action against obesity In Chapter 7, Marzag et al have focused their contribution on natural polyphenols and their relationship with epigenetic modifications, particularly as potent inhibitors of DNA methyl transferase Chapter covers different biological activities of Eucommia ulmoides Oliver leaves, including the antiobesity effects In Chapter 9, Javed and Atta-ur-Rahman present the increasing interest in Aloe vera extracts not just for their use in cosmetics but in a wide variety of other illnesses Their chemistry and processing techniques have also been discussed Carbasugars are a class of carbohydrates that are known to possess various biological activities including glycosidase inhibition, antitumor, anticancer, antiviral, antifungal, antibacterial, and antimalarial activities Usami, in Chapter 10, discusses different aspects with reference to the chemical synthesis of such compounds In Chapter 11, Esteve et al discuss the antioxidant and antimicrobial potential of leaf vegetable products xvii xviii Preface Van Camp et al have presented a comprehensive discourse in Chapter 12 on milk fat globule membrane materials, their isolation techniques, healthbeneficial properties, and applications as functional foods and nutraceuticals In Chapter 13, Batista and da Silva Bolzani discuss the current state of the art of vibrational circular dichroism spectroscopy for the determination of absolute configuration of various natural products Moreover, quantum chemical calculations have also been discussed In Chapter 14, Tiwari and Gupta have presented a comprehensive review on the bioactive secondary metabolites from rare actinomycetes Particular emphasis has been placed on their structures, relevant biological activities, and source organisms I hope that this volume will be received with the same interest and enthusiasm as the previous volumes of this long-standing series on natural product chemistry I would like to thank Ms Taqdees Malik, Ms Darshna Kumari, and Ms Humaira Hashmi for their assistance in the preparation of this volume I am also grateful to Mr Mahmood Alam for his editorial assistance Atta-ur-Rahman, FRS International Center for Chemical and Biological Sciences H.E.J Research Institute of Chemistry University of Karachi Karachi, Pakistan Chapter Recent Insights into the Emerging Role of Triterpenoids in Cancer Therapy: Part II Rosa Tundis, Francesco Menichini and Monica Rosa Loizzo Department of Pharmacy, Health Sciences and Nutrition, University of Calabria, Rende (CS), Italy Chapter Outline Introduction Antitumor Activity of Triterpenoids The Cycloartane Group The Cucurbitane Group The Friedelane Group 2 The Tirucallane Group The Lupane Group Miscellaneous Compounds Concluding Remarks References 10 11 25 27 30 INTRODUCTION In this chapter, we report the recent insights into the role of triterpenoids in cancer therapy In the first chapter, we have focused our interest on triterpenoids with oleanane, dammarane, hopane, lanostane, and ursane skeleton and their synthetic derivatives [1] Herein, we report an overview of the most recent progress in the in vitro and in vivo studies on the anticancer properties of natural triterpenoids with a cycloartane, cucurbitane, friedelane, tirucallane, and lupane skeleton and their synthetic derivatives with a special focus on the structure–activity relationship (SAR) Cancer is a complex genetic disease with hallmark traits acquired during their multistep development including activating cell invasion and metastasis, exhibiting genetic diversity, inflammation, reprogramming of energy metabolism, sustaining cell-proliferative signaling, evading activity of cell population growth suppressors, enabling replicative immortality, inducing angiogenesis, evading immune destruction, and resisting programmed cell death [2] Studies in Natural Products Chemistry, Vol 41 http://dx.doi.org/10.1016/B978-0-444-63294-4.00001-2 Copyright © 2014 Elsevier B.V All rights reserved Studies in Natural Products Chemistry Natural products derived from plant sources have been a rich source of agents of value to medicine More than half of currently available drugs are natural compounds or are related to them, and in the case of cancer this proportion surpasses 60% This situation is accompanied by increasing interest from drug companies and institutions devoted to the search for new drugs Additionally, many natural compounds have been considered leads or heads of series and their later structural modification has afforded compounds with pharmacological activity and extraordinary therapeutic possibilities Recent efforts into the research and development of anticancer drugs derived from natural source have led to the identification of a variety of triterpenoids, characterized as possessing a wide variety of remarkable antitumor properties, for example, induction of cell-cycle arrest, induction of apoptosis, and differentiation, as well as inhibition of cell growth and proliferation, or a combination of two or more of these mechanisms [3] In our recent work, we demonstrated the interesting antiproliferative activity on renal, prostate, and melanoma cancer cell lines of Sarcopoterium spinosum and its major constituent tormentic acid [4] This ursane-type triterpene demonstrated a higher cytotoxicity than the positive control against renal cell adenocarcinoma ACHN cell line with an inhibitory concentration 50% (IC50) value of 23.7 mM (vinblastine IC50 value of 25.0 mM) The potential antitumor properties of triterpenoids would have broader implications if we consider that these secondary metabolites represent the largest group of naturally occurring phytochemicals and that are also present in common foods ANTITUMOR ACTIVITY OF TRITERPENOIDS The Cycloartane Group Cancer chemopreventive effects and antiproliferative activity against several cancer lines of cycloartane-type triterpenoids have been reported [5,6] Recently, two cycloartane glycosides isolated from the aerial parts of Thalictrum fortunei, 3-O-b-D-glucopyranosyl (1 ! 4)-b-D-fucopyranosyl(22S,24Z)-cycloart-24-en-3b,22,26,30-tetraol 26-O-b-D-glucopyranoside (1) and 3-O-b-D-glucopyranosyl (1 ! 4)-b-D-fucopyranosyl-(22S,24Z)-cycloart-24-en3b,22,26,29-tetraol 26-O-b-D-glucopyranoside (2), demonstrated IC50 values of 6.8, 24.3, 5.6 mg/ml and 3.3, 7.8, 3.1 mg/ml toward Bel-7402, LoVo, and NCIH460 human tumor cells, respectively (Table 1) [7] In the same year, from Astragalus stereocalyx 12 cycloartane-type triterpene glycosides were isolated and were tested for their potential cytotoxicity in vitro against HeLa (human cervical cancer), HT-29 (human colon cancer), U937 (human leukemia), and H446 (human lung cancer) [8] 3-O-b-D-Glucopyranosyl-16-O-b-D-glucopyranosyl-3b,6a,16b,24(R),25-pentahydroxycycloartane was the most potent compound against Chapter Emerging Role of Triterpenoids in Cancer Therapy TABLE In Vitro Cytotoxicity of Cycloartane-Type and Cucurbitane-Type Triterpenes Compound Cell Line IC50, ED50 Ref 3-O-b-D-Glucopyranosyl (1 ! 4)-b-Dfucopyranosyl-(22S,24Z)cycloart-24-en-3b,22,26,30-tetraol 26-O-b-D-glucopyranoside (1) Bel-7402, LoVo, NCIH-460 6.8, 24.3, 5.6 mg/ml [7] 3-O-b-D-Glucopyranosyl (1 ! 4)-b-Dfucopyranosyl-(22S,24Z)cycloart-24-en-3b,22,26,29-tetraol 26-O-b-D-glucopyranoside (2) Bel-7402, LoVo, NCIH-460 3.3, 7.8, 3.1 mg/ml [7] 25-Pentahydroxycycloartane HeLa 29.9 mM [8] Askendoside G HeLa 24.4 mM [8] 3-O-b-D-Glucopyranosyl-16-O-b-Dglucopyranosyl-3b,6a,16b,24(R),25pentahydroxycycloartane HeLa 10 mM [8] Cyclotrisectoside MCF-7 30 mM [9] 6-O-b-D-Xylopyranosyl-3b,6a,16b,24atetrahydroxy-20(R),25-epoxycycloartane HL-60 45 mM [9] Sinocalycanchinensin E (3) (ỵcolchicine) KB-C2 1.5 mg/ml [10] 25-O-Acetylcimigenol-3-O-b-Dxylopyranoside (4) MCF-7, R-MCF-7 4.0, 5.3 mg/ml [11] 25-O-Acetylcimigenol-3-O-a-Larabinopyranoside (5) MCF-7, R-MCF-7 4.3, 4.8 mg/ml [11] 25-O-Acetylcimigenol-3-O-[40 -O-(E)-2butenoyl]-b-D-xylopyranoside (6) HepG2 1.3 mM [12] 25-O-Acetylcimigenol-3-O-[30 -Oacetyl]-b-D-xylopyranoside (7) HepG2 0.7 mM [12] 30 -O-Acetyl-23-epi-26-deoxyactein (8) HepG2 1.4 mM [12] Gardenoin A CHAGO, HepG2 1.6, 4.5 mg/ml [13] Gardenoin C CHAGO, HepG2, SW-260 4.4, 2.8, 2.5 mg/ml [13] G292, MG-63, HT-161, HOS, SAOS-2, SJSA 50 nM [14] Cycloartane skeleton Cucurbitane skeleton Cucurbitacin B (9) Continued Studies in Natural Products Chemistry TABLE In Vitro Cytotoxicity of Cycloartane-Type and Cucurbitane-Type Triterpenes—Cont’d Compound Cell Line IC50, ED50 Ref Cucurbitacin D (10) HT-29 0.12 mM [15] 3-epi-Isocucurbitacin D HT-29 0.039 mM [15] Cucurbitacin I HT-29 0.19 mM [15] Cucurbitacin E 2-O-b-Dglucopyranoside BGC-823, A549 4.98, 3.2 mM [16] Machilusides A (12) A2780, HCT-8, Bel-7402, BGC-823, A549 0.4–6.5 mM [17] Machilusides B (13) A2780, HCT-8, Bel-7402, BGC-823, A549 0.4–6.5 mM [17] HeLa cells (IC50 value of 10 mM), while 3-O-{a-L-rhamnopyranosyl-(1 ! 4)[a- L -arabinopyranosyl-(1 ! 2)]-b- D -glucopyranosyl}-3b,6a,16b,24(R)25pentahydroxycycloartane, and askendoside G exhibited IC50 values of 29.9 and 24.4 mM, respectively All the other compounds exhibited a lower cytotoxic activity Previously, from A aureus other 18 cycloartane-type triterpene glycosides were isolated [9] Their potential antiproliferative activity was tested against HL-60 (human promyelocytic leukemia), MCF-7 (human breast cancer), HT-29 (human colon carcinoma), A549 (human lung adenocarcinoma), and PC3 (human prostate cancer) cell lines using etoposide as positive control Among tested compounds, cyclotrisectoside exhibited an IC50 value of 30 mM against MCF-7 cells, while 6-O-b-D-xylopyranosyl-3b,6a,16b,24atetrahydroxy-20(R),25-epoxycycloartane was cytotoxic against HL-60 cells with an IC50 value of 45 mM (Fig 1) 29-nor-Cycloartanes, isolated from Sinocalycanthus chinensis, were tested against KB (human epidermoid carcinoma of nasopharynx), K562 (leukemia), and MCF-7 (breast carcinoma) cell lines, as well as multidrugresistant (MDR) human cancer cell lines, including KB-C2 (colchicineresistant KB) and K562/Adr (doxorubicin-resistant K562) [10] Sinocalycanchinensin E (3) showed significant enhanced cytotoxicity against KB-C2 cells in the presence of colchicine with an IC50 value of 1.51 mg/ml Since colchicine had no effect on the growth of KB-C2 cells at this concentration level, it was suggested that sinocalycanchinensins E might show some MDR-reversing effects ... Studies in Natural Products Chemistry, Vol 41 http://dx.doi.org/10.1016/B978-0-444-63294-4.00001-2 Copyright © 2014 Elsevier B.V All rights reserved Studies in Natural Products Chemistry Natural products. .. Pulsatilla chinensis, largely used in Chinese medicine This compound mediated induced apoptosis in HL-60 cells by decreases in bcl-2 expression and telomerase activity [43] 14 Studies in Natural Products. .. b-anomers of 28-O-acetylbetulin-3-yl-D-glucopyranoside seem to 20 Studies in Natural Products Chemistry TABLE In Vitro and In Vivo Studies of Triterpenoids Compound In Vivo Model In Vitro Model Mechanism