Bioactive Natural Products (Part I)

793 Pages·2003·11.183 MB·3-797\793

by  Atta-ur Rahman (Eds.)

FOREWORD
"Studies in Natural Products Chemistry" has become the world's leading series of
volumes in the field of isolation, structure elucidation, biological activity and synthesis of
natural products, with comprehensive reviews written by leading experts. Volume 1 of the
series was published in March 1988 and during the last 15 years 27 volumes have been
published. From Volume 21 onwards, the series has been devoted to bioactive natural
products. Natural products present a huge source of organic substances with differing
structural features. The very large number of terrestrial and marine natural products
found in differing environmental conditions with correspondingly different biosynthetic
patterns gives medicinal chemists access to millions of substances with differing
bioactivity profiles. This represents a genuine treasure chest for discovering new
medicinal agents against a variety of diseases. The series on bioactive natural products
should therefore be of considerable interest not only to natural product chemists but also
to medicinal chemists, pharmacologists, and synthetic organic chemists working in
academia and industry. I hope that the present volume will be received with the same
excitement and enthusiasm as the previous volumes of his encyclopaedic series.
I would like to express my thanks to Mr. Shakeel Ahmad for his assistance in the
preparation of the index. I am also grateful to Mr. Waseem Ahmad for typing and to Mr.
Mahmood Alam for secretarial assistance.
Atta-ur-Rahman
Ph.D. (Cantab.), Sc.D. (Cantab.)
Chairman, Higher Education Commission
Government of Pakistan
January, 2003
PREFACE
In various segments of the scientific community, natural products research comes in
and out of favor In a cyclic manner as a function of time. Irrespective of this rhythmic
pattern, the true and absolute value of natural products research is immutable, in the
context of both applied and basic investigations. Clearly, therapeutic modalities
throughout the world rely heavily on natural product drugs and formulations. Similarly,
although acknowledgements may be less overt or absent, many aspects of basic
research programs are intimately related to natural products. In essence, natural
products play an integral and ongoing role in promoting numerous aspects of scientific
advancement.
Obviously, for progress to be realized on a widespread basis, general dissemination of
contemporary information is necessary. Incredibly, we now see the 28th volume in the
series Studies in Natural Product Ctiemistry edited by Professor Atta-ur-Rahman. The
significance of this indelible effort cannot be overestimated. More specifically, in the
same impeccable manner as the former volumes, we are again presented with cutting-
edge contributions of great importance. The first paper presents over 100 compounds
obtained from Broussonetia spp., and discusses biological activities. This is followed by
similar contributions dealing with the genus Licania and Ginkgo biloba. Additional
papers describe in detail a number of interesting and important natural compounds or
structural classes: retinoids, tetramic acid metabolites, isoprenylated flavonoids, plant
polyphenols, crocin, marcfortine and paraherquamide, acarlcides, podolactones,
triterpene glycosides and sulfur-containing marine compounds. An additional paper
focuses on the antitumor activities of lipids, and a final contribution deals with natural
product amelioration of cancer chemotherapy-Induced adverse reactions.
These astute summaries are provided by well-respected authors from seven different
countries. Assembly of the volume is a notable achievement; the work as a whole
nicely illustrates the types of critical discoveries that emanate from the interface of
chemistry and biology. Volume 28 can stand as a proud member of this great family of
useful reference books.
John M. Pezzuto
Professor and Dean
Schools of Pharmacy, Nursing
and Health Sciences
Purdue University
CONTRIBUTORS
Kazuo Abe Graduate School of Pharmaceutical Sciences, The
University of Tokyo, Tokyo 113-0033, Japan
Alejandro F. Barrero Department of Organic Chemistry, Institute of
Biotechnology, University of Granada, Avda.,
Fuentenueva, 18071, Granada, Spain
Anna Rita Bilia Dipartimento di Scienze Farmaceutiche, Universita di
Firenze, Via Gino Capponi 9, 55100 Firenze, Italy
Alessandra Braca Dipartimento di Chimica Bioorganica e Biofarmacia,
Universita di Pisa, Via Bonanno 33, 56126, Pisa, Italy
Lorenzo Bramati ITB-CNR, Via F. Ui Cervi, 93 - 20090 (MI), Italy
Dominique L. Cartier FRE 2125 CMIS, 6 rue de TUniversite 29000 Quinq)er,
France
Hugo D. Chludil Departamento de Quimica Organica, Facultad de Ciencias
Exactas y Naturales, Universidad de Buenos Aires,
Pabellon 2, Ciudad Universitaria, (1428) Buenos Aires,
Argentina
Guido Flamini Dipartimento di Chimica Bioorganica e Biofarmacia, Via
Bonanno 33, 56126 Pisa, Italy
Toshio Fukai School of Pharmaceutical Sciences, Toho University, 2-2-
1 Miyama, Fimabashi, Chiba 274-8510, Japan
Nolwenn Gauthier Cancer Immunotherapy Research Laboratory, Ecole
Pratique des Hautes Etudes, INSERM U517, Faculty of
Medicine, 7 Bd Jeanne d'Arc, 21079 Dijon, France
Emilio L. Ghisalberti Department of Chemistry, University of Western
Australia, Nedlands, 6009 W.A., Australia
M. Haga Department of Hygienic Chemistry, Faculty of
Pharmaceutical Sciences, Health Sciences, University of
Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293, Japan
Yoshio Hano School of Pharmaceutical Sciences, Toho University, 2-2-
1 Miyama, Funabashi, Chiba 274-8510, Japan
M. Mar Herrador Department of Organic Chemistry, Institute of
Biotechnology, University of Granada, Avda.,
Fuentenueva, 18071, Granada, Spain
Jean-Francois Jeannin Cancer Immunotherapy Research Laboratory, Ecole
Pratique des Hautes Etudes, INSERM U517, Faculty of
Medicine, 7 Bd Jeanne d'Arc, 21079 Dijon, France
Yoshiyuki Kimura Second Department of Medical Biochemistry, School of
Medicine, Ehime University, Shigenobu-cho, Onsen-gun,
Ehime 791-0295, Japan
A. Douglas Kinghom Program for Collaborative Research in the Pharmaceutical
Sciences and Department of Medicinal Chemistry and
Pharmacognosy, College of Pharmacy, University of
Illinois at Chicago, Chicago, Illinois 60612, USA
Roger Labia FRE 2125 CNRS, 6 rue de I'Universite 29000 Quimper,
France
Byung H. Lee Preclinical Development, Pharmacia Animal Health, 7000
Portage Road, Kalamazoo, MI 49001, USA
Dongho Lee Chemistry and Life Sciences, Research Triangle Institute,
P.O. Box 12194, Research Triangle Park, North Carolina
27709, USA
Departamento de Quimica Organica, Facultad de Ciencias
Marta S. Maier
Exactas y Naturales, Universidad de Buenos Aires,
Pabellon 2, Ciudad Universitaria, (1428) Buenos Aires,
Argentina
Grupo de Productos Naturales, Centro de Quimica
Jeannette Mendez
Organica, Escuela de Quimica, Facultad de Ciencias,
Universidad Central de Venezuela, Apartado de Correos
47102, Caracas 1020-A, Venezuela
Markus Minoggio ITB-CNR, Via F. Hi Cervi, 93 - 20090 (MI), Italy
Jose F. Quilez Del Moral Department of Organic Chemistry, Institute of
Biotechnology, University of Granada, Avda.,
Fuentenueva, 18071, Granada, Spain
Ivano Morelli Dipartimento di Chimica Bioorganica e Biofarmacia,
Universita di Pisa, Via Bonanno 33, 56126, Pisa, Italy
Satoshi Morimoto Graduate School of Pharmaceutical Sciences, Kyushu
University, Fukuoka 812-8582, Japan
Ana P. Murray Departamento de Quimica Organica, Facultad de Ciencias
Exactas y Naturales, Universidad de Buenos Aires,
Pabellon 2, Ciudad Universitaria, (1428) Buenos Aires,
Argentina
Taro Nomura School of Pharmaceutical Sciences, Toho University, 2-2-
1 Miyama, Funabashi, Chiba 274-8510, Japan
Takashi Ochiai Faculty of Pharmaceutical Sciences, Fukuoka University,
Fukuoka 814-0180, Japan
Alena Pance Cancer Immunotherapy Research Laboratory, Ecole
Pratique des Hautes Etudes, INSERM U517, Faculty of
Medicine, 7 Bd Jeanne d'Arc, 21079 Dijon, France
Piergiorgio Pietta ITB-CNR, Via F. Ui Cervi, 93 - 20090 (MI), Italy
Cosimo Pizza Dipartimento di Scienze Farmaceutiche, Universita di
Salemo, Via Ponte Don Melillo, 84084 Fisciano, Salemo,
Italy
Michele R. Prinsep Department of Chemistry, University of Waikato, Private
Bag 3105, Hamilton, New Zealand
Daniele Reisser Cancer Immunotherapy Research Laboratory, Ecole
Pratique des Hautes Etudes, INSERM U517, Faculty of
Medicine, 7 Bd Jeanne d'Arc, 21079 Dijon, France
Hiroshi Saito Graduate School of Pharmaceutical Sciences, The
University of Tokyo, Tokyo 113-0033, Japan
K. Sasaki Department of Hygienic Chemistry, Faculty of
Pharmaceutical Sciences, Health Sciences, University of
Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293, Japan
Alicia M. Seldes Departamento de Quimica Organica, Facultad de Ciencias
Exactas y Naturales, Universidad de Buenos Aires,
Pabellon 2, Ciudad Universitaria, (1428) Buenos Aires,
Argentina
Hiroshi Shimeno Faculty of Pharmaceutical Sciences, Fukuoka University,
Fukuoka 814-0180, Japan
Yukihiro Shoyama Graduate School of Pharmaceutical Sciences, Kyushu
University, Fukuoka 812-8582, Japan
Shinji Soeda Faculty of Pharmaceutical Sciences, Fukuoka University,
Fukuoka 814-0180, Japan
Minoru Sugiura Graduate School of Pharmaceutical Sciences, The
University of Tokyo, Tokyo 113-0033, Japan
Hiroyuki Tanaka Graduate School of Pharmaceutical Sciences, Kyushu
University, Fukuoka 812-8582, Japan
Futoshi Taura Graduate School of Pharmaceutical Sciences, Kyushu
University, Fukuoka 812-8582, Japan
Nunziatina De Tommasi Dipartimento di Scienze Farmaceutiche, Universita di
Salerno, Via Ponte Don Melillo, 84084 Fisciano, Salerno,
Italy
Alain R. Valla VA R&D Pepiniere d'entreprises, 140 Bd de Creac'h
Gween 29561 Quimper, France
K. Wada Department of Hygienic Chemistry, Faculty of
Pharmaceutical Sciences, Health Sciences, University of
Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293, Japan
AUa-ur>Rahinan (Ed.) Studies in Natural Products Chemistry, Vol. 28
© 2003 Elsevier Science B.V. All rights reserved.
BIOACTIVE COMPOUNDS FROM THE GENUS
BROUSSONETIA
DONGHO LEE^ and A. DOUGLAS KINGHORN*
Program for Collaborative Research in the Pharmaceutical Sciences
and Department of Medicinal Chemistry and Pharmacognosy, College of
Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612,
USA,
ABSTRACT: The genus Broussonetia of the Moraceae (mulberry family) is of both
ethnomedical and industrial interest. Of the approximately 30 species in this genus, only
three have been subjected to previous phytochemical investigation, namely, B. kazinoki,
B. papyriferay and B, zeylanica. From over 100 compounds isolated from these species,
the major secondary metabolites reported thus far are alkaloids of the pyrrolidine type
and several types of flavonoids. Some of these compounds have exhibited various
biological activities, such antioxidative, aromatase inhibitory, cytotoxic, glycosidase
inhibitory, and platelet aggregation inhibitory effects. The biologically active
constituents of the species in the genus Broussonetia are discussed in detail.
INTRODUCTION
The genus Broussonetia L*Her. ex Vent, of the Moraceae (mulberry
family) is represented by lactiferous trees or shrubs. Broussonetia
comprises about 30 species and is distributed throughout various regions
of the w^orld including Africa, East Asia, and North America [1,2]. Thus
far, only three species of the genus Broussonetia have been studied for
their secondary metabolites, namely, B, kazinoki, B. papyrifera, and B.
zeylanica.
Broussonetia kazinoki Siebold & Zucc. is a deciduous tree
growing to 4.5 m that flowers in August. It occurs in mainland China,
Japan, and Korea [1]. The plant requires well-drained soil but can grow in
Address correspondence to this author at Program for Collaborative Research in the
Pharmaceutical Sciences and Department of Medicinal Chemistry and Pharmacognosy
(M/C 781), College of Pharmacy, University of Illinois at Chicago, 833 South Wood
Street, Chicago, Illinois 60612, U.S.A. E-mail: [email protected].
^Current address: Chemistry and Life Sciences, Research Triangle Institute, P.O. Box
12194, Research Triangle Park, North Carolina 27709, U.S.A.
nutritionally poor soil [3]. Preparations made from B. kazinoki have been
used as a tonic to increase vision and sexual potency, and to treat boils,
eczema, infant colic, and leukorrhea [4,5]. Various extracts of 5. kazinoki
have exhibited antifungal, antiinflammatory, antioxidant, and
antispasmodic activities [6-10].
Broussonetia papyrifera (L.) L'Her. ex Vent, is a deciduous tree
growing up to 15 m that is commonly called the paper mulberry. It is
native to East Asia, then later introduced and naturalized in the United
States. It flowers from August to September, and the seeds ripen from
September to November [1,11]. The plant prefers light and well-drained
soil and' is easily cultivated in a warm sunny position in any soil of
reasonable quality [3]. Fibers from the bark are used in making paper,
cloth, and rope. These fibers can be produced by beating strips of bark on
a flat surface with a wooden mallet [12]. 5. papyrifera has been used for
cancer, dyspepsia, and pregnancy [13]. In mainland China, the fruits of 5.
papyrifera have been employed for impotency and ophthalmic disorders
[4,14], Also, the leaf juice of 5. papyrifera is diaphoretic and laxative and
the stembark is hemostatic [4]. Antifungal and antioxidant activities of the
extracts ofB. papyrifera were reported [6,7,9].
Broussonetia zeylanica (Thwait.) Comer is endemic to Sri Lanka
and its tough bark-fibers were used to make string [15].
Several types of bioactive compounds have been reported from the
genus Broussonetia including glycosidase inhibitory alkaloids and
aromatase inhibitory or cytotoxic flavonoids. This chapter reviews the
biologically active constituents from the genus Broussonetia reported by
the end of 2001.
BIOACTIVE COMPOUNDS FROM BROUSSONETIA KAZINOKI
The bioactive secondary metabolites reported from Broussonetia kazinoki
can be classified into major two groups, alkaloids and flavonoids (Table
1), Fig. (1). The Kusano group at Osaka University of Pharmaceutical
Sciences in Japan reported over 20 pyrrolidine alkaloids, broussonetines
A-H, K-M, 0-T, V-X, and Mi, and broussonetinines A and B, four
pyrrolidinyl piperidine alkaloids, broussonetines I, J, Ji, and J2, two
pyrroline alkaloids, broussonetines U and Ui, and one pyrrolizidine
alkaloid, broussonetine N, from hot water extracts of 5. kazinoki [16-24].
As shown in Table 1, some of these alkaloids exhibited strong
Table 1. Bioactive Compounds from Broussonetia kazinoki
Compound type/name Activity Reference
ALKALOIDS
Pyrrolidines
Broussonetine C (1) Inhibition of glycosidases* [16]
Broussonetine D (2) Inhibition of glycosidases* [16]
Broussonetine E (3) Inhibition of glycosidases" [17]
Broussonetine F (4) Inhibition of glycosidases* [17]
Broussonetine G (5) Inhibition of glycosidases* [18]
Broussonetine H (6) Inhibition of glycosidases* [18]
Broussonetine K (7) Inhibition of glycosidases* [20]
Broussonetine L (8) Inhibition of glycosidases* [20]
Broussonetine M (9) Inhibition of glycosidases* [21]
Broussonetine 0 (10) Inhibition of glycosidases* [21]
Broussonetine P (11) Inhibition of glycosidases* [21]
Broussonetine Q (12) Inhibition of glycosidases* [21]
Broussonetinine A (13) Inhibition of glycosidases* I [17]
Broussonetinine B (14) Inhibition of glycosidases* [17]
Pyrrolizidine
Broussonetine N (15) Inhibition of glycosidases* [22]
FLAVONOIDS
Diphenylpropanes
KazinolD(16) Cytotoxicity against human tumor cell lines'* [25]
Ka2inolK(17) Cytotoxicity against human tumor cell lines** [25]
Table 1. Bioactive Compounds from Broussonetia kazinoki (continued)
Compound type/name Activity Reference
Flavans
7,4'-Dihydroxyflavan (18) Cytotoxicity against human tumor cell lines'* [25]
Antioxidant activity*" [26]
KazinolA(19)
Inhibition of tyrosinase** [26]
Antioxidant activity*^ [26]
KazinolE(20)
Inhibition of tyrosinase' [26]
KazinolQ(21) Cytotoxicity against human tumor cell lines'* [25]
KazinolR(22) Cytotoxicity against human tumor cell lines'* [25]
Flavonols
Broussonol A (23) Cytotoxicity against human tumor cell lines'* [27]
Broussonol B (24) Cytotoxicity against human tumor cell lines'* [27]
Broussonol C (25) Cytotoxicity against human tumor cell lines'* [27]
Broussonol D (26) Cytotoxicity against human tumor cell lines'* [27] 1
"Glycosidase inhibitory activity expressed as ICso value (jiM); 1: p-Gal = 0.036, p-Man = 0.32; 2: P-Gal =
0.029, P-Man = 0.34; 3: a-Glc = 3.3, P-Glc == 0.055, P-Gal = 0.002, p-Man = 0.023; 4: a-Glc = 1.5, p-Glc =
0.01, P-Gal = 0.004, P-Man = 0.028; 5: P-Glc = 0.024, P-Gal = 0.003, P-Man = 0.76; 6: P-Glc = 0.036, p-Gal =
0.002, P-Man = 0.32; 7: P-Glc = 0.026, P-Gal = 0.005, P-Man = 0.3; 8: P-Glc = 0.017, P-Gal = 0.004, p-Man =
0.2; 9: P-Gal = 8.1; 10: P-Glc = 1.4, P-Gal = 0.17, P-Man = 8.2; 11: P-Glc = 2.4, P-Gal = 0.2, P-Man = 7.6; 12:
P-Glc = 1.4, P-Gal = 0.6, P-Man = 20.0; 13: P-Gal = 0.016, a-Man = 0.3; 14: P-Gal = 0.01, a-Man = 0.29; 15:
P-Glc = 6.7, p-Gal = 2.9, P-Man = 3.3 (P-Gal = p-Galactosidase; a-Glc = a-Glucosidase; P-Glc = p-
Glucosidase; a-Man = a-Mannosidase; P-Man = P-Mannosidase).
'*Cytotoxicity expressed as ED50 value (^ig/mL); 16: PLC/PRF/5 = 3.3, 212 = 7.0, HT3 = 3.6; 17: HT3 = 8.6:
18: HT3 = 11.6, SiHa = 8.9, CaSki = 17.4; 21: PLC/PRF/5 = 3.5, T24 = 2.3, 212 = 3.8, HT3 = 4.3, SiHa - 4.7;
22: HT3 = 9.3, SiHa = 9.3, CaSki = 8.2; 23: A546 = 8.7, HCT-8 = 9.1; 24: A546 = 5.52, HCT-8 = 8.8; 25:
A546 = 7.8, HCT-8 = 9.6; 26: KB = 4.5 (key to cell lines; 212 = inducible Ha-ras oncogene transformed
NIH/3T3; A549 = human lung carcinoma; CaSki = human cervical carcinoma; HCT-8 = human ileocecal
carcinoma; HT3 = human cervical carcinoma; KB = human epidermoid carcinoma; PLC/PRF/5 = human
hepatoma; SiHa = human cervical carcinoma; T24 = human hepatoma).
'^Antioxidant activity shown by l,l-diphenyl-2-picryl-hydrazyl (DPPH) radical scavenging activity (IC50 pM);
19:41.4,20:33.4.
''Activity not specified.
nCso 241.3 nM.