Fortschritte der Chemie organischer Naturstoffe Progress in the Chemistry of Organic Natural Products

314 Pages·1997·21.22 MB·English

by  Prof. A. Cavé, Prof. D. Cortes, Dr. B. Figadère, Dr. A. Laurens, Prof. G. R. Pettit (auth.), Prof. W. Herz, Prof. G. W. Kirby, Prof. R. E. Moore, Prof. Dr. W. Steglich, Prof. Dr. Ch. Tamm (eds.)

70
Fortschritte der Chemie
organischer Naturstoffe
Progress in the
Chemistry of Organic
Natural Products
Founded by
L. Zechmeister
Edited by
W. Herz, G. W. Kirby,
R. E. Moore, W. Steglich,
and Ch. Tamm
Authors:
A. Cave, D. Cortes,
B. Figadere, A. Laurens,
G. R. Pettit
Springer-Verlag Wien GmbH
Prof. W. HERZ, Department of Chemistry,
The Florida State University, Tallahassee, Florida, U.S.A.
Prof. G. W. KIRBY, Chemistry Department,
The University ofGlasgow, Glasgow, Scotland
Prof. R. E. MooRE, Department of Chemistry,
University of Hawaii at Manoa, Honolulu, Hawaii, U.S.A.
Prof. Of. W. STEGLICH, Institut fiir Organische Chemie der Universităt
Miinchen, Miinchen, Federal Republic of Germany
Prof. Dr. CH. TAMM, Institut fiir Organische Chemie der Universităt Basel,
Basel, Switzerland
This work is subject to copyright.
All rights are reserved, whether the whole or part of the material is concerned, specifically those
of translation, reprinting, re-use of illustrations, broadcasting, reproduction by photocopying
machi nes Of similar means, and storage in data banks.
1[:' 1997 by Springer-VerlagWien
Originally pnblished by Springer-Verlag/Wien in 1997
Softcover reprint of the hardcover 1s t edition 1997
Library ofCongress Catalog Card Number AC 39-1015
Typesetting: Thomson Press (India) Ltd., New Delhi
Graphic design: Ecke Bonk
Printed on acid-free and chlorine-free bleached paper
With 86 partly coloured Figures
ISSN 0071-7886
ISBN 978-3-7091-7349-7 ISBN 978-3-7091-6551-5 (eBook)
DOI 10.1007/978-3-7091-6551-5
Contents
List of Contributors VII
The Dolastatins.
By G. R. PETTIT
1. Introduction 2
2. Dolabella auricularia 3
3. Isolation and Structure Determination of the Dolastatins 4
4. Synthesis of the Dolastatins 12
4.1 Dolastatin 3 ...... . 12
4.2 Dolastatin 10 ..... . 14
4.2.1 Dolaphenine (Doe) 14
4.2.2 Dolaproine (Dap) ... . 18
4.2.3 Dolaisoleuine (Dil) ... . ..... . 24
4.2.4 Dolaproinyl-Dolaphenine (Dap-Doe) ... . 32
4.2.5 Conversion of Dap-Doe to Dolastatin 10 . 33
4.2.6 Chromatography of Dolastatin 10 ......... . 36
4.2.7 High-Field NMR Analysis of Dolastatin 10 .... . 39
4.3 Syntheses of (6R)-Isodolastatin 10 and Other Chiral modifications of
Dolastatin 10 ..................... . 39
4.3.1 Crystal Structure of (6R)-Isodolastatin 10 .. . 40
4.3.2 Molecular Modeling of (6R)-Isodolastatin 10 41
4.4 Structural Modifications of Dolastatin 10 43
4.5 Synthesis of Dolastatin 15 ...... . 45
4.6 Synthesis of Dolastatin C ...... . 47
5. Spectral and Analytical Characterization 48
5.1 Dolastatin 10 ..... 48
5.2 Dolastatins 11 and 12 ..... 51
5.3 Dolastatin 13 52
5.4 Dolastatin 14 55
5.5 Dolastatin 15 55
6. Cytostatic and Antineoplastic Activities 57
6.1 Dolastatins 10-15 ......... . 57
6.2 Dolastatin 10 Structural Modifications 63
6.2.1 Chiral Isomers ......... . 63
6.2.2 Structural Substitutions ..... . 63
VI Contents
7. Biochemical Mechanisms of Action . . ..... . 68
7.1 Inhibition of Tubulin Assembly and Mitosis 68
7.2 Effects on Actin . . . . . . 69
8. Pharmacology and Toxicology 69
9. Conclusion .. 70
Acknowledgements 70
References 70
Acetogenins from Annonaceae.
By A. CAVE, B. FIGADERE, A. LAURENS, and D. CORTES 81
I. Introduction 81
II. Classification 82
Synonyms of Acetogenins 84
Listing (Structures and Physical Data) 89
Distribution ..... 180
III. Extraction and Isolation 188
IV. Structure Elucidation 189
V. Biogenetic Hypotheses 226
VI. Syntheses 231
VII. Biological Activities 264
Acknowledgements 273
References .... 273
Author Index 289
Subject Index 297
List of Contributors
CAVE, Prof. A., Laboratoire de Pharmacognosie, Faculte de Pharmacie, F-92296 Chatenay-
Malabry, France.
CORTES, Prof. D., Departemento de Farmacologia, Farmacognosia y Farmacodinamica,
Faculdad de Farmacia, Avenida Andres Estelles, E-46100 Burjasot (Valencia), Spain.
FIGADERE, Dr. B., Laboratoire de Pharmacognosie, Faculte de Pharmacie, F-92296
Chatenay-Malabry, France.
LAURENS, Dr. A., Laboratoire de Pharmacognosie, Faculte de Pharmacie, F-92296
Chatenay-Malabry, France.
PETTIT, Prof. G. R., Cancer Research Institute, Arizona State University, Tempe, AZ 85287-
1604, U.S.A.
The Dolastatins
G. R. PETTIT, Cancer Research Institute and
Department of Chemistry, Arizona State University,
Tempe, Arizona, USA
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . 2
2. Dolabella auricularia . . . . . . . . . . . . . . . . . . . . . . . . . . 3
3. Isolation and Structure Determination of the Dolastatins . . 4
4. Synthesis of the Dolastatins . . . . . . . . . . . . . . . . . . . 12
4.1 Dolastatin 3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
4.2 Dolastatin 10 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
4.2.1 Dolaphenine (Doe) . 14
4.2.2 Dolaproine (Dap) . . . . . . . . . . . . . . . . 18
4.2.3 Dolaisoleuine (Dil) . . . . . . . . . . . . . . . 24
4.2.4 Dolaproinyl-Dolaphenine (Dap-Doe) . . . . 32
4.2.5 Conversion of Dap-Doe to Dolastatin 10 . . 33
4.2.6 Chromatography of Dolastatin 10 . . . . . . 36
4.2.7 High-Field NMR Analysis of Dolastatin 10 . 39
4.3 Syntheses of (6R)-Isodolastatin 10 and Other Chiral Modifications of
Dolastatin 10 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
4.3.1 Crystal Structure of (6R)-Isodolastatin 10 . . . . 40
4.3.2 Molecular Modeling of (6R)-Isodolastatin 10 . 41
4.4 Structural Modifications of Dolastatin 10 . . . . . 43
4.5 Synthesis of Dolastatin 15 . . . . . . . . 45
4.6 Synthesis of Dolastatin C . . . . . . . . 47
5. Spectral and Analytical Characterizations . 48
5.1 Dolastatin 10 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
5.2 Dolastatins 11 and 12 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
5.3 Dolastatin 13 . 52
5.4 Dolastatin 14 . . . . . . . . . . . . . . . 55
5.5 Dolastatin 15 . . . . . . . . . . . . . . . 55
6. Cytostatic and Antineoplastic Activities . . . . . . . . 57
6.1 Dolastatins 10-15 . . . . . . . . . . . . . . . . . . . 57
A. Cavé et al., Fortschritte der Chemie organischer Naturstoffe Progress in the
Chemistry of Organic Natural Products © Springer-Verlag Wien 1997
2 G. R. PETTIT
6.2 Dolastatin 10 Structural Modifications . . . . . . . . . . . . . . . . . . . . . 63
6.2.1 Chiral Isomers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 63
6.2.2 Structural Substitutions . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
7. Biochemical Mechanisms of Action . . . . . . . . . . . . . . . . . . . . . . . . .. 68
7.1 Inhibition of Tubulin Assembly and Mitosis. . . . . . . . . . . . . . . . . . 68
7.2 Effects on Actin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
8. Pharmacology and Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
9. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
1. Introduction
Certain marine animals were known to the ancients for their potent
biological constituents and presumed use in primitive medicine. The early
periods of recorded history contain references to support these assump-
tions (1). Illustrative are hieroglyphics on the Egyptian Pharaoh Ti's tomb
(approximately 2700 BC) that describe the poisonous puffer fish Tet-
raodon stellatus. One of the earliest recorded uses of a marine organism in
primitive medical practice has been attributed to the Roman, Gaius
Plinius Secundus (AD 29-79, Pliny the Elder), who recommended that the
sting system of the stingray be ground up and used for treatment of
toothache and in obstetrics. One of the first modern pharmacological and
chemical studies of potent marine animal constituents involved tet-
rodotoxin from the poisonous puffer fish (2,3). About 40 years ago some
especially important observations began to be recorded. Illustrative was
the fact that extracts from certain sponges and coelenterates were shown
to have antibiotic properties (4-8) and that marine invertebrates produce
various other potentially medically useful components (9-11). Very im-
portantly, from the viewpoint of anticancer drug discovery, were reports
that starfish meal (12-14) and fractions from the peanut worm Bonellia
fulginosa (15,16), certain sea cucumbers, and molluscs [clams (16) and
oysters (9,11)] exhibited antitumor activity against sarcoma-180 and
Krebs-2 ascites tumor (10,17-19).
In 1965-66, we began the first systematic study of marine invert-
ebrates, vertebrates, and plants as a vast untapped resource for discovery
of promising new anticancer drugs with the presumed unprecedented
structures necessary to improve human cancer treatment. During the next
four years, we evaluated components from many such marine organisms
References. pp. 70-79
The Dolastatins
3
from a broad geographic area that included the Atlantic and Pacific coasts
of North and South America and the coasts of Asia. Antineoplastic
activity was assessed by use of the Walker 256 carcinoma (intramuscular)
and both a lymphoid (L121O) and lymphocytic leukemia (PS) as develop-
ed at the U.S. National Cancer Institute. By 1968 our original expecta-
tions concerning certain marine animals as potential sources of new
anticancer drugs were amply confirmed and reported in 1970 (20). In the
same period, we began the first such investigation ofterrestrial arthropods
for antineoplastic constituents, and initial results were reported in 1968
(21). Subsequently, we have isolated and characterized a substantial
number of new cytotoxic, cytostatic and/or antineoplastic marine animal
constituents (22, 23). We continue to devote considerable efforts to isolat-
ing such very active, albeit trace, constituents of certain exceptionally
promising marine animal extracts. Two of the earliest leads we uncovered
(1968 and 1972), which provided unprecedented structural types and led
to clinical candidates that meet the rigorous criteria of the U.S. National
Cancer Institute, were the bryostatin (22) and dolastatin series (23).
Discovery of the bryostatins in the phylum Ectoprocta (Bryozoa) species
Bugula neritina has been reviewed in a preceding chapter (22). The present
review will be focused on discovery of the dolastatins.
2. Dolabella auricularia
The phylum Mollusca contains a great variety of terrestrial and
marine organisms that have evolved an even more astonishing spectrum
of reproductive and defensive strategies. Among the marine Mollusca, the
Aplysiomorpha, Nudibranchia, and Sacoglossa constitute the three lar-
gest orders of opisthobranch sea slugs [shell-less molluscs (24)]. The
aplysiomorphs feed on marine algae. The herbivorous Sacoglossa even
have the ability to cultivate in their digestive glands ingested chloroplasts
and then survive for weeks at a time on solar radiation and dissolved
atmospheric gases. In contrast, the nudibranchs are carnivorous and free
swimming. The dorid nudibranchs are even capable of consuming
bryozoans, ascidians, acorn barnacles, sponges, and tunicates. Such var-
ied dietary selections in turn serve as useful sources of potent compounds
for devising powerful chemical defenses for these soft-bodied and slow-
moving animals. In the aplysiomorpha class, Gastropoda species in the
family Aplysiidae are commonly known as sea hares (24). The Romans
first designated Mollusca of the family Aplysiidae in this fashion owing to
a similarity between the ears of a hare and the auriculate tentacles of these
gastropods (25).
4 G. R. PETTIT
The great Roman natural scientist Pliny the Elder in his comprehen-
sive study (26) of about 60 A.D. first described a most potent Indian Ocean
sea hare of the genus Dolabella. Extracts from this animal and two related
Aplysia species from the Mediterranean were well known for their toxic
properties during the reign of Nero. Such toxic mixtures are believed to
have been used by Agrippina, mother of Nero (A.D. 37-68), to dispatch
relatives in the way of his ascent to being Roman emperor. Indeed,
Locusta, servant to Agrippina Minor, is believed to have murdered
Caesar Augustus and Claudius Britannicus, among others, with potions
from a Dolabella sp. believed to be auricularia (27). That species of sea hare
was probably the one first described by Pliny, and the minor variations
recorded in subsequent literature as, e.g., D. andersoni, D. cali{ornica,
D. ecaudata, and D. scapula are actually one species, namely, D. auricularia
(28). By 150 A.D. Nicander (25) recognized the possibility of using such
extracts for treatment of certain diseases. In 1568 the French scholar
Grevin described in vivid details the potency of extracts prepared from
a sea hare presumed to be Dolabella auricularia (29). In addition to the
zoological studies already noted (24, 28) and one published in 1974 (31),
early scientific studies of Dolabella auricularia were focused on various
biological properties ranging from cardiac behavior (32-36) to calcium
transport (37), wall muscle physiology (38), and hemocyanin content (39).
Evaluations of toxic fractions were first conducted in the 1969-73 period
(40-42). However, the potential of the Indian Ocean Dolabella with
respect to modern medical problems was not recognized until we un-
covered evidence in 1972 for extremely active anticancer constituents in
the Indian Ocean Dolabella auricularia (30). Presumably the dolastatins
are important representatives of the potent D. auricularia components
recognized from ancient (26,27) to modern (40-42) times.
3. Isolation and Structure Determination of the Dolastatins
By October, 1972 our broad geographic exploratory survey of marine
organisms for antineoplastic constituents had been extended to the
Western Indian Ocean and concentrated in the region from Mauritius to
South Africa. With the capable assistance of my marine zoologist col-
league, Claude Michel, we were able to evaluate Mauritius specimens of
the olive green (and pear-shaped) Dolabella auricularia. Against the U. S.
National Cancer Institute's (NCI) P388 lymphocytic leukemia (PS sys-
tem), ethanol extracts of D. auricularia gave 67 to 135% life extension at
doses of 176 to 600 mg/kg. In short, it was a very high priority lead and
was pursued on that basis.
Rej"erences, pp. 70-79