Progress in the Chemistry of Organic Natural Products

272 Pages·2004·5.843 MB·English

by  H. Budzikiewicz, T. Flessner, R. Jautelat, U. Scholz, E. Winterfeldt (auth.), Prof. W. Herz, Prof. H. Falk, Prof. G. W. Kirby (eds.)

87
Fortschritte der Chemie
organischer Na turstoffe
Progress in the
Chemistry of Organic
Natural Products
Founded by
1. Zechmeister
Edited by
W. Herz, H. Falk,
and G. W. Kirby
Authors:
H. Budzikiewicz, T. Flessner, R. Ja utelat,
U. Scholz, E. Winterfeldt
Springer-Verlag Wien GmhH
Prof. W. Herz, Department of Chemistry,
The Florida State University, Tallahassee, Florida, U.S.A.
Prof. H. Falk, Institut fiir Chemie,
Johannes-Kepler-Universitat, Linz, Austria
Prof. G. W. Kirby, Chemistry Department,
The University of Glasgow, Glasgow, Scotland
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© 2004 Springer-Verlag Wien
Originally published by Springer-Verlag Wien New York in 2004
Softcover reprint of the hardcover l st edition 2004
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With 63 partly coloured Figures
ISSN 0071-7886
ISBN 978-3-7091-7199-8 ISBN 978-3-7091-0581-8 (eBook)
DOI 10.1007/978-3-7091-0581-8
Contents
List of Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. VIII
Cephalostatin Analogues - Synthesis and Biological Activity
T. Flessner, R. Ja utelat, U. Scholz, and E. Winterfeldt ................. .
1. Introduction ............................................ .
2. Synthesis of Bissteroidal Pyrazines ............................. 15
2.1. Synthesis of Symmetrical Pyrazines and Subsequent
Desymmetrization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
2.2. Directed Synthesis of Unsymmetrical Pyrazines . . . . . . . . . . . . . . . . . 28
2.2.1. Nonacyclic Cephalostatin Analogues . . . . . . . . . . . . . . . . . . . . 37
2.2.2. Dienes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
3. A-D-Ring Functionalization .................................. 42
3.1. Introduction of the Steroidal ~14.15_Bond ..................... 44
3.2. Chemical Modifications on the ~14.15_Double Bond. . . . . . . . . . . . . . 56
4. The Spiroketal Area of Cephalostatins . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
5. Summary ............................................... 70
Acknowledgements .......................................... 74
References ................................................ 75
Siderophores of the Pseudomonadaceae sensu stricto
(Fluorescent and Non-Fluorescent Pseudomonas spp.)
H. Budzikiewicz ............................................ 81
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
1.1. General. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
1.2. The Bacterial Genus Pseudomonas . . . . . . . . . . . . . . . . . . . . . . . . . . 84
1.3. Iron Supply for Microorganisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
2. The Typical Siderophores of the Fluorescent Pseudomonads -
the Pyoverdins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
2.1. History.............................................. 91
2.2. Detection of Siderophore Producing Strains and
Screening Methods. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
2.3. Naming of Pyoverdins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
2.4. Pyoverdin Production and Isolation . . . . . . . . . . . . . . . . . . . . . . . . . . 99
2.5. The Structure of Pyoverdins and of Related Compounds . . . . . . . . . . . 101
VI Contents
2.5.1. General. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 1
2.5.2. Types of Chromophores (Fig. 4). . . . . . . . . . . . . . . . . . . . . . . . 102
2.5.3. The Dicarboxylic Acid Side Chain. . . . . . . . . . . . . . . . . . . . . . 108
2.5.4. The Peptide Part. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
2.5.5. Structural Variations of Pyoverdins. . . . . . . . . . . . . . . . . . . . . . 118
2.6. Structural Studies by NMR and Mass Spectrometry. . . . . . . . . . . . . . . 119
2.6.1. Formation of Peptide Fragment Ions
and their Nomenclature. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
2.6.2. Ionization Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
2.6.3. Fragmentation of Structural Elements of Pyoverdins
and Related Siderophores . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
2.7. Synthetic Studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
2.8. Metal Complexes of Pyoverdins . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
2.8.1. Fe Complexes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
2.8.2. Ga3+ Complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
2.8.3. Cr3+ Complexes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
2.8.4. Other Metal Complexes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
2.9. The Three-Dimensional Structure of the Pyoverdin Complexes. . . . . . . 143
2.10. Pyoverdin-Mediated Iron Transport into the Bacterial Cell. . . . . . . . . . 144
2.11. Siderophores Related to the Pyoverdins . . . . . . . . . . . . . . . . . . . . . . . 151
2.11.1. 5,6-Dihydropyoverdins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
2.11.2. Ferribactins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152
2.11.3. Azotobacter and Azomonas Siderophores . . . . . . . . . . . . . . . . . 153
2.12. Biosynthesis of the Pyoverdins and Azotobactins. . . . . . . . . . . . . . . . . 156
2.13. Selected Pyoverdin Systems. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
2.13.1. Pseudomonas aeruginosa. . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
2.13.2. Pseudomonas tolaasii and Related Species. . . . . . . . . . . . . . . . 164
2.13.3. Pseudomonas syringae and Related Species. . . . . . . . . . . . . . . 166
2.13.4. Pseudomonas fluorescens G 173. . . . . . . . . . . . . . . . . . . . . . . 168
2.14. Corrected Structures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
2.14.1. Pyoverdin PAOlo . . . . . . . . . . .. . . . . . . .. . . . . . . . .. . . . . 171
2.14.2. Pseudobactins 7SRI and A225 . . . . . . . . . . . . . . . . . . . . . . . . 171
2.14.3. Pseudobactins A214 and ATCC 39167 . . . . . . . . . . . . . . . . . . 172
2.14.4. Pseudobactin WCS 358 and Pyoverdin
CFBP 2461 (Ll). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172
2.14.5. Pyoverdin CFBP 2392 (no. 15). . . . . . . . . . . . . . . . . . . . . . . . 174
2.14.6. Pyoverdin BTP7 (no. 32). . . . . . . . . . . . . . . . . . . . . . . . . . . . 174
2.14.7. Azotobactins (nos. 47, 48) and Azoverdin (no. 37). . . . . . . . . . 174
3. Other Siderophores of Fluorescent Pseudomonads . . . . . . . . . . . . . . . . . . . 17 5
3.1. Catecholate Siderophores . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
3.2. Lipopeptidic Siderophores. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176
3.2.1. Corrugatin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176
3.2.2. Ferrocins. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
3.3. Salicyclic Acid and Derived Siderophores. . . . . . . . . . . . . . . . . . . . . . 177
3.3.1. Salicylic Acid. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
3.3.2. Pseudomonine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
3.3.3. Pyochelin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178
3.3.4. Micacodicin and Related Siderophores . . . . . . . . . . . . . . . . . . . 183
3.4. Hydrogen Cyanide. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
Contents VII
3.5. Hydroxamate Siderophores . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
3.6. Foreign Siderophores . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186
3.7. Pyridine-2,6-di(monothiocarboxylic acid)
and Related Compounds (57) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187
3.8. Alkyl-4-hydroxyquinolines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190
3.9. Ferrorosamine (Pyrimine) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
4. Iron Sequestering. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
5. Pseudomonas and Health. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
6. Pseudomonas and Agriculture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 200
7. Pseudomonas and Environmental Problems. . . . . . . . . . . . . . . . . . . . . . . . 201
Notes Added in Proof. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202
Acknowledgements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202
Abbreviations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 203
Appendices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204
Bacterial Species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204
Bacterial Culture Collections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 204
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 205
Books, Chapters, and Review Articles. . . . . . . . . . . . . . . . . . . . . . . . . . . 205
Original Publications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205
Author Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239
SUbject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254
List of Contributors
Budzikiewicz, Prof. Dr. H., Institut fur Organische Chemie, Universitat zu Kiiln,
GreinstraBe 4, D-50939 Kiiln, Germany, e-mail: [email protected]
Flessner, Prof. Dr. T., Bayer HealthCare AG, Pharma Research, D-42096 Wuppertal,
Germany, e-mail: [email protected]
Jautelat, Dr. R., Medicinal Chemistry, Research Center Europe, Schering AG, D-13342
Berlin, Germany, e-mail: [email protected]
Scholz, Dr. U., Bayer Chemicals AG, Fine Chemicals, D-51368 Leverkusen, Germany,
e-mail: [email protected]
Winterfeldt, Prof. Dr. Dr. h. c. E., Institut fur Organische Chemie, UniversiHit Hannover,
D-30167 Hannover, Germany, e-mail: [email protected]
Cephalostatin Analogues - Synthesis
and Biological Activity
Timo Flessner!, Rolf Jautelat2, Ulrich Scholz3,
and Ekkehard Winterfeldt4
1 Pharma Research, Bayer HealthCare AG, Wuppertal, Gennany*
2 Medicinal Chemistry, Schering AG, Berlin, Gennany*
3 Central Research, Bayer Chemicals AG, Leverkusen, Gennany*
4Institut fiir Organische Chemie der Universitiit Hannover,
Hannover, Gennany
Contents
1. Introduction
2. Synthesis of Bissteroidal Pyrazines ............................. 15
2.1. Synthesis of Symmetrical Pyrazines and Subsequent
Desymmetrization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
2.2. Directed Synthesis of Unsymmetrical Pyrazines ................. 28
2.2.1. Nonacyclic Cephalostatin Analogues .................... 37
2.2.2. Dienes ......................................... 39
3. A-D-Ring Functionalization .................................. 42
3.1. Introduction of the Steroidal .6,14.15 -Bond ..................... 44
3.2. Chemical Modifications on the .6,14,15_ Double Bond ............. 56
4. The Spiroketal Area of CephaJostatins . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
5. Summary ............................................... 70
Acknowledgements .......................................... 74
References ................................................ 75
1. Introduction
The cephalostatin field started off with the seminal publication of
Pettit et ai. in 1988 describing structure and biological activity of
cephalostatin 1 (1) (84). Since then several reviews have covered the
activities regarding isolation, structure elucidation, biological activities,
and synthetic efforts up to 1995 (1, 2, 34-36, 54, 111). This account
will focus on the synthesis and biological activity of cephalostatin
analogues as published until early 2002. The authors understand the
*Current address.
2 T. Flessner et al.
purpose of this review to provide a complete overview of the
cephalostatinJritterazine analogue field. However, this article will in
parts be biased to describe some work of the Winterfeldt group in more
detail, based on the personal experience of the authors.
Natural products from a wide variety of sources have always played
an important role in medical treatment. Either these compounds or their
derivatives are employed as drugs or as starting points for diverging drug
discovery programs or as tools to investigate and elucidate novel targets
for the treatment of diseases. In this respect at least one third of the
currently available drugs are based on natural products or close
derivatives and numerous prominent "synthetic drugs" would have
not been found without natural products leading the way.
In 1955, the National Cancer Institute (NCI) started a large program
aimed at identifying novel compounds possessing anti-tumor effects.
Based on the excellent track record of natural products, a substantial part
of these efforts was directed towards natural products and only from
1955 to 1980 approximately 130000 extracts from plants and animals
were examined.
In 1974 extracts originating from the marine worm Cephalodiscus
gilchristi, which was collected from the bottom of the Indian Ocean
along the South-African coast in 1972, showed tumor inhibiting
properties in the in vivo P388 model of murine lymphozytic leukemia
(32-41% life time extension at 25-37.5mg/kg) (84), the standard NCI
model at that time.
The group of G. Pettit from Arizona State University proceeded with
further investigations and finally reported the identification, isolation,
and structural elucidation of cephalostatin 1 (1) in 1988 (84). This
compound was the major carrier of activity in the Cephalodiscus
gilchristi extracts. Cephalostatin 1 (1) compromises one of the most
potent tumor cell growth inhibiting agents ever tested at the NCI. Its
EDso in the in vitro P388 murine leukemia cell assay is outstandingly
low at around 0.1 pM and the GIso values in the NCI's in vitro 60 cell
line panel (NCI number of cephalostatin 1 (1) is: S363979, data
available on the Internet (117)) - which followed the in vivo P388 model
as the initial screening system of the NCI in the early 90's - are an
average of approx. 1 nM, making 1 approximately 25 times more potent
than the extraordinary strong cytostatic Taxol in this assay system (NCI
number: NSC125973, data available via Internet (117)).
During succeeding years the Pettit group was able to add cephalo
statins 2 to 19 to this novel class of compounds. These new cephalo
statins possessed varying biological activities, with most displaying
average GIso values in the NCI panel in the low nanomolar range (see
References, pp. 75-80
Cephalostatin Analogues 3
gS,P~12
.... N
o 12'
'x0,~" 0
~ W. 22.' Cephalostatin 1 (1)
23'OH
H -
"0
o
N ::"...
HI'" ~OO
HO
N'" OH
HO HO 0 OH
~.oo ~ OH Ritterazine B (2) OSW-1 (3) OO~~OM e
,\' -
Fig. 1. Biologically active bissteroidal pyrazines and the closely related OSW-l
Table 1 for detailed information), but none reached the potency of
cephalostatin 1 (1) (62, 85-87, 91-93, 96, 98). Based on this discovery
of the novel cephalostatins with outstanding biological activity the Pettit
group submitted several patent applications early on (88-90, 95).
In 1994 the group of Fusetani from the University of Tokyo added
the so-called ritterazines, e.g., ritterazine B (2), to the arsenal of
cephalostatins and bissteroidal pyrazines in general (27). The ritterazines
were isolated from the tunic ate Ritterella tokioka from the coastline of
Japan - therefore in a completely different phylum more than 5000 miles
away from the discovery point of the cephalostatins. Intrigeously similar
in molecular architecture, the ritterazines as well show tumor cell growth
inhibiting properties in vitro in the low nanomolar range in the NCI
panel-analogous to the cephalostatins (but in a reduced degree towards
P388 cells; see Table 1). To date 26 ritterazines have been reported by
the Fusetani group (27-33). Cephalostatins and ritterazines clearly
define a common class and are tightly interwoven. In fact, cephalostatin
7 and cephalostatin 16 on the one hand and ritterazine J, K, L, and M on
the other share the same steroidal moiety (South 7; see Table 1). This
leaves space for the assumption that a symbiotic microorganism may be
responsible for the production of such tightly related compounds with no