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FACS
Newsletter 2/2001
Recent Research Progress of FACS
Young Chemist Awardee
The Synthesis of Potential
Chemotherapeutic
Agents Based on Leads from Nature
Margaret A. Brimble
Department of Chemistry
The University of Auckland, 23 Symonds St.
Auckland, New Zealand
Email:m.brimble@auckland.ac.nz |
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Natural products have long been regarded as ¡°Nature¡¯s medicine chest¡±
providing a rich source of lead compounds to synthesize for pharmaceutical
development. Natural product synthesis has also been described as an ¡®enabling science¡¯
because
it provides unlimited opportunity for discovery at the interface with biology and
medicine. Our research in synthetic organic chemistry and medicinal chemistry focuses on
making and modifying naturally occurring bioactive compounds that have been isolated from
plants, animal tissue, microbes or marine and soil organisms, which are rare or hard to
isolate in abundance. These compounds provide rich and diverse chemical structures that
challenge the synthetic chemist to develop new synthetic methodology for the construction
of the novel and diverse heterocyclic arrays which they contain.
Over the last decade our research group in Australasia has focused on
the development of flexible synthetic approaches to several natural products which have
important biological activity. The synthesis of the molecules described in detail below
has also allowed the preparation of synthetic analogues of the natural compound which may
lead to improvements in biological activity and an understanding of the way the naturally
occurring compounds act.
SYNTHESIS OF PYRANONAPHTHOQUINONE
ANTIBIOTICS
The pyranonaphthoquinone family of antibiotics, of
which one of the simplest members is kalafungin, exhibits inhibitory activity against a
variety of pathogenic fungi, yeast and gram-positive bacteria. Another property of these
compounds is their ability to act as bioreductive DNA alkylating agents via quinone
methide intermediates thereby resulting in cross-linking of DNA strands. These alkylated
DNA adducts then interfere with the cell replication process. This concept of bioreductive
alkylation offers an exciting mechanism of drug action for the development of new
antineoplastic agents based on the pyranonaphthoquinone skeleton.
Our research group has developed an efficient synthesis of
several simpler members of pyranonaphthoquinone antibiotics as well as the
spiroacetal-containing pyranonaphthoquinone, griseusin A, and the C-glycosidic
pyranonaphthoquinone, medermycin, which exhibits antileukaemia activity. The first
efficient synthesis of a dimeric pyranonaphthoquinone similar to the antiviral agent,
crisamycin, has also been successfully executed using our synthetic strategy.
SYNTHESIS OF NATURAL PRODUCTS CONTAINING
BIS-SPIROACETAL RING SYSTEMS
| The polyether antibiotics salinomycin and
CP44,161 exhibit antimicrobial activity against gram-positive bacteria, mycobacteria and
fungi. They also play an important role in veterinary medicine as growth promotants in
ruminants. The characteristic property of these polyether antibiotics is their ability to
act as ionophores and conduct ions across membranes. |
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The main structural feature of these polyether
antibiotics is the presence of the bis-spiroacetal ring system. Our synthetic approach2
to the bis-spiroacetal ring systems of epi-17-deoxy-(O-8)-salinomycin and
antibiotic CP44,161 hinged on the use of a key oxidative cyclization of a
hydroxyspiroacetal to a bis-spiroacetal. Our work in this area has culminated in the
synthesis of an isomer of the tetracyclic BCDE moiety of the polyether antibiotic,
CP44,161.
¡¡ ¡¡ |
During
chemical investigations of polar bioactive molecules from microalgae and shellfish, two
lipid-soluble macrocycles, spirolides B and D, were isolated from the digestive glands of
both mussels (Mytilus edulis) and scallops (Placopecten magellanicus).
These macrocycles contain a novel bis-spiroacetal ring system and an unusual
seven-membered spiro-linked cyclic iminium moiety. They cause potent and characteristic
symptoms in the mouse bioassay and were found to be weak activators of type L calcium
channels. The spirolides are therefore useful lead compounds for the development of new
therapeutic agents to treat cardiovascular disorders such as hypertension.
We have recently completed the
synthesis of the bis-spiraocetal moiety of the spirolides using an iterative oxidative
cyclization to construct this key ring system. |
SYNTHESIS OF THE ANTIFUNGAL AGENTS THE
PAPULACANDINS
| The
papulacandins are a group of aryl-C-glycosyl spiroacetal antifungal agents isolated
from Papularia spherosperma which exhibit potent in vitro activity against Candida
albicans and Pneumoocystis carinii pneumonia, the common opportunistic
infection in AIDS patients. We have therefore been involved with the synthesis of
analogues of the papulacandins in order to provide a better understanding of the
structural elements responsible for the potent antifungal activity exhibited by this
family of antibiotics. |
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SYNTHESIS OF THE HUMAN RHINOVIRUS 3C
PROTEASE INHIBITOR THYSANONE
 |
The replication of many
animal and plant viruses relies on proteolytic processing and is dependent upon two
virally encoded enzymes, 3C-protease and 2A-protease. Human rhinoviruses are responsible
for causing common colds in humans, therefore, 3C-protease and
2A-protease are attractive targets for the development of antiviral chemotherapeutic
agents for eventual control / cure of the common cold. Thysanone, isolated from Thysanophora
penicilloides, is one of few effective inhibitors of human rhinovirus 3C-protease. We
have therefore engaged in the synthesis of thysanone in order to provide lead compounds
for understanding the mechanism of 3C-protease inhibition. |
SYNTHESIS OF ANTI-HELICOBACTER PYLORI
AGENT CJ-12,954
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Recent studies have
shown a relationship between gastric and duodenal ulcers and the presence of the
microaerophilic spiral-shaped Gram negative bacterium Helicobacter pylori which is
present in the mucus layer of the stomach. The natural product CJ-12,954 produced by Phanerochaete
velutina, exhibits potent activity against Helicobacter pylori and is therefore
a lead compound for the treatment of ulcers in humans. Recent research has been directed
towards the first synthesis of CJ-12,954 and analogues thereof, in order to provide novel
antiulcer agents. |
SYNTHESIS OF LIGANDS FOR NICOTINIC
ACETYLCHOLINE RECEPTORS BASED ON METHYLLYCACONITINE
 |
Methyllycaconitine
(MLA) is the principal insecticidal toxin isolated from the cattle-stock poison
Delphinium brownii. MLA is a potent inhibitor of ?-bungarotoxin nicotinic acetylcholine receptor (nAChR) binding in mammalian
and insect neural membranes. At
this subset of nAChR, methyllycaconitine is the most potent small molecule antagonist yet
reported. Methyllycaconitine is therefore a valuable neurobiological tool for the study of
the comparative pharmacology of nicotinic acetylcholine receptors and is a lead compound
for the treatment of Alzheimer¡¯s disease.
The synthesis of simpler tricyclic ABE analogues of methyllycaconitine
has been undertaken such that the pharmacological properties of these simpler analogues
can be evaluated.
This area of research is a collaborative project with Dr Malcolm McLeod at the
University of Sydney and Dr Paul Savage at CSIRO, Division of Molecular Science,
Melbourne. |
References
1. M. A. Brimble,¡°Synthetic Strategies Towards Pyranonaphthoquinone Antibiotics,¡±Pure and Applied Chem.,2000, 72,
1635-1639.
2. M. A. Brimble, ¡°Synthetic
Studies Towards Natural Products Containing Bis-spiroacetals.¡±J. Heterocyclic Chem., 1999,36,1373-1389.
Awardee curriculum vitae
Margaret Anne Brimble graduated from University of Southampton of United Kingdom in 1985 majoring in chemistry. She is currently Proffesor and Chair of Organic Chemistry Deoartment of University of Auckland, New Zealand. Her professional affiliations include Royal Australian Chemical Institute, New Zealand Institute of Chemistry, Royal Society of Chemistry, Internaitonal Society of Heterocyclic Chemistry and New Zealand Association of Womenin Science. Her research inetrests include organic synthesis, asymmetric synthesis and the synthesis of biologically active molecules, such as herbacides, insect antifeedants, insecticides, polyether antiotics, DNA binding agents, topoisomerase inhibitors and crown ethers based on spiroacetals. She has won many prizes and awards in the past including Prince and Princess of Wales Science Award by Royal Society of New Zealand in 1992.
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