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JOSÉ CARLOS MENÉNDEZ AN. R. ACAD. NAC. FARM.
entities. Thus, only about 11,000 marine natural products are known, in contrast
to more than 155,000 terrestrial compounds. In this talk, after a schematic review
of the main marine antitumour compounds and their mechanisms of action, the
pyridoacridines and tryprostatins are discussed in more detail. The mechanisms of
antitumour activity are also briefly reviewed including angiogenesis inhibition,
apoptosis induction, interruption of the cell cycle at several stages, DNA fragmen-
tation through the generation of reactive oxygen species, inhibition of DNA-related
enzymes (topoisomerases, polymerases, transcription factors), interaction with
tubulin and microtubules and lysosome membrane depolarization. Finally, some
routes for the synthesis of the pyridoacridines and the tryprostatins are discussed.
Key words: Antitumour compounds.—Marine compounds.—Pyridoacridines.—
Tryprostatins.—Organic synthesis.
EXTENDED SUMMARY
New marine antitumour compounds
Although oceans cover about 70% of the Earth’s surface and contain most of
the biosphere, they are almost unexplored regarding the search for new chemical
entities. Thus, only about 11,000 marine natural products are known, in contrast
to more than 155,000 terrestrial compounds.
About 70% of the marine organisms that have yielded natural products belong
to five phylla, namely Porifera, Mollusca, Cnidaria, Echinodermata and Tunicata.
They are normally very primitive organisms that use bioactive secondary
metabolites as an environmental adaptation mechanism and, because they often
inhabit unique ecological niches, can be expected to produce structurally unique
compounds, among which ecteinascidin-743 (trabectedin), aplidin, bryostatin, the
dolastatins, kahalalide F and discodermolide, are currently undergoing clinical
evaluation. Their mechanisms of action are very varied, and include angiogenesis
inhibition, apoptosis induction, interruption of the cell cycle at several stages, DNA
fragmentation through the generation of reactive oxygen species, inhibition of
DNA-related enzymes (topoisomerases, polymerases, transcription factors),
interaction with tubulin and microtubules and lysosome membrane depolarization.
Pyridoacridines are a group of strongly coloured, polycyclic alkaloids isolated
from marine organisms, with potent cytotoxic activities. Their mechanism of action
is not completely understood, although topoisomerase II inhibition, apoptosis
induction and oxygen radical generation have been proved to take place in the case
of ascididemin. Pyridoacridines are obtained in tiny amounts from their natural
sources because they are not easily accesible and also because they produce very
low concentrations of the alkaloids. This has stimulated their preparation by total
synthesis, and strategies based on the use of hetero Diels-Alder, Suzuki and
Friedländer reactions as the key steps are discussed. Finally, a route is described
for the total synthesis of tryprostatin B, a cell cycle inhibitor isolated from a
marine fungal strain, based on the tandem prenylation-cyclization of a 2,5-
piperazinedione precursor followed by rearrangement of the prenyl chain.
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