Bioactive Agents from Natural Sources: Trends in Discovery and Application - Advances in Biochemical Engineering Biotechnology - page 116

profiling and clinical testing are missing. Focus on marine biotechnology is
actually forced by results indicating that marine microorganisms are substanti-
ally involved in the biosynthesis of marine natural products isolated from
collected macroorganisms such as invertebrates.
It remains open whether marine natural products will play an important role
in drug discovery and development in future.Today,toxic principles dominate
the spectrum of biologically active metabolites isolated from marine sources.
This fact may partly be due to the major application of cytotoxicity-directed
screening assays. However, it has to be considered that defence strategies are
necessary to survive in the highly competitive marine environment thus resul-
ting in a tremendous diversity of highly toxic compounds affecting numerous
targets involved in eukaryotic cell signaling processes.
The extreme toxic potential ofmarine metabolites often prevents their appli-
cation in medicine. However, a number of metabolites proved to be valuable
tools in biochemistry, cell and molecular biology. For instance the neurotoxic
maitotoxin [109-112] (interaction with extracellular calcium; enhancement of
calcium influx [113]), the neurotoxic brevetoxin B [114] (interaction with the
binding-site-5 of voltage-sensitive sodium channels [115]), tetrodotoxin and
saxitoxin (voltage clamp analysis to study sodium channels and excitatory
phenomena [116]; tetrodotoxin abolishes brevetoxin B activity [117]),okadaic
acid [118-120] (analysis of phosphorylation and dephosphorylation processes
in eukaryotic cell metabolism [121]),and palytoxin (stimulation of arachidonic
acid metabolism synergistically with TPA-type promoters [122]).
Various other marine natural products exhibit considerable toxic potency
which actually gives hope to clinical use mainly in anticancer therapy:
i) Didemnin B,isolated from the ascidian Trididemnum solidum ,was the first
marine metabolite which reached human clinical trials. To provide suf-
ficient quantities total synthesis ofthe depsipeptide had to be realized [123].
The didemnins exhibit anticancer as well as antiviral and immunosuppres-
sant activities by inhibiting protein biosynthesis without interacting with
the DNA,and independent of the cell cycle [124,125].
ii) The bryostatins isolated from the bryozoan Bugula neritina [126] affect pro-
tein kinase C at picomolar concentrations [127,128].At present,the poten-
tial use of bryostatin 1 in anticancer treatment is studied in clinical trials.
Multi-gram quantities have been made accessible following current good
manufacturing practices (cGMP) [129].
iii) The alkaloid type ecteinascidin 743 which first has been isolated by
Rinehart and coworkers from the mangrove associated ascidian Ecteinasci-
dia turbinata [130] expresses potent broad spectrum cytotoxic properties
by reacting with a guanine rich site in the DNA's minor groove [131].Clini-
cal studies sponsored by the company PharmaMar are currently underway.
However,clinical studies on marine metabolites are often hampered by insuffi-
cient supply of material,as it was reported for dolastatin 10 from the sea hare
Dolabella auricularia [107].In the case of manoalide,obtained from the sponge
Luffariella variabilis , it remains open whether its use will be restricted to an
application in studying inflammatory processes on the cell level or whether it