Table of Contents Table of Contents
Previous Page  123 / 280 Next Page
Information
Show Menu
Previous Page 123 / 280 Next Page
Page Background

collaboration with top research groups worldwide, especially

from Japan, the US, France, the UK, Ireland and Portugal. This

research was funded by several European framework

programmes (Detectox, Biocop, Atlantox, microAqua, Spies-

Detox, Ciguatools, Beads).

Therapeutic potential

Due to the ample variety of mechanisms of action, the potential

damaging effect of marine toxins is rather complex: muscle

paralysis, neuron death, hepatotoxicity, diarrhoea, organ damage,

etc. But surprisingly, these same modes of action provide several

extremely interesting potential uses.

The most fascinating molecule by far is yessotoxin. This is a

polyether molecule of about 1,100 daltons with a complex

mechanism in which phosphodiesterase 4A seems to play an

important role in its apoptotic

effect.We

have found that

yessotoxin is active at the nanomolar level to inhibit the growth of

the majority of the US National Cancer Institute set of 60 tumour

cell lines; in addition this is effective in inhibiting the

in vivo

growth

of several tumour types induced in mice. Importantly, these

apoptotic effects are not observed in non-malignant cells.

What is surprising about yessotoxin is that we have also observed

an intense inhibitory effect of Alzheimer’s markers in triple

transgenic mutated mice with Alzheimer’s and an important

inhibitory effect of histamine release in rat mast cells (a marker of

allergy), a very significant genomic decrease of metabolic

markers, pointing at potential antidiabetic and

anticholesterolemic use (all these effects were covered by their

respective patents).

Although not with so many potential uses, we had also intellectual

property of the use of gambierol (a derivative of ciguatoxin) and

cyclic imines as anti-Alzheimer’s drugs. This research was funded

by the European projects Pharmatlantic, BAMMBO and the

ongoing PharmaSea.

Marine compounds

Even though marine toxins are many, the sea is a large reservoir of

pharmacological compounds, especially sponges, fungi and

bacteria.We

have explored some compounds, such as

crambescins and gracilins isolated from the sponge genera

Crambe

and

Spongionella

, respectively, or hymenialdisine and

hymenin from an axinellid sponge, from cyanobacterium,

autumnalamide from

Phormidium autumnale,

and

anhydroexfoliamycin and undecylprodigiosin from

Streptomyces

all of them show very promising effects as anti-Alzheimer’s

compounds and for neurodegenerative disorders such as

Parkinson’s disease and cerebral ischaemia, and some of them

as immunosupressors.

Clearly, the major limitation to the use of these compounds is

their chemical complexity, which means a challenge to organic

chemists, their scarcity for studies involving large amounts, and

the fact that intellectual property cannot be obtained as they are

natural marine compounds.

Therefore, our current occupation is to replace the natural

compound of interest to a therapeutic use with synthetic

analogues for which intellectual property can be issued. This

requires collaboration with strong organic chemistry groups as the

stereochemistry and the structures themselves are in many cases

affordable by only a few groups of international relevance.

The fact that marine compounds are privileged structures saves

plenty of time to guess which are the best ones, since the number

of possible stereoisomers is 2

99

for maitotoxin or 2

64

for palytoxin,

which illustrates the immense complexity of the chemistry of

marine compounds. Also, the rule of five described by Lipinski in

1997 does not often apply to many of these compounds.

Our conclusion is clear, the future of new pharmacological

compounds resides largely in an unexplored field: the oceans.

Dr Luis M Botana

Group Director

Department of Pharmacology

University of Santiago de Compostela

Campus of Lugo

Spain

te l :

+ 34 982 822 233

luis.botana@usc.es http://www.usc.es/es/investigacion/grupos/farmacoloxia_fi cotoxinas/ www.horizon2020projects.com

H O R I Z O N 2 0 2 0 P R O J E C T S : P O R TA L

I S S U E S E V E N

123

P R O F I L E

B I O T E C H N O L O G Y F O R H E A L T H

Fig. 3 Marine toxin research provides new enterprise opportunities as

a source of new knowledge