Drugs from the depths of the ocean

[Guest guest]

Drugs from the depths of the ocean

02 Jun 2005

For Tadeusz Molinski, the sea is full of riches -- and he does not mean

oil fields or fisheries. Molinski, a professor of chemistry at the

University of California, , is searching for new treatments for

cancer, infectious diseases and other conditions that could be made

from natural products in the soft bodies of some of the ocean's

simplest inhabitants.

" Three quarters of the world is covered by oceans, and we've only

dipped below the surface, " Molinski said.

This chemist sees natural products from marine organisms as an

opportunity to answer questions in biology and find potential leads for

the next generation of drugs, whether those are anti-fungals or

treatments for cancer. Many pharmaceutical drugs on the market, from

aspirin to cholesterol-lowering " statins, " are derived from natural

products such as plants or bacteria. Molinski says modern developments

in analytical chemistry, including highly sensitive instrumentation,

sophisticated screening capabilities and discoveries from mapping the

human genome, have created a renaissance of interest in these sources

of potential medicines.

Molinski's laboratory studies the chemistry and biology of marine

natural products, or chemical compounds made by sea creatures. It is

part of a developing focus on pharmaceutical chemistry within the UC

chemistry department, including research on biologically active

molecules and high-throughput screening techniques.

Most of Molinski's samples come from sponges and tunicates, marine

creatures that can neither swim away from a diver nor bite. Recently,

the researchers have also begun to collect samples from cyanobacteria,

single-celled organisms that occur as slimy mats or filaments in places

such as coral reefs and mangrove lagoons.

Some of these compounds have biochemical activities that could be

useful in medicine -- killing microbes, stopping growth of cancer

cells, or affecting the flow of calcium in and out of cells.

Marine natural products are an eclectic mix of chemical types, drawing

on all the pathways of metabolism, Molinski said. Some are related to

fats and proteins; others include elements such as bromine, sometimes

bonded into improbable structures.

" It's a rich, complex and edited chemical library, " Molinski said.

" They're really fascinating little jewels made by niche creatures. "

As well as being largely unexplored, the chemistry of these marine

organisms is very different than that of land plants and animals,

reflecting both a different environment and millions of years of

separate evolution. That should make it harder for microbes to evolve

resistance to such drugs, as they are being attacked from a completely

different direction.

Molinski, a certified diver, and his graduate students make regular

collecting trips to study sites in Micronesia, Western Australia and --

using a seagoing vessel, the R/V Seward based in Florida -- the

Atlantic Ocean around the Bahamas. Warm tropical waters support a wider

variety of sponges, making them richer prospecting grounds.

Back in the lab, the scientists put extracts from the animals they have

collected through a battery of tests. If they find something with

interesting properties, the researchers attempt to isolate and identify

the molecule.

The next step is to start from conventional chemistry and make the

compound in the lab, then try to find the simplest structure with the

same properties. This work can pull in techniques from different areas

of chemistry and biochemistry, but the pathways used to make these

products naturally are far too complex to reproduce with current

genetic engineering techniques, Molinski said.

One of their finds is phorboxazole, made by an Indian Ocean sponge

collected by Molinski's team off the coast of Western Australia.

Phorboxazole A is a potent toxin that in the laboratory, can inhibit

the growth of a wide range of tumor cell types even at very low

concentrations. It appears to block cancer cells from dividing at a

different, earlier step than that targeted by other clinically

important anticancer drugs.

" It uses a different mechanism to any known drug, it's unlike anything

else, " Molinski said.

Chemists are now investigating phorboxazole and related compounds to

see if they can be made more efficiently.

" It's excited a lot of chemists and cancer biologists, " Molinski said.

Molinski's group has also gone fishing for drugs that modulate calcium

channels within cells, in collaboration with Isaac Pessah, professor

and director of the Center for Children's Environmental Health at the

UC School of Veterinary Medicine. The controlled release of

calcium is a key step in many cellular processes.

" In any cell you can think of, calcium plays a role in shaping

responses, activating or inhibiting enzymes, changing the shape of the

cell, triggering cell division, " Pessah said. Calcium is also a key

signal in both fertilization and programmed cell death, he said.

Pharmaceuticals that affect calcium channels range from drugs given to

organ transplant patients to suppress the immune system, to treatments

for high blood pressure and heart disease.

Pessah's research group works with calcium channel modulators and other

biomolecules derived from plants and scorpion venom. But when Pessah

and Molinski got to talking at a party some years ago, they quickly

realized that they could apply the same methods to screen 124 sponges

that Molinski's group had recently collected off the coast of Western

Australia.

In one of the samples they came up with xestospongin C, the first of a

class of drugs now widely used in research studies on calcium

transport. Xestospongins block the ability of a signaling molecule

called inositol 1,4,5 trisphosphate (IP3) to trigger the release of

calcium within cells.

In most cases, scientists do not know why marine organisms make these

compounds, Molinski said. As much as five percent of the animal may be

made up of one compound -- a big investment of energy and resources.

Chemical ecology is the field of research that explores how natural

products serve the organisms that produce or harbor them. The compounds

could be chemical defenses to deter predators. For example, some fish

" taste " food items before swallowing them, sometimes spitting the item

out and sucking it back in several times before rejecting or eating it.

Some could be natural anti-fouling agents that stop a creature that

does not move, like a sponge, from being overgrown with other sea life.

Others might be released into the seawater as pheromones to encourage

larvae to join an existing colony, or to attract a mate.

Molinski's group is collaborating with Jay Stachowicz, assistant

professor in the UC Section of Evolution and Ecology and his

graduate student, Amy Larson, at the Bodega Marine Laboratory, and with

Joe Pawlik, a professor at the University of North Carolina at

Wilmington, to address some of these questions.

Discovering natural products is a great training tool because it

requires skills in all areas of chemistry and a wide view of allied

disciplines, Molinski said.

" It's like a crossword puzzle where you have to find the clues, " he

said. " Natural products engage your intellectual curiosity with a sense

of wonder that comes from standing at the shores of new worlds. "