Nature's Chemical Weapons Save Lives

"Many marine organisms have developed chemical means to defend themselves. These chemical warfare agents continue to be useful lead compounds for cellular studies and drug development," said Daniel Romo, a synthetic organic chemist and associate professor in the Department of Chemistry at Texas A&M.

One of Romo's current research interests is structural, synthetic, and biomechanistic investigations of marine natural products displaying potent physiological effects.

One such compound, pateamine A, isolated from a marine sponge found off the shores of New Zealand, has been studied by Romo's group for seven years. Its novel structure and immunosuppressive activity drew the group's interest.

"Immunosuppressive compounds are used clinically for patients undergoing organ transplantation," Romo said. "Such compounds are given to moderate the activity of the immune system so that the body does not reject the organ."

Romo's group completed a total synthesis of Pateamine A in 1998, putting together this complex molecule bond by bond from simple and commercially available starting materials.

Since that time, Romo's group has been synthesizing derivatives of this natural product based on the published synthetic route. One set of derivatives will enable these chemists, in collaboration with biochemists, to find a potentially new cellular protein involved in the normal human immune response.

The hypothesis is that binding of pateamine A to this protein is the basis of its immunosuppressive effects. They also hope to find compounds that have increased chemical stability and potentially increased immunosuppressive activity.

This study has the potential to lead to the development of new immunosuppressive drugs. In fact, an invention disclosure was recently submitted describing pateamine A derivatives, and two pharmaceutical companies have inquired about licensing these compounds.

In the field of organic synthesis, Romo and other chemists construct larger molecules from much simpler ones by "stitching" together carbon-carbon, carbon-oxygen, and carbon-nitrogen bonds, etc. by chemical reactions.

The group selects naturally occurring organic compounds that exhibit valuable biological and/or therapeutic properties-immunosuppressive, neurotoxic, and anti-cancer-as targets for total synthesis.

This objective may require using organic synthesis to elucidate the structure of the natural product, which includes the number and mode of attachment of the various atoms in the compound.

Once the structure of the compound is known, researchers can then focus their studies on developing a way to synthesize these compounds from simple organic building blocks in a concise and economical fashion.

This becomes especially important for organic compounds derived from non-readily renewable resources such as marine sponges especially when they are produced by the organism in small quantities as is often the case.

"One milestone in this type of research is to synthesize the natural product from small building blocks," Romo said. " However, research does not end there but rather this non-trivial accomplishment opens opportunities to begin studying why these compounds are immunosuppressive, toxic, anti-cancer, antibacterial, etc."

After developing a synthesis of the natural product, Romo collaborates with biologists and biochemists to uncover how and why these organic compounds exert these biological activities.

"This is an iterative process since a synthesized compound may have a slight variation from the natural product," Romo said. "The biological activity of the derivative guides us to synthesize yet another derivative to answer another question regarding structure and activity of the compounds."

Romo said that many natural marine compounds have the potential to shed light on the still relatively poorly understood inner workings of human, bacterial, fungal, and tumor cells.

"This has important implications for our continued fight against many human ailments," Romo said, "because the more we know about how cells work, the better we will be equipped in controlling the activity and function of those cells."