HOME>CSJ Awards 2005

Bioorganic Studies on Marine Natural Products

Posted: Sep. 11, 2014

Award Recipient: Prof. Daisuke Uemura Graduate School of Science, Nagoya University

Dr. Daisuke Uemura has performed pioneering work on bioactive substances derived from marine organisms, and has found many important natural products. The discovery of a new bioactive compound often leads to dramatic breakthroughs in related scientific fields. To realize such a discovery, it is vital to set an objective and to study the molecular structure using state-of-the-art separation and analytical techniques. In addition, research must be performed while taking future applications into consideration without being satisfied with only a structural study. Dr. Uemura's studies are good examples of this approach.

His work can be outlined as follows:

1) Palytoxin, a super-carbon-chain compound
Palytoxin is a huge molecule with a molecular weight of about 3300 that was isolated by P. J. Sheuer and others in 1971. Its structural determination presented many difficulties. Dr. Uemura elucidated its planar structure in 1981 by repeatedly carrying out site-specific oxidative degradation and determined the structure of the degraded products using a sample that was originally isolated from Palythoa tuberculosa of Okinawa origin. He also elucidated the complete stereostructure in 1982. Furthermore, he determined that palytoxin exhibits extremely strong toxicity by bonding to Na+, K+-ATPase and opening the ion channel.

2) Halichondrins, remarkable antitumor macrolides
Dr. Uemura considered the sponge to be a condensed body of marine microorganisms, and used it as the focus for searching for distinctive compounds. Halichondrin B is a highly important compound in terms of antitumor activity. It exhibited excellent results in animal tests, such as a high life-prolonging rate, and can be administered via different routes, such as intravenously. Although structural studies have been carried out mainly using its analogue norhalichondrin A, the structure was finally determined based on X-ray crystallography of the p-bromophenacyl ester. Its potential practical application as an anticancer agent is being studied by drug manufacturers, and a halichondrin derivative is currently in the last phase of clinical testing.

3) Pinnatoxin, a shellfish poison
Food poisoning caused by the sea shell Atrina(Pinna) pectinata japonica often occurs in the vicinity of the Ariake Sea. The precise cause of this poisoning was unclear for some time. Dr. Uemura noted that a Chinese government agency had announced that the viscera of Pinna attenuata should not be eaten. He discovered pinnatoxin, which is a strong Ca2+ channel activator, by refining the extract of the viscera of the Okinawan mollusk P. muricata, which is related to A. pectinata japonica and P. attenuata, and monitoring the acute toxicity. Pinnatoxin is characterized by a unique amphoteric polyether carbocycle, and its toxicity corresponds to that of the globefish poison tetrodotoxin. Furthermore, he theorized a biosynthetic pathway which included the Diels-Alder reaction for the azaspiro framework. In addition, he found an extremely small amount of petriatoxins, which showed strong acute toxicity toward mice, in the viscera of a different kind of bivalve. He elucidated that these compounds possessed the same basic structure as pinnatoxins, and the results strongly suggested that the symbiotic algae could be the true producers of these compounds.

4) Bioactive alkaloids of marine organism origin
Norzoanthamine is a kind of alkaloid extracted from the Zoanthus sp. of Amami Oshima origin. He found that this compound had depressive effects during the production of IL6 using an in vitro test, and administered this compound orally to a spayed mouse. As a result, the weight and strength of the femur remarkably increased, and this finding may lead to the development of a treatment for osteoporosis. Moreover, he discovered pinnaic acid and halichlorine, which have a unique spiro structure, during the search for another alkaloid. While these compounds were obtained from completely different kinds of samples, they have the same basic framework. He expected that the true producer was a symbiont, as in the case of pinnatoxin. Taking this opportunity, he began serious studies on the symbiosis of algae products, and discovered a new compound, symbioimine, which suppresses the differentiation of osteoclasts. It has been realized as a compound that may be suitable for the treatment of osteoporosis.

5) Discovery of natural products by focusing on ecosystem dynamism
Recently, in the search for bioactive substances, "rational" molecular design using computers and "exhaustive" development by so-called combinatorial chemistry have become fairly common due to the rapid growth of molecular biology and the computational sciences. Dr. Uemura has described the importance of "unpredictability", which is liable to be forgotten when these techniques are used. His attitude regarding the need for a better understanding of the virtues of diversity in natural products and the need for a premium on perspicacity based on careful observations and experience in the field has led to many opportunities in the field of natural product chemistry in our country. For instance, he considered a finding in Okinawa that the crown of thorns starfish swarm around the viscera of Toxopneustes pileolus, and clarified that arachidonic acid and α-linolenic acid can be used to bait the crown of thorns starfish, which damages coral. An attraction-capture experiment was actually carried out off the coast of the main Okinawa island, and the efficacy of this approach was confirmed. Similarly, he identified an attractant for Drupella, which causes serious damage to coral, and suggested the possibility of a new method of extermination to replace human-wave tactics. Moreover, he discovered a new compound, nakiterpiosin, which exhibits cellular toxicity, by considering the relation between live coral and the black sponge which grows on the coral.

As described above, Dr. Uemura has performed pioneering studies on natural bioactive substances, and has made many world-renowned achievements, in the study of organic chemistry concerning marine natural products. The outstanding results of his many studies are highly praised both at home and abroad. Consequently, his achievements deserve recognition in the form of The Chemical Society of Japan Award.