By David N. Leff
For ages, women have admired — and desired — coral as a pink-to-rose-red gemstone. Soon they may appreciate it as the source of a potent drug against ovarian cancer.
Besides their vividly beautiful calcium carbonate cytoskeletons, corals possess nematocysts — needle-tipped poison sacs surrounding their food-seeking tentacles. By injecting this nerve toxin into passing prey, they paralyze the creatures they intend to devour.
Almost like poetic justice, it appears that this venomous substance works against cancer by paralyzing the cytoskeletons of tumor cells.
Off Australia's northeastern coast lies the Great Barrier Reef, world-famous home to the world's largest coral concentration. At the diagonally opposite end of that island continent, the Bennett Shoal — roughly offshore from the southwestern city of Perth — also harbors congregations of coral.
Here in the early 1990s, marine biologist William Fenical collected specimens of a soft-coral species, which he identified as Eleutherobia. Fenical, who is at the Scripps Institution of Oceanography, in La Jolla, Calif., named the specimen's toxin eleutherobin.
He and his co-discoverers received U.S. patent No. 5,473,057 on Dec. 5, 1995, covering eleutherobin.
After preliminary tests of its anticancer potential with the Bristol-Myers Squibb Co., of New York, Fenical commented: "The stuff was so extraordinarily potent that it was dangerous to handle. You could dilute it a million-fold, and it still killed cells very powerfully."
Toxins Effect Similar To Taxol
He and his collaborators found that Eleutherobia's chemical weapon was killing tumor cells by a molecular mechanism similar to that deployed by Taxol, an anticancer product of forest yew trees rather than Indian Ocean coral. Taxol is marketed by Bristol-Myers.
Chemist K. C. Nicolaou, head of chemistry at the Scripps Research Institute, in La Jolla, explained that mechanism: "It involves the polymerization of tubulin to microtubules, which make up the cell's cytoskeleton, followed by stabilization of those microtubules. So during the cell division cycle," he added, "specifically during mitosis, the mitotic spindle cannot smoothly divide to give you two daughter cells. So the paralyzed tumor cell tumbles out of the cell cycle and dies without replicating."
A decade ago, far from Australia's Bennett Shoal, an Italian expedition had discovered in the Mediterranean Sea a different coral species, Sarcodictyon roseum, with toxins somewhat similar to eleutherobin. They named them sarcodictyins, but reported their anticancer activity only recently.
Because the quantity of both native compounds on hand was so exceedingly scanty, Nicolaou set out to synthesize the complex molecules in his laboratory, and thus generate a steady supply for investigators researching their activity as anticancer chemotherapeutic agents.
In its issue dated Nov. 15, 1997, the international German-language fortnightly journal Angewante Chemie (Applied Chemistry) published Nicolaou's report, in English and German versions, titled "Total synthesis of eleutherobin."
And today's issue of the weekly Journal of the American Chemical Society, dated Nov. 19, 1997, carries his paper on "Synthesis of the tricyclic core of eleutherobin and sarcodictyins and total synthesis of sarcodictyin A."
Nicolaou's point of departure was the structural, as well as functional, similarity between eleutherobin and Taxol. "When you look at this with a little bit of intuition," he told BioWorld Today, "one can actually see the similarities of this compound to Taxol. There's a lipophilic part in the structure, and a rigid scaffold as well as a side chain, all reminiscent features of the Taxol molecule."
For openers in the synthesis process, early this year, he and his co-authors took as starting material a common, inexpensive, food-industry oil, carvone by name. It's found in caraway and dill seeds, and used in flavoring, liqueurs, perfumery and soaps.
"When we looked at those two coral-derived molecules," Nicolaou said, "there's a part of their structure that reminded us of carvone. So we decided to pick up that product, and build up that segment of the eleutherobin that looked like carvone, and then elaborate that piece, and bring in the remaining building blocks — functionalities — to complete the molecular synthesis."
He continued: "Now we are excited that we have a synthetic entry into this class of compounds, and we're busy using combinatorial chemistry and other synthetic techniques, to produce a library of eleutherobin and sarcodictyin analogues for biological screening purposes."
Nicolaou went on: "The chemical synthesis will hopefully make the compounds in large quantities, to study their biological profiles in more detail, to determine whether they are going to be potential anticancer agents."
He describes this work as a continuum with his synthesis of epothilone, as reported last May. (See BioWorld Today, May 15, 1997, p. 1.) That product, he recalled, "was found in soil bacteria, and also behaved the same way as taxol from the forest, and eleutherobin and sarcodictyins from the ocean." It's now under development, he said, presumably including animal testing, by a pharmaceutical partner.
NCI Panel Shows '100-Fold Potency'
So far, Nicolaou recounted, "We have screened eleutherobin in ovarian tumor cell lines, and find it to be quite active."
Moreover, as his paper reports, "The tumor tissue selectivity of eleutherobin, determined in the National Cancer Institute's 60-cell panel, showed an approximate 100-fold increased potency [over the mean cytotoxicity] toward selected breast, renal, ovarian, and lung cancer cell lines."
It added that paclitaxel (the generic name for Taxol) had 84 percent similar tumor-type selectivity with eleutherobin.
After finishing the chemical synthesis "a month or so ago," Nicolaou is "currently making larger amounts of this compound, and we plan to test it for anticancer activity in animals, in collaboration with some of our partner companies."
He tempered his "excitement" with the sober caveat that "there is always risk of failure associated with any drug discovery and development program. What we can say for certain at these early stages of the research is that the new substances look very promising in killing cancer cells, and now we know how to make and fine-tune them in the laboratory for further biological investigation." *