science/technology TOTAL SYNTHESIS OF SEA COMPOUNDS Researchers accomplish first syntheses of eleutherobin and sarcodictyin, complex cytotoxic agents derived from sea corals StuBorman C&EN Washington R esearchers at Scripps Research Insti- tute, La Jolla, Calif., have achieved the first total synthesis of eleuthe- robin, a promising anticancer agent ob- tained from a Pacific sea coral, and have determined the compound's absolute ste- reochemical structure [Angew. Chem. Intl. Ed. Eng. f 36, 2520 (1997)]. They also have accomplished the first total synthesis of sarcodictyin A, a compound from a Mediterranean coral \J. Am. Chem. Soc, 119, 11353 (1997)]. Sarcodictyin bears a close structural resemblance to eleuthero- bin and also has shown cytotoxic activity. The syntheses were carried out in less than six months by chemistry professor K. C. Nicolaou and coworkers at Scripps and at the University of California, San Diego. The members of Nicolaou's syn- thetic team included postdoctoral fel- lows Jinyou Xu, Floris van Delft, Takashi Ohshima, Sanghee Kim, Seijiro Hosoka- wa, Dionisios Vourioumis, and Tianhu Li, and graduate student Jeffrey Pfefferkom. Eleutherobin and the sarcodictyins share the mechanism of action of Bristol- Myers Squibb's commercial anticancer agent Taxol. Eleutherobin is more potent than the sarcodictyins and therefore of greater immediate interest. The eleuthe- robin synthesis solves the problem of ob- taining adequate supplies of the rare natu- ral compound for testing and potential therapeutic use, and both syntheses will facilitate the creation of analogs for biolog- ical screening purposes. Eleutherobin was isolated in 1994 from a member of the Eleutherobia fami- ly of corals by William Fenical, director of the Center for Marine Biotechnology & Biomedicine at Scripps Institution of Oceanography, also in La Jolla, and co- workers. The researchers obtained the rare coral from a shallow area called Ben- nett's Shoal, which is located in the Indi- an Ocean off the coast of Australia. When Fenical's postdoc, Thomas Lin- del, extracted eleutherobin from the cor- al and tested the compound in a bioassay for cytotoxicity, he was surprised at the unusually high level of activity it exhibit- ed. It had similar potency to that of Tax- ol, which is derived from yew trees. "Eleutherobin is Taxol's counterpart from the oceans," says Nicolaou. "It's a very scarce substance." Eleutherobia cor- als are rare, but even if they can be locat- ed, he says, "one has to be concerned about potential damage to marine life by massive coral collection." Fenical and coworkers initially ob- tained "only about 10 mg of eleuthero- bin—the world supply for the last three years—so it wasn't possible for anyone to do much biology with it," says Nico- laou. "Chemical synthesis comes to the rescue now. They're very excited that we can make it synthetically, so its biolo- gy can be studied and its true potential as an anticancer agent can be determined." Reprinted with permission from "Tropical Pacific Invertebrates," Coral Reef Press, Beverly Hills, Calif. Two species of Eleutherobia corals, the family from which eleutherobin was obtained. Using a range of analytical techniques, including column and high-performance liquid chromatography, mass spectrome- try, UV spectroscopy, and nuclear mag- netic resonance spectroscopy, Fenical, Iindel, and researcher Paul R. Jensen pu- rified eleutherobin and determined its structure, except for its absolute stereo- chemical configuration \J. Am. Chem. Soc, 119, 8744 (1997)]. Research scientists Byron H. Long, Anna Maria Casazza, Joan Carboni, and Craig R. Fairchild in the Oncology Drug Scripps Research Institute eleutherobin and sarcodictyin team consists of Nicolaou (seated), and (from left) Li, Hosokawa, Xu, Pfefferkom, Vourioumis, Kim, van Delft, and (inset) Ohshima. 64 NOVEMBER 24 1997 C&EN
Transcript
s c i e n c e / t e c h n o l o g y
TOTAL SYNTHESIS OF SEA COMPOUNDS Researchers accomplish first syntheses of eleutherobin and sarcodictyin, complex cytotoxic agents derived from sea corals
StuBorman C&EN Washington
R esearchers at Scripps Research Institute, La Jolla, Calif., have achieved the first total synthesis of eleuthe
robin, a promising anticancer agent obtained from a Pacific sea coral, and have determined the compound's absolute stereochemical structure [Angew. Chem. Intl. Ed. Eng.f 36, 2520 (1997)]. They also have accomplished the first total synthesis of sarcodictyin A, a compound from a Mediterranean coral \J. Am. Chem. Soc, 119, 11353 (1997)]. Sarcodictyin bears a close structural resemblance to eleutherobin and also has shown cytotoxic activity.
The syntheses were carried out in less than six months by chemistry professor K. C. Nicolaou and coworkers at Scripps and at the University of California, San Diego. The members of Nicolaou's synthetic team included postdoctoral fellows Jinyou Xu, Floris van Delft, Takashi Ohshima, Sanghee Kim, Seijiro Hosokawa, Dionisios Vourioumis, and Tianhu Li, and graduate student Jeffrey Pfefferkom.
Eleutherobin and the sarcodictyins share the mechanism of action of Bristol-Myers Squibb's commercial anticancer agent Taxol. Eleutherobin is more potent than the sarcodictyins and therefore of greater immediate interest. The eleutherobin synthesis solves the problem of obtaining adequate supplies of the rare natural compound for testing and potential therapeutic use, and both syntheses will facilitate the creation of analogs for biological screening purposes.
Eleutherobin was isolated in 1994 from a member of the Eleutherobia family of corals by William Fenical, director of the Center for Marine Biotechnology & Biomedicine at Scripps Institution of Oceanography, also in La Jolla, and coworkers. The researchers obtained the rare coral from a shallow area called Bennett's Shoal, which is located in the Indian Ocean off the coast of Australia.
When Fenical's postdoc, Thomas Lin-del, extracted eleutherobin from the coral and tested the compound in a bioassay for cytotoxicity, he was surprised at the unusually high level of activity it exhibited. It had similar potency to that of Taxol, which is derived from yew trees.
"Eleutherobin is Taxol's counterpart from the oceans," says Nicolaou. "It's a very scarce substance." Eleutherobia corals are rare, but even if they can be located, he says, "one has to be concerned about potential damage to marine life by massive coral collection."
Fenical and coworkers initially obtained "only about 10 mg of eleutherobin—the world supply for the last three years—so it wasn't possible for anyone to do much biology with it," says Nicolaou. "Chemical synthesis comes to the rescue now. They're very excited that we can make it synthetically, so its biology can be studied and its true potential as an anticancer agent can be determined."
Reprinted with permission from "Tropical Pacific Invertebrates," Coral Reef Press, Beverly Hills, Calif.
Two species of Eleutherobia corals, the family from which eleutherobin was obtained.
Using a range of analytical techniques, including column and high-performance liquid chromatography, mass spectrometry, UV spectroscopy, and nuclear magnetic resonance spectroscopy, Fenical, Iindel, and researcher Paul R. Jensen purified eleutherobin and determined its structure, except for its absolute stereochemical configuration \J. Am. Chem. Soc, 119, 8744 (1997)].
Research scientists Byron H. Long, Anna Maria Casazza, Joan Carboni, and Craig R. Fairchild in the Oncology Drug
Scripps Research Institute eleutherobin and sarcodictyin team consists of Nicolaou (seated), and (from left) Li, Hosokawa, Xu, Pfefferkom, Vourioumis, Kim, van Delft, and (inset) Ohshima.
6 4 NOVEMBER 24 1997 C&EN
Key step in eleutherobin synthesis is hydrogenation and ring closure oc
.1 OTBS H3C
9C(NH)CCI3
OPMB OTES
' 2 & T E S TBSO ° ^ b o h y d r a t e
.OTES H3?H 79H^
Glycosylation
(+)-Carvone
H3C CH3
Hydroxyaldehyde
Ring closure
H3C CH3 OTBS
Glycosyl acetylenic OTBS aldehyde
H3C OTES
5 ,>CH3
0 T E S Oxidation and elaboration
H,C
H3C CH3
10-Membered cyclic alcohol
Selective hydrogenation of acetylenic bond
to cis double bond
Spontaneous ring closure and methyl
acetal formation •
H3C OH
H3C CH3 ^Q
^OTBS
Cyclic enynone OTBS
o o H 3 C - N ^ y ^ ^ O ^ C ( C H 3 ) 3
A/-methylurocanic acid mixed anhydride ^
Esterification and deprotection H3C CH3
Tricyclic alcohol
OTES = triethylsilyl ether OPMB = p-methoxybenzyl ether OTBS (orTBSO) = terf-butyldimethylsilyl ether Ac = acetyl group
H3C CH3
Eleutherobin
Discovery unit of Bristol-Myers Squibb, Princeton, N.J., working in collaboration with Fenical's group, found that eleutherobin has the same mechanism of action as Taxol—it prevents the disassembly of cell microtubules, making it impossible for cells to divide. The compound also uses the same binding site as Taxol on tubulin, the protein that forms microtubules.
This type of mechanism was discovered in Taxol by molecular pharmacology professor Susan Band Horwitz of Albert Einstein College of Medicine, Bronx, N.Y., in 1979- The mechanism was once unique to Taxol, as far as anyone knew. Today, there are additional members of the micro-tubule-stabilization "club," but not all that many—the epothilones, discodermolide, eleutherobin, and the sarcodictyins.
"We have Taxol from the forest," says Nicolaou. "We have the epothilones from
the soil—the bacterial kingdom—and now we have eleutherobin from the oceans. And they all act with the same mechanism of action—tubulin polymerization. Taxol is a billion-dollar drug, and the epothilones are now under development by major pharmaceutical companies."
UC San Diego, which operates Scripps Institution of Oceanography, has patented eleutherobin and has licensed it to Bristol-Myers Squibb. Information about eleutherobin's anticancer potential has been slow in emerging, leading to rumors that it was being kept secret. But Bristol-Myers Squibb's Fairchild explains: "We did not want to discuss incomplete biological information, preferring to wait until more complete in vivo antitumor activity testing could be carried out. This was a problem due to the lack of compound."
The sarcodictyins were discovered by chemistry professor Francesco Pietra of
the University of Trento, Italy, and coworkers. They isolated the compounds from a Mediterranean stoloniferan coral in 1987, and reported the compound's Taxol-like cytotoxic activity in a patent filed in 1996. The patent was based on experiments carried out in 1995 in collaboration with scientists from Pharmacia, Nerviano, Italy.
Pietra's group found that, like eleutherobin, the sarcodictyins act by a microtubule stabilization mechanism. But in a tubulin assay performed by the researchers, the cytotoxic activity of the sarcodictyins turned out to be only about one-tenth the activity of Taxol and eleutherobin.
The Nicolaou group's total syntheses of eleutherobin and sarcodictyin A add to their syntheses of Taxol in 1994 and the epothilones in 1996. Their starting material for both eleutherobin and sarcodictyin A was (+>carvone, an inexpen-
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CIRCLE 17 ON READER SERVICE CARD 6 6 NOVEMBER 24, 1997 C&EN
science
Sarcodictyin A lacks eleutherobin's sugar
H,C
H3C CH3
*OH COOCH3
Sarcodictyin A
sive natural product derived from oil of caraway or dill seeds.
In the eleutherobin synthesis, the (+> carvone structure was first extended and glycosylated. A 10-membered ring was formed in a ring-closure reaction, and the cyclic product was oxidized and elaborated to a cyclic enynone. The most innovative step in the eleutherobin synthesis was a second, more elaborate ring closure in which the 10-membered cyclic enynone was converted (via an intermediate) to a bicyclic system containing a nine-membered cyclic ether and a dihy-drofuran ring. The resulting compound was then esterified and deprotected to form eleutherobin.
The researchers used a similar synthetic strategy to make sarcodictyin A, except that the glycosylation was skipped because sarcodictyin lacks eleutherobin's sugar group.
Taxol helps some patients with refractory cancers that don't respond well to any other treatments. But Taxol and other tubulin-stabilization agents have one major drawback: their activity is not specific to cancer cells. They can also act on other cells undergoing cell division.
Taxol therefore causes serious side effects, including immune system suppression, nausea, and hair loss. Other micro-tubule-stabilizing drugs may have different side effects, but there's no guarantee they will be "better" side effects. In fact, they could be worse. That possibility, and many other uncertainties about the biological action of eleutherobin and the sarcodictyins, makes their therapeutic potential anything but certain.
Nevertheless, the new total syntheses ease the path toward further studies, opening the way to possible large-scale production of the compounds and to the creation of variations on a theme. "We're now applying combinatorial chemistry and solid-phase chemistry to make analogs," says Nicolaou.^
