7/31/2019 9.1_fenical

1/5

S H O R T P A P E R

MARINETH E

BIODIVERSITY AND THE M ED ICINE CABINETSTATUS OF NE W DRUGS FROM MA RINE

ORGANISMS

By Wil l iam Fenical

O D I V E R S I T Y P R O V I D E S the foundation

There is no question that the develop-f human life. Sub-

W i l l i a m F e n i c a l , S c r i p p s I n s t i t u t i o n o fo g r a p h y , U n i v e r s i t y o f C a l i fo r n i a - S a n D i e g o ,

l la , C A 9 2 0 9 3 - 0 2 3 6 , U S A .

many newly developed drugs. One exam-ple is the recently approved anticancerdrug taxol, a compound extracted fromthe bark of the North American Yew tree.Taxol, perhaps by virtue of its uniquemechanism of action, has shown excel-lent results in treating several forms ofcancer that were previously difficult totreat.

As we move toward the 21st century,there has never been a greater need fornew drugs. The age demographics of so-ciety is changing to provide a focus ondiseases, such as Alzheimers and arthri-tis, which create even greater threats tothe quality of life. Heart disease contin-ues as the major threat, while cures forcancer and AIDS continue to elude sci-ence. Unfortunately, many of the "'won-der drugs" generated over the past severaldecades have become less useful due tothe development of drug resistance.Many pathogenic bacteria, once suscepti-ble to antibiotics, have developed sophis-ticated biochemical methods to escapethe effects of these drugs. A strain ofdrug-resistant mycobacterium, the path-ogen that causes tuberculosis, for exam-ple, is almost totally resistant to our arse-nal of antibiotic drugs. Some infectionsare, today, produced by bacteria that areimmune to all known antibiotics. Simi-larly, some forms of cancer have evolvedmultiple drug resistance, making virtuallyall drug treatments ineffective.

Despite advances in molecular biologyand in computer-assisted drug design,Nature still provides the foundation forthe discovery of new medically importantcompounds. Because of this, vigorousnew programs such as the U.S. NationalCancer Institute's (NCI) "'Natural Product

National Cancer Drug Discovery Pro-gram" have established worldwide explo-rations. But unlike the past, these effortshave included the inhabitants of theworld's oceans as a new source of biodi-versity and novel drugs.

In contrast to the terrestrial environ-ment, little ethnomedicinal information isavailable to guide current marine re-search. With the exception perhaps ofsouthern China, few societies have usedmarine organisms as crude drugs. Thusstudies now in progress have relied onecological observations of chemical de-fense and survival to identify those organ-isms that might be expected to containdrug candidates. Pharmacological investi-gations of marine organisms are relativelynew and have been founded on the estab-lishment of unprecedented "scientificbridges" between the marine and pharma-ceutical sciences. Today, approximatelyone-half of all cancer drug discovery fo-cuses on marine organisms, and forecastsfor the future are bright. In fact, some ofthe most important recent discoverieshave been from the marine environment.

Marine drug discovery began in thelate 1970s by early investigators demon-strating, unequivocally, that marine plantsand animals were genetically and bio-chemically unique (Fig. l). Over 6,000structurally unprecedented, and oftenhighly bioactive metabolites have nowbeen isolated from marine plants and ani-mals. After the uniqueness of marine me-tabolism became accepted, programsbegan to evolve that linked academic ma-rine scientists with biomedical re-searchers in the pharmaceutical indus-tries. Programs, which established thefoundations of today's efforts, were cre-

"ANOGRAPHY'VoI. 9, NO. 119 96 23

7/31/2019 9.1_fenical

2/5

se com pet i t ion fo r spa ce an d surv ival on cora l reeJs i s so in tense, organ-

1980s in the United States, in

Unlike the majority of terrestrial drug

ied with

(de Silva ande t a l . , 1992).

A 2, an enzyme centr ally involved in

true of okadaic acid, a cyclic polyetherfirst isolated from the sponge H a l i c h o n -dria okadai , but later recognized as a pri-mary product of the red tide dinoflagel-late P r o r o c e n t r u m l i m a , which isconcentrated in the sponge. Okadaic acidis a selective inhibitor of the enzyme pro-tein phosphatase, allowing this compoundto be used as a probe of basic cellularphosphorylation processes. Okadaic acidand manoalide are now commerciallyavailable for biochemical research.

Because the development of newdrugs is highly competitive, it is oftendifficult to acquire information on themost recent discoveries. Scientists tend topublish only their discoveries that are notlikely to lead to true drugs. The signifi-cant investment of the NCI in the discov-ery of new cancer drugs has, however,begun to yield rich dividends, and thesenew drugs are proceeding well past thestages of initial discovery. Currently,there are five new drug candidates in var-ious stages of human clinical trials withinthe United States and Europe, and it islikely that several others may be in clini-cal trials in Japan. Reaching the clinicaltrial stage signifies that the compoundshave received considerable advanced test-ing and that their potential is undeniable.

Consistent with the concept of marinechemical defense, all of the new cancerdrug candidates discovered are from soft-

bodied and vulnerable marine inverte-brates. Perhaps the first molecule di scov-ered was the unique cyclic ester bryo-statin 1 (Fig. 2), isolated and defined byresearchers at Arizona State University(Pettit et al . , 1982). Bryosta tin 1 occursas a trace component of the common bry-ozoan B u g u l a n e r i t i n a , which occursworldwide often as a conspicuous com-ponent of the fouling communities onpier pilings. The molecule was recog-nized as a very potent inhibitor of numer-ous leukemia cells in culture. In fact,bryostatin 1 was the most selective an-tileukemia agent ever discovered. As isoften the case, only selected populationsof this well-known animal were found tocontain bryostatin 1. This, coupled withthe fact that bryostatin 1 comprises onlyappr oxima tely 1 X 10 ~% of the animalmass, created major problems in acquir-ing sufficient amounts of the compoundto undertake advanced testing. The col-lections were accomplished, however,and although the results of clinical trialsare not yet complete, there is no questionthat bryostatin 1 shows promise in thetreatment of acute leukemia. Regardlessof the results of these trials, it has alreadybeen acknowledged that bryostatin 1 is achemically and pharmacologically uniquesubstance of great interest in basic med-ical research. This compound possessesunprecedented immunostimulatory prop-erties, and it activates protein kinase C(Suffness et at., 1989), an important reg-ulator of hormone-mediated signal trans-duction, and a novel enzyme target forthe development o f new antitumor drugs.

In the 1970's, as part of an NCI-spon-sored survey of Caribbean invertebrates,the impressive cytotoxic properties of ex-tracts of the mangrove ascidian E c -t e i n a s c i d i a t u r b i n a t a (Fig. 3) were dis-covered. Although it was clear, eventhen, that this animal contained sub-stances of great potential importance, thegreat difficulty encountered in isolatingand identifying the active substance(s)rendered this project virtually unsolvable.Here too, the active substances werepresent in vanishingly small amounts (1x 10 ~%), and the compoun ds were ap-parently of a very new and difficult toisolate structural class. After 20 years ofadvancements in chemistry, the activesubstances, named the ecteinascidins,were isolated and described by re-searchers at the University of Illinois andthe Harbor Branch Oceanographic Insti-tution (Rinehart e t a l . , 1990; Wright e t

OCE ANOGrAFHv 'VoI . 9 , No . 1 19 96

7/31/2019 9.1_fenical

3/5

N e w M a r i ne A n t i c a n c e r D r u g C a n d i d a t e s~ O A c~ " " , t HHH 2 C H 2 / r " ~ J ~ C O 2 C H 3 . ~ H '~ * mO H

b r y o s t a t i n 1

O C H a

H HO A c " H '- == - - C H aN ,

v-o X, % !2O S~==~.,tlH a C O N

e c t e i n a s c i d i n 7 4 3

0H c . - - I L - o _ / o

- - ( o oJ oc. ,HaO\~/NH.~Nc~ O ~ O H

C H 3 0 H

H H3 C* * H ~ H H * ' NH 3 C ~ , N

I I I / / f ~ o I I H a C O H O S IIC H 3 0 0 H a c H 3 C O H 0

d o l a s t a t i n 1 0

dldemnin B

~ H H H { H" o ~o~' ~oO O O H

OH O , " H H H H | H 'H H ~ O OH O ~ = E O O. o . J I ~ y "~ " ,

h a h ch o n d r ln B

F i g . 2 : N e w m a r i n e a n t i c a n c e r d r u g c a n d i d a t e s .

, 1990). The most abundant compound,

i n v i t r o and

which has raised the question of a possi-ble microbial source existing within thetissues of this ascidian.

Another Caribbean ascidian, T r i d i d e m -h u m s o l i & m T , has also been recognized tocontain substances of potential use incancer chemotherapy. This ascidian wasfound to contain a series of cyclic pep-tides, the didemnins, all of which wereclosely related. The most medically im-portant of these compounds, didemnin B(Fig. 2), showed impressive cytotoxicityagainst lymphomas and significantly ex-tended the survival of mice in the P-388leukemia assay. On the basis of these en-couraging properties, a large scale collec-

tion of this animal was undertaken andlarger amounts of didemnin B were iso-lated. Unfortunately , didemnin B has sub-sequently been found to exhibit signifi-cant toxicity at doses near those requiredfor life extension. Although clinical trialsof didemnin B are not yet complete, thiscompound may be limited in its use. It isimportant to point out, however, that theevaluation of new drugs is a complexprocess in which both negative and posi-tive results are continuously evaluatedover time. Taxol, for example, requiredover 20 years of study before it was ap-proved as a cancer drug.

A more recent addition to the list ofexcit ing marine anticancer agents isdolastatin 10, a linear peptide discov-ered by researchers at Arizona StateUniversity (Pettit e t a l . , 1987) from thesea hare D o l a b e l l a a u r i c u l a r i a (Fig. 4),collected in the Indian Ocean. Found incomplex mixtures with related peptides,dolastatin 10 showed outstanding inhib-itory effects against several forms ofskin cancers in laboratory, studies. Moreimportantly, subsequent whole animaltesting showed this peptide to providesignificant effects in controlling humanB-16 and LOX mehmoma in implantedmice. On the basis of these impressiveproperties, the NCI has been aggressivein adva ncin g dolastatin 10 for clinicalevaluation. Like the other moleculesmentioned here, the results of clinicaltrials are not yet known. A curiosity ofthis work is the true origins of the pep-tides in D . a u r i c u l a r i a , Sea hares aremost often herbivores, and it has beenunequivocally demonstrated that theseshell- less mollusks acquire defensivechemicals from their diets rather thansynthesizing them as many animals do.Thus dola statin 10 and its relatives aremost likely of an algal dietary origin.Based on our knowledge of the chem-istry of marine algae, the dolastatinsare likely to be produced by filamen-tous blue-green algae (cyanobacteria),which are often abundant in these habi-tats. The preferences of selected seahares to consume blue-green algae hasindeed been documented. But, to thebest of my knowledge a dietary' sourcefor the dolastatins has not beenidentified.

Last, marine sponges have contributedthe largest chemical diversity of all themarine invertebrates. Because most ofthese animals are soft-bodied and providesignificant food for consumers, their re-

EANOGRAPH'~,Vo1. 9. No. 1,1996 25

7/31/2019 9.1_fenical

4/5

7~

." A c l o s e - u p v i e w o f t h e C a r i b b e a n m a n g r o v e a s c i d i a n E c t e i n a s c i d i a t u r b in a t a .a n i m a l c o n t a i n s t h e e c t e i n a s c i d in s , a n e w c l a s s o f a n t i c a n c e r a g e n t s a b o u t t o b e

i s o l a t e d a n d f i r s t i d e n t i f i e d i n J a p a n ( H i -r a t a a n d U e m u r a , 1 9 8 6 ) . T h i s i n t e r e s t i n gm e t a b o l i t e w a s d i s c o v e r e d i n t h e s p o n g eH a l i c h o n d r i a o k a d a i (F i g . 5 ) , va r i ous co l -l e c t io n s o f w h i c h h a v e y i e l d e d a v a r i e t yof d i ve r se t ox i ns . Ha l i chond r i n B (F i g . 2 )i s a n o v e l c o m p o u n d , r e l a t e d m o s t c l o s e l y

e a r. M a n y o f t h es e c o m p o u n d s h a v e

B , a n o v e l p o l y e t h e r , w a s

." T h e s e a h a r e s a r e s h e l l - l e s s m o l l u s k s t h a t a c c u m u l a t e d e f e n s i v e s u b s t a n c e sD o l a b e l l a a u r i c u l a ri a , h a s y i e l d e d a p o t e n t n e w a n t i c a n c e r d r u g c a n d i d a t e .

t o s e v e r a l o f t h e t o x i n s p r o d u c e d b y t o x i -gen i c d i nof l age l l a t e s . B eca use o f t h i s r e l a -t i o n s h i p , a n d b e c a u s e H . o k a d a i h a d b e e nf o u n d t o c o n c e n t r a t e o k a d a i c a c i d , am e t a b o l i t e o f t h e d i n o f l ag e l l a te P r o r o c e n -t r u m l i m a m e n t i o n e d e a r l ie r , i t s e e m s l o g -i c a l t h a t t h e c o m p o u n d m a y a l s o b e o fd i n o f la g e l l a te o r i g i n p r o b a b l y a c q u i r e d b yt h e f i lt e r f e e d i n g p r o c e s s . S u p p o r t i n g t h i sc o n c e p t , h a l i c h o n d r i n B h a s r e c e n t l y b e e ni s o l a t e d b y s e v e r a l i n v e s t i g a t o r s f r o m av a r i e t y o f s p o n g e s . B e c a u s e t h is i s th em o s t r e c e n t a d d i t i o n t o t h e l i s t o f m a r i n ed r ugs unde r go i ng c l i n i ca l t r i a l s , l i t t l e da t aa r e a v a i l a b l e t o p r e d ic t s u c c e s s . H a l i c h o n -d r i n B s h o w s s e l e c t i v e a n t i t u m o r e f f e c t sa g a i n s t h u m a n o v a r i a n c a n c e r s i n m i c e , a sw e l l a s a c t i v i t y a g a i n s t m e l a n o m a a n dv a r i o u s f o r m s o f l e u k e m i a . I t s e e m s c l e a rt h a t H a l i c h o n d r i n B is o n e o f th e m o s tp r o m i s i n g n e w a n t i c a n c e r d r u g i s o l a t e d t oda t e .

I n d i s c u s s i o n s o f m a r i n e d r u g s , i t i si m p o r t a n t t o d i s t i n g u i s h b e t w e e n m o l e -c u l e s p r o v i d i n g " d r u g l e a d s " a n d t h o s em o l e c u l e s m o r e a d e q u a t e l y d e s c r i b e d a s" d r u g c a n d i d a t e s " t h a t a r e p r e s e n t e d h e r e .M a r i n e p l a n t s a n d a n i m a l s h a v e p r o v i d e dl i t e ra l l y h u n d r e d s o f c o m p o u n d s t h a t c a nb e d e f i n e d a s th e f o r m e r , b u t f e w h a v e a d -van ced t o t he s t age s o f c l i n ica l t r i a ls . T hem o l e c u l e s p r e s e n t e d h e r e a r e t h u s c o n -c r e te e x a m p l e s o f t h e e x c i t in g a d v a n c e sb e i n g m a d e i n m a r i n e d r u g d i s c o v e r y .

T he appr oa ch o f t h i s a r ti c le i s no t mean tt o m i n i m i z e th e i m p o r t a n c e o f t h e n u m e r -ous mar ine drug leads that are s t i l l in ear lys t ages o f p r ec l in i ca l eva l ua t i on . T o t he con-t r ar y , m y k n o w l e d g e o f t h e s e c o m p o u n d ssugges t s t ha t t hey have a l r eady con t r i bu t eds i g n i f i c a n t l y t o b i o m e d i c a l r e s e a r c h a n dm ay i ndee d r eac h t he s t a t us o f c l in i ca l t r i-a ls . R e c e n t e x a m p l e s o f m o l e c u l e s b e i n gi n t e n s e l y s t u d i e d a r e d i s c o d e r m o l i d e , au n i q u e i m m u n o s u p p r e s s i v e a n d c y t o t o x i ca g e n t , i s o l a t e d b y H a r b o r B r a n c h O c e a n o -gr aph i c I ns t i t u t i on s c i en t i s t s f r om t he deepw a t e r s p o n g e D i s c o d e r m i a d i s s o l u t a ( G u -n a s e k e r a et al., 1990) , and cur ac i n , a nove la n t i c a n c e r a g e n t f r o m t h e C a r i b b e a n b l u e -g r e e n a l g a L y n g b y a m a j u s c u l a , r e c e n t l yd i s c o v e r e d b y r e s e a r c h e r s a t O r e g o n S t a t eU n i v e r s i t y ( G e r w i c k e t a l . , 1 9 9 4 ) . D i s c o -d e r m o l i d e h a s r e c e n t ly b e e n s h o w n t o p o s -ses s t he i den t i ca l t ubu l i n po l ymer s t ab i l i z -i n g p r o p e r t i e s a s t a x o l , ( t e r H a a r e t a l . ,1 9 9 6 ) w h i c h c e r t a i n l y i n d i c a t e s t h a t c o m -pr ehen s i ve p r ec l in i ca l s tud ie s shou l d be un -de r t aken . I n o t he r t he r apeu t i c a r eas , s eve r a lm o l e c u l e s h a v e s h o w n s i g n i f i c a n t p r o m i s ei n t h e t r e a tm e n t o f i n f l a m m a t i o n a n d p a i n .

6 OCEANOGRAPHY'Vo1. , NO. 11996

7/31/2019 9.1_fenical

5/5

i v e c o m p o u n d s f r o m i ts f o o d s o u rc e , t h e s p o n g e H a l i c h o n d r i aAs e xe mpl i f i e d i n the c ase o f ha l ic hondr in B , Ha l i c h iondr ia spe c i e s c on ta in un ique ,

t e r o s in s , i s o la t e d f r o m t h eP s e u d o p t e r o g o r g i a

b y S c r i p p s I n s t i t u t i o n o fet al . ,

6 ), s h o w i m p r e s s i v e a n t i - i n f l a m m a t o r y

r o g r e s s e d t o t h e

T h e h i s t o r y o f r e s e a r c h s u p p o r t i n t h ea n d i n a m o r e f u n -N O A A , S e a G r a n t

h i le N I H s u p p o r t h a s be e ne f o r th e d e v e l o p m e n t o f th eu l d b e c r e d i te d f o r p r o v i d i n g

o f th i s w o r k . B e g i n n i n ge r e p r e -

t u r e a n d u n r e f i n e d, t h e S e a G r a n ti n v e s t e d in th e l o n g - t e r m d e -

p m e n t o f th i s f ie l d. T h e s u c c e s s e s

t h e N a t i o n a l a n d S t a te S e a G r a n t P r o -g r a m s f o r t h e i r i n s i g h t a n d c o m m i t m e n ti n e s t a b l i s h i n g t h i s i m p o r t a n t a r e a .

W h a t i s t h e fu t u r e o f m a r i n e d r u g r e -s e a r c h ? C l e a r l y t h i s r e q u i r e s g a z i n g i n t oa c r y s t a l b a l l . W h a t a p p e a r s l i k e l y i s t h a ts t u d ie s o f n e w d r u g l e a d s f r o m m a r i n es o u r c e s w i l l s i g n i f i c a n t l y e x p a n d . A s t h es c i e n t i f i c b r i d g e s b e t w e e n m a r i n e s c i e n c ea n d d r u g d i s c o v e r y c o n t i n u e t o b e b u i l t ,n e w a n d e n l a r g e d c o l l a b o r a t i o n s w i l ll e ad to e x p a n d e d p h a r m a c o l o g i c a l r e -s e a r c h . T h e r e i s n o d o u b t t h a t t h e s e s t u d -i e s w i l l i d e n t i f y n o v e l m a r i n e d r u g c a n -d i d a t e s i n d i v e r s e a r e a s o f th e r a p e u t i cd e v e l o p m e n t . W h e n o n e c o n s i d e r s th es c o p e o f m a r i n e b i o d i v e r s i t y , i n c l u d in gs u c h m a j o r , u n i n v e s t i g a t e d g r o u p s a s m a -r i n e b a c t e r i a a n d f u n g i , i t s e e m s l i k e l yt h a t m a r i n e s o u r c e s c o u l d b e th e m a j o rs o u r c e o f n e w d r u g s f o r th e n e x t d e c a d e .R e f e r e n c e sd e S i l v a , E . D . an d P . J . S ch eu e r , 1 9 8 0 : M an o a l i d e ,

an an t i b i o t i c s e s t e r t e rp en o i d f ro m t h e m ar i n es p o n g e Luffar iel la variabil is. Tetrahedr, mLett., 21, 1611 1614.

Gerw i ck , W . H. , P . J . P ro t ean , D . G . Nag l e , E . Ham el ,A . B l o t ch i n an d D . L . S l a t e , 1 9 9 4: S t ru c t u re

o f cu rac i n A , a n o v e l an t i m i t o t i c , an t i p ro l i f -e r a t i v e , an d b r i n e s h r i m p t o x i c n a t u ra l p ro d -u c t f r o m t h e m a r i n e c y a n o b a c t e r i u m Lyng-bya majuscula. J. Org. Chem., 59,1 2 4 3 - 1 2 4 5 .

G u n a s e k e r a , S . P . , M . G u n a s e k e r a a n d G . K . S c h u l t e ,1 9 9 0 : D i s co d e rm o l i d e : a n ew b i o ac t i v ep o l y h y d r o x y l a t e d l a c t o n e f r o m t h e m a r i n es p o n g e Discodermia dissoluta. J. Org.Chem., 55, 4 9 1 2 -4 9 1 5 . e r r a t u m . 1 9 9 1 . J .Org. Chem., 56, 1346.

Hay , M . E . an d W . F en i ca l , 1 9 9 6 : C h em i ca l eco l o g yan d m ar i n e b i o d i v e r s i t y : i n s i g h t s an d p ro d -u c t s f r o m t h e s e a . Oceanography, 9, 1 0 - 2 0 .

H i r a t a , Y . a n d D . U e m u r a , 1 9 86 : H a l i c h o n d r i n s - -a n t i t u m o r p o l y e t h e r m a c r o l i d e s f r o m a m a -r i n e s p o n g e . Pure Appl . Chem., 58 , 7 0 1 - 7 1 0 .

L o o k , S . A . , W . F e n i c a l , R . S . J a c o b s a n d J .C l a r d y , 1 9 8 6: T h e p s e u d o p t e r o s i n s ; a n t i -i n f l a m m a t o r y a n d a n a l g e s i c n a t u r a l p r o d -u c t s f r o m s e a w h i p P s e udop t e r ogor g i ae l i sabe thae . Pro c . Nat l . Acad . Sc i. USA,83 , 6 2 3 8 - 6 2 4 0 .

P en i t , G . R . , C . L . Hera l d , D . L . Do u b ek , D . L . Her -a l d , E . Arn o l d an d J . C l a rd y , 1 9 82 : I s o l a t i o nan d s t ru c t u re o f b ry o s t a t i n 1. J. Am. Chem.Soc., 104, 6 8 4 6 - 6 8 4 8 .

_ _ , Y . K a m a n o , C . L . H e r a l d , A . A . T u i n m a n ,F . E . Bo e t t n e r , H . K i z u , J .M . S ch m i d t , L .B a c z y n s k y j , K . B . T o m e r a n d R . J. B o n t e m s ,1 9 87 : I s o l a t i o n an d s t ru c t u re o f a r em a rk ab l em ar i n e an i m a l an t i n eo p l as t i c co n s t i t u en t :d o l a s t a t i n 1 0 . J. Am . Chem. Soc., 109 ,6 8 8 3 - 6 8 8 5 .

P o t t s , B . C . M . , D . J . F au l k n e r , M . S . d e C arv a l h o an dR . S . Ja c o b s , 1 9 9 2: C h e m i c a l m e c h a n i s m o fi n a c t i v a t i o n o f b e e v e n o m p h o s p h o l i p a s e A tb y t h e n a t u ra l p ro d u c t s m an o a l i d e , l u f f a r i e l -l o l i d e an d s ca l a r ad i o l . J. Am. Chem. Soc.,114, 5 0 9 3 - 5 1 0 1 .

R i n eh a r t , K . L . , J r . , J . B . G l o e r , J . C . C o o k , S . A .M i z s a k an d T . A . S cah i l l , 1 9 8 1: S t ru c t u res o ft h e d i d em n i n s ; an t i v i r a l an d cy t o t o x i c d ep -s i p ep t i d es f ro m a C ar i b b ean t u n i ca t e . J . Am.Chem. Soc., 103, 1 8 5 7 - 1 8 5 9 ., T . G . H o l t , N . L . F r e g e a u , J . G . S t r o h ,P . A . K e i f e r , F . S u n , L . H . L i a n d D . G .M a r t i n , 1 9 9 0 : E c t e i n a s c i d i n s 7 2 9 , 7 4 3 ,7 4 5 , 7 5 9 A , 7 5 9 B , a n d 7 7 0 : p o t e n t a n t i t u -m o r a g e n t s f ro m t h e C a r i b b e a n t u n i c a teE c t e i nas c i d i a t ur b i na t a . J . Or g . Che m. ,55 , 4 5 1 2 - 4 5 1 5 .

S u f f n e s s , M . , D .J . N e w m a n n a n d K . S h a d e r , 1 9 8 9:D i s c o v e r y a n d d e v e l o p m e n t o f a n t i n e o p l a s -t i c ag en t s f ro m n a t u ra l s o u rces . I n : Bioor-ganic Chemis to, , vol . 3 . P.J . Scheuer , ed .S p r i n g e r - V e r l a g , N e w Y o r k , 1 3 I - 1 6 8 .

t e r Haa r , E . , R . J . Ko w al s k i , E . Ham el , C . M . L i n ,R . E . L o n g l e y , S . G u n a s e k e r a , H . S . R o s e n -k ran z an d B . W . Day , 1 9 9 6 : D i s co d e rm o l i d e ,a cy t o t o x i c m ar i n e ag en t t h a t s t ab i l i z e s m i -c r o t u b u l e s m o r e p o t e n t l y t h a n t a x o l . Bio-chemistry, 35, 2 4 3 - 2 4 5 .

W r i g h t , A . E . , D . A . F o r l eo , G . P . Gu n aw ard an a , S . P .G u n a s e k e r a , F . E . K o e h n a n d O . J . M c -C o n n e l l , 1 9 90 : An t i t u m o r t e t r ah y d ro i s o -q u i n o l i n e a l k a l o i d s f ro m t h e co l o n i a l a s c i d -Ja n Ecteinascidia mrbinata. J. Org. Chem.,55 , 4 5 0 8 - 4 5 1 2 . E l

APHYVoI. 9 , No. 1 .19 96 2 7