Clifford W. J. Chang University of West Florida Pensocola, 32504
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Marine Natural Products Other Than Pigments
The oceans as potential storehouse for man's future needs has long been recognized. Cousteau's (1) dire prediction of the viability of the oceans by the year 2000 has forced man to reevaluate his attitude regarding the oceans as a natural resource that can be taken for granted. For example, we know little about the biology, chemistry, and ecology of the approximately one-half million marine species living in the large bodies of water which comprise ahout 71% of the earth's surface. If werestrict our perspective to the chemistry of marine natural products we discover apprehensively that we know even less about their chemical and pharmacological properties. Relatively few proven structures have been postulated for these difficultly purified compounds. Perhaps, the current awarenms that some of these compounds from marine organisms are potentially beneficial drugs has in recent years stimulated considerable interest in this area of research (2, 3) introduction
This paper is concerned with some current work involving some intriguing marine natural products other than the pigmentary compounds described earlier in THIS JOURNAL (4). My discussion will be confined to some of the more novel molecules isolated from various marine organisms. The unique features inherent in these molecules provide a challenge to the structural chemist in unraveling their structures and to the synthetic chemist who will someday synthesize these compounds. The Toxins
Although a number of sterols, terpenoids, alkaloids, and
niements have been isolated (5. 6). Derhaos the most in.teresting compounds of recent years have been saxitoxin I s
and tetrodotoxin 11. Saxitoxin (7. . 8.) is found in the dinoflagellate Gonyaulax catenella-commonly associated with the red tide phenomenon-and in certain shellfish located along the west Coast of North America (e.g., Alaska butterclam Saxidomus giganteus, California mussel Mytilus californianus). Tetrodotoxin (9-11), isolated mainly from the ovaries and liver from the Japanese "tora fugu" or tiger puffer fish (Spheroides rubripes), has gained a notorious prominence since the flesh from this fish is highly esteemed as a delicacy and thus a very early interest in this toxin is understandable.
Some Marine Natural Products
Compound
Molecular Formula
Classification
LDao
(pglkg)
Toxins Saxitoxin1 ClaHlaN7032HCI Cyclo-base Tetrodotoxin I1 C I I H I ~ N ~ O ~ Hemilactal-base Palytoain CllrH~61N1078a Base Holothurin A Saponin OtherComPounds 5-trans-PGAz VIII CzoHaoOn Lipid Gorgosterol IXa C8oH600 Sterol Pacifenol X C I J H ~ I O Z B ~ ~ C I Sesquiterpene eProvisional. ~Subcutaneously. " Intrsveneously.
Both saxitoxin and tetrodotoxin represent two of the most deadly low molecular weight organic molecules (see table). For comparison, the steroidal alkaloid, batrachotoxin I11 (LD50 2). obtained from the amphibian Columhian poison arrow frog (12) is included. The contrast is even more astoundina if the less virulent poison stwchnine (LD5o 500), a n d the notorious inorganic comp&nd sodium cyanide (LDao 10,000) are compared. As Professor woodward remarked (10) with reference to tetrodotoxin: ". . . if the physiologically absurd equation of men with mice he made, it may be anticipated that half a milligram of tetrodotoxin should be sufficient to deprive an averaged-sized man of his life." Although batrachotoxin is more toxic (to mice) than either saxitoxin or tetrodotoxin. the structural features of these latter two compounds far exceed batrachotoxin in thier resplendent architecture. A first impression of tetrodotoxin and saxitoxin is dominated by th,i novelty of their highly compact structures. Their molecular formulas bear a number of heteroatoms (nitrogen and oxygen) equal to the number of carbon atoms. As "normal" organic compounds both saxitoxin and tetrodotoxin have only one typical methylene or methine function bonding to only carbon and hydrogen atoms. As "abnormal" organic compounds, saxitoxin has the "cyclol" part structure and tetrodotoxin possesses the hemilactal moiety.
Interestindv. the timelv studies on tarichatoxin isolated from the e&s' and embryos of the salamander Taricha torosa and the demonstration of the tarichatoxin-tetrodotoxin identity (13) provided food for thought for chemists and hioloeists (and evolutionists) on anv. ~ossihle sala. mander-pufferfish relationship. The definitive work of these novel molecules can best be summarized by Woodward's final remarks on the tetrodotoxin problem expressed before the Third International 260
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Symposium on the Chemistry of Natural Products held in Kyoto, Japan in 1964 (7). The appearance of the anay in the tetrodotoxin molecule presents a clear lesson for the future in its intimidation that if normally non-interacting groups are appositely attached to a rigid skeleton, or otherwise brought into forced proximity, they may he expected to co-operate in the formation of structural groupings which are not observed in simpler systems. It is worthy of note that tetrodotoxin is yet another in the long series of natural products whme study has time and again turned up for the first time new and unique systems, and provided stimulating insights into the fundamental behaviour of organic chemical systems. The phylum Echinodermata includes the asteroids (sea stars) and the holothurians (sea cucumbers). Both classes of marine animals elaborate similar tvnes of toxic sanonins. Saponins are glycosides, for the most part, linked to sterols. The latter compounds are commonly referred to as aglycones that are obtained on hydrolysis of the saponins. The toxic components occur as mixtures of closely related saponins. Recent chemical investigations on the asterosaponins from the sea star Marthasterias glacialis (14) and on the holothurian saponins from Actinopyga agassizi (15) have shown that these saponins are glycosidic sulfates. Degradative work in this class of toxins is intrinsically met with difficulties since several aglycones may result, some of which are attifacts. For example, several aglycones were ohtained from holothurin A, a crude fraction precipitated as the cholesterol complex (16). One of the compounds, the heteroannula; dienoid, IV, was frequently encountered following acid hydrolysis. Following mild anhydrous hydrolysis (methanol-HC1) the aglycone was later demonstrated to he V. The sanonin. holothurian A, for example, was characterized ha;ing the following seouence: a~lvcone-D-xvlose-D-glucose-3-O-methyl-D&cose-D-&inovose with the &fate moiety probably hound to xylose (15). Perhaps as an indicator to more novel and complex molecules that are to he derived from marine sources in the is a toxin isolated from a zoanthid (nrohahlv ~ - future ~ the genus Palythoa) of the phylum ~oelenterata.'kalyto'in (17) is a nonvolatile, amorphous, hydroscopic solid with a specific rotation of +26 f2" in water. In some respects it is unlike the toxins previously discussed. It has an LDm of 0.15 pg/kg as determined intraveneously in mice and uolike a high molecular weight polypetide (e.g., the deadly hotulinu'toxin) it is the most toxic substance among the low to medium molecular weight toxins known to date. With no repetitive amino acid or sugar units palytoxin is estimated to have a molecular weight in the order of 3300. The structure is yet unknown. ~
~
~
Prostaglandins and Sterols
Previous work on the goraonian Plexaura homomalla (phylum Coelenterata) led-to-the discovery of two prostaglandin derivatives (18). Spectral data and chemical work involving neutral permanginate oxidation provided results which were in accord for the (15R)-PGAz compound VIa and its acetate methyl-ester derivative. These naturally occurring marine prostaglandins, however, were shown to he biologically inactive in lowering blood pressure in mammals in contrast to the physiologically active PGAz (its C-15 epimer VIb) isolated from mammalian sources. In more recent work the Upjohn research group (19-21) reported the presence of natural mammalian prostaglandms with the (15s)-configuration in some forms of P. homomalla. Esterified derivatives of (15s)-PGAz VIb, (15s)-PGEz VII, and a new naturally occurring prostaglandin (21). 5-trans-PGAz WI, were ohtained after careful chromatographic separation. Moreover, the advantage of utilizing those readily availahle natural products as precursors in the syntheses of the biologically important PGEz and PGFz was realized (20). Prostaglandins a t present are under intensive investigation (221 by various lahoratories with respect to their hormonal properties in relation to female reproductive physiology. Some thirty years ago Bergmann and coworkers (23) isolated a C30 or C ~ Imonounsaturated sterol from the gorgonian Plexaura flexuosa and proposed the name gorgosterol. In 1970 three groups from California, Hawaii, and Oklahoma reported the structural features of gorgosterol (24). The biologically unusual sterol with an elevencarbon side chain attached to C-17 of the common cholesterol ring skeleton is unprecedented since normal sterols contain eight, nine, or ten carbon atoms as part of the alkyl side chain unit. Moreover, the cyclopropane moiety and the alkyl suhstituents a t C-22 and C-23 are unique when compared to other sterols derived from terrestrial sources. Gorgosterol was shown to have the structure M a whose absolute configuration was later established by X-ray analysis of the 3-hromo-derivative IXh (24, 25). An isomer of gorgosterol is acanthasterol (26, 27) with an alkene function a t the AT-instead of A5-position. It was isolated (26) from the "crown of thorns" sea star Acanthaster planci which recently gained notoriety as the destructive force responsible for the demise of portions of the Great Barrier coral reefs of Australia and reefs at Guam. Volume 50, Number 4. April 1973
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X
XI
Conclusion
Increasing reports of unusual classes of marine natural products are appearing in the chemical literature. For example, the compounds, pacifenol X and johnston01 XI ex. tracted from the algae Laurencia pacifica and L. j o h ~ t o nii respectively, represent the first examples of natural compounds containing both covalently bonded bromine and chlorine atoms (28, 29). Indeed, more fascinating compounds of structural and biological significance will be uncovered in the future. The author is indebted to Professor Scheuer whose laboratory provided and stimulated the author's interest in the chemistry of marine natural products. Literature Cited ( I ) Cou8teau. J. Y., "Our Oceans are Dying" in the N w York Times. Nau. 14. 1971. IV. 13.3. The Auaeiated Reaa article appeared in the Penrocdo Journoi. Oct. 19,1971. (2) Badow. M. H., "Marine Pharmedogy," Tho Williams and Wilkina Co.. Ballmore, 1 9 8 . p ~ 1-7. .
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131 Halsfcad, B. W.. "Poisonous and Venomour Marine Animals of the World? U.S. Go*. ~ i n t i n g o f hwashington, , D. c., 196s. 1967, 197nvo1a.I, 11, m. 14) Chanp,C. W. J., J. CHEM. EDUC.50.102 (19731. 151 Schcuer, P. J.. "Chemiatryaf Marine Natural Products," AcademicR~as,in pre~s. I61 Grossert, J. S., C h e m Soe Re".. 1,111972). 171 Wong. J. L.. Oertedin, R., and Rappapart. H.. J Amer. Chem Soe, 93. 7344 11971). and earlierrefrroncereited therein. 18) Schantz, E. J.. Lynch. J . M.. Vayvada, 0.. Matsumoto, K., and Rappoport. H.. B i a c h a m i l v . 5. 1191 (19661,andreferencescited therein. 63,171 119661,endrefer~ncereitedtherein. 19) Tsuda. K..Nolurwis~~nscholten, D ~ ~ .9.49119641. (101 woodward. R.B . . P ~ ~ P Achsm.. 1111 Goto. T.. Kishi.. Y... Takahsshi.. S... and Hirata. Y.. Tetrohedmn. 21. W59 119651. and references ciredtherein. (121 Tokuyams,T.,Da?v. J.,snd Witkop,B.,J. Amer C h m Soc.. 91,3931 (19691. 1131 Mosher, H. S., Fuhrman, F. A., Buehwsld. H. D., and Fisehsr, H. G.. Sciensr 111.11W11964l. (141 Turner. A. B., Smith, D. S. H., and Mackie, A. M., Nature, 233, 209 (19711, and references e i f d therein. (16) C h a n l r y . ~ . ~ .s.n d ~ . a a i . ~ . .~ ~ t ~ 2s. h189.~ 1911 d 11969). ~ ~ ~ . (16) Chanley. J.D., Mecetti, T., Sobolka, H.E., Tetmhadmn, 22,1857 119661. (171 Mo0re.R.E.. andScheuer.P. J..Scicncr, 172,495 119711. (18) W~inheimer.A.~ . , ~ "spraggina. d R. L..~ ~ ~ ~ h5185~ (1969~. d ~ ~ ~ ~ . ~ ~ cis) schneidor. W. P.. ~amiiton.R. D.. and ~ h u l s n d L. . E..J. mar c h m sor. 94. 2122(1972). (201 ~ u n d y .G. L.. sehneider, W. P.. ~ m c o ~ nF.. H., and pike, J. E.,J. *me,. c h m . sac.. 9i.2123 (19721. (211 Bmdy. G . L., Daniels. E. G.. Lincoln. F. H.. and Pike, J. E., J Amsr. Cham. Soc.. 94.2124 (1972). 1221 R ~ ~ W ~ P, I I and . shaar, J. E. i ~ d ~ . ~ . . ~ ~ cN ~ Y.~A C~ O ~~s .c ~i . 1ds .i ~ . - ~ ~ ~ 119711. hi^ volume indudas eonvihutions on the .hemistry, biwynthaia, me. tabolism andmechanism of actianof prostaglandins. (231 B ~ w.. M C ~L ~ ~M. " . J., ~ e n d ~ n f~. r ,D. J.. J.~ o,~.them.. ~ S . Z ~~119431. I . 1241 Hale. R. L., Leclereq, J.. Tursch, B., Djarssi, C., G r m . Jr., R. A,, Wainheimer. A. J.. Gupts. K.,sndScheuer,P. J.. J A m s r Chsm. Soc., 92.217911970l. (251 ~ i " N ~ .c..~ d . ,R.L.. end oieraasi. c.. J A ~ c h s~m SO
