Sponges, Cancer Chemotherapy, and Cellular Aging

SPONGES, CANCER CHEMOTHERAPY, AND CELLULAR AGING SEYMOUR S. COHEN, Ph.D." I. Sponges and Spongonucleosides I have been interested for many years in several unusual nucleosides first isolated by the late Werner Bergmann [?, 2] from a sponge, Cryptotethya crypta. These are known by the trivial names ofspongouridine and spongothymidine and are the i-/3-D-arabinosyl derivatives of the pyrimidines uracil and thymine, respectively. Until now these substances have been detected in only a single species ofsponge. The arabinosyl nucleosides are present in large amounts in the free state and are readily extractable by alcohol or acetone when the live sponge is plunged into these solvents. The arabinosyl compounds have not yet been found in the nucleic acids of Cryptotethya, which contain the normal ribonucleotides in its RNA and deoxyribonucleotides in its DNA [3]. My own interest in these unusual nucleosides stemmed initially from our studies of the biosynthesis and metabolism of both D-arablnose and various pyrimidine nucleosides as aspects ofour work on the metabolism ofphage-infected bacteria [4, 5]. The discovery ofthe arabinosyl nucleosides is ofsome interest to students ofcomparative biochemistry. Bergmann's major interest was in the sterols of sponges and, indeed, he has shown that these sterols differ markedly from sterols of other phyla. His method of extracting Cryptotethya with boiling acetone was designed to isolate lipids, but to his surprise large * American Cancer SocietyResearch Professor ofBiochemistry, University ofPennsylvaniaSchool ofMedicine, Philadelphia, Pennsylvania. My collaborators in our studies with these compounds and with Cryptotethya have been Miss Hazel D. Barner, Dr. H. Tono, Dr. M. Hubert-Habart, and Mis. J. L. Stem. We are happy to acknowledge the co-operation of the Lerner Marine Laboratory at Bimini, B.W.I., in obtaining fresh specimens of Cryptotethya. I am grateful to Dr. J. Hunter ofthe Upjohn Company, Dr.J. Fox ofthe Sloan-Kettering Institute, and to Dr. B. R. Bakerofthe University ofBuffalo for samples of D-arabinosyl nucleosidesand to Dr. L. Rhuland ofthe Upjohn Company for a large preparation oftubercle bacillus. 215 amounts ofcrystalline spongothymidine deposited in his Soxhlet apparatus . We have wondered whether a clue to the unusual synthetic activities of this sponge is not obtained from the taxonomic description of the sponge. The late de Laubenfels recorded not only diat diis organism was obtained in io to 15 feet of water off Bimini in the Bahama Islands, but also diat aldiough relatively abundant, it had to be dredged from beneath the sands. De Laubenfels was unable to see any specimens on the sea floor and said that diis sponge grows almost or quite buried. In keeping with successful growth under sand, the pores and oscules are minute, preventing the entrance oflarge sand grains. Our examinations ofthe organism, distribution of compounds widiin its fluids, and its metabolic properties indicate diat water flow through Cryptotethya must be severely limited. Since the sponge exists in diick slabs, it seems reasonable to suppose that in this habitat the organism is at least partially anaerobic. We note that diis environment cannot be entirely anaerobic since Bergmannfound some sterols, i.e., clionasterol and possibly poriferasterol as well, in Cryptotethya, and it is well known that sterol biosynthesis has an obligate oxygen requirement . Nevertheless, we ask whether the ecological niche of this sponge does not determine in some major respect the origin of the unnatural nucleosides. The structures ofspongonucleosides and die relationofthe D-arablnosyl moiety to ribosyl and deoxyribosyl residues are presented in Figure 1. It can be seen that the D-arablnosyl compounds have a good deal in common widi both the ribosyl and deoxyribosyl series ofnucleic acid derivatives. The years following Bergmann's discovery saw a great growth ofinterest in the chemistry of the nucleic acids from many points ofview, among which were the possibilities ofpreparing analogues which might possess antitumor activity. A number ofworkers have succeeded in syndiesizing D-arabinosyl nucleosides, including spongouridlne and spongocytidine. One such chemical route of synthesis has suggested ideas concerning the possible biosyndietic origin ofthe deoxyribose found in DNA. We could imagine, for instance, the formation ofthe intermediates, the pyrimidine oJ:2' anhydronucleosides, which are hydrolytically cleaved to the arabinonucleosides but which might be reductively cleaved to deoxyribonucleosides . This possibility induced us to explore D...