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Cyclic AMP was converted to its phosphotriesters according to the classical approach of phosphate activation with a sulfonyl chloride, followed by esterification with an alcohol. The methyl, ethyl, propyl, butyl and cetyl triesters were prepared, and some of their physical-chemical properties determined. Alkaline hydrolysis of these alkyl phosphotriesters resulted predominantly in ring opening. On the other hand, nucleophilic attack by thiourea led to the formation of cAMP as the main product. The conclusion can be drawn from these results that cAMP phosphotriesters could serve as suitable storage forms of cAMP, and cyclic triesters may be the best vehicle of transporting nucleotides through biological membranes.

The partition coefficients, K-values, of adenosine, guanosine, cytidine, uridine, 51-adenylic acid (AMP), 51-guanylic acid (GMP), 51-cytidylic acid (CMP), and 51-uridylic acid (UMP) between water and aqueous sodium dodecanoate has been determined by gel filtration on Sephadex G-25. Below the critical micelle concentration of the surfactant, K-values for all nucleotides and nucleosides are similar. Differential uptake of the four nucleotides and nucleosides is observed, however, by micellar sodium dodecanoate. K-values for adenosine, AMP; guanosine, GMP; cytidine, CMP; and uridine, UMP are 6.16·103, 9.52·103; 12.0·103, 14.6·103; 19.6·103, 19.6·103, 34.2·103 and 40.3·103. Similar K-values for corresponding pairs of nucleotides and nucleosides imply that the predominant interaction is between the pyrimidine or purine rings of the substrates and the charged Stern layer of the surfactant. Prebiotic significance of these results is discussed.

Selective compartmentalization of amino acids and nucleotides according to their polarities is proposed as a physical-chemical model for the origin of the genetic code. Assumptions made in this hypothesis are: (1) an oil-slick covered the surface of the primitive ocean, constituents of which formed association colloids or micelles at the water-oil-air interfaces; (2) depending on the polarity of the media, these aggregates possessed hydrophilic and hydrophobic interiors where selective uptake of amino acids and nucleic acid constituents could take place; and (3) condensation and polymerization in the micellar phase were enhanced. According to the chromatographically observed polarities, for example, lysine and uridylate fall into the hydrophilic compartment, and phenylalanine and adenylate are enriched in the hydrophobic environment. These components could eventually be condensed to form a charged adaptor loop with an anticodon which is complementary to the presently valid codon. Only two groups of amino acids, hydrophilic and hydrophobic, were recognized by the primitive translation mechanism. Implications of this hypothesis for the further development of the genetic code is discussed. The catalytic power of micelles have been substantiated by successful synthesis of nucleotides under relatively mild conditions using thiophosphates as high energy phosphates.

The P-O-ethyl ester of cAMP has been synthesized, its inhibition of solid and ascites tumors studied, and its pattern of urinary excretion followed. Et-cAMP is more effective than cAMP against solid sarcoma 180 in mice and against Ehrlich ascites carcinoma cells in tissue culture. The urinary excretion pattern of injected E-t-cAMP suggests that about two-thirds of the injected dose (13 mumol per animal) is retained in the rat rather than being promptly excreted. Liver slice studies of the effect on glycogenolysis suggest that the Et-cAMP is converted to cAMP intracellularly. The compound crystallizes in space group P21 with one molecule per asymmetric unit. The base ring has the anti conformation. The ethyl group is endo to the base ring and is axial in the flattened chair-conformer six-membered ring formed by the 3'-5' O-P-O cyclization. In most other respects the structure of the compound is closely similar to the known structures of other cyclic nucleotides.

Summary We are proposing a simple model by which acidic polysaccharides of the critical charge density 1 minus/1 carbohydrate unit can be converted into anion exchangers by complexing with a trivalent cation. We have constructed a complex of alginic acid and Al3+ which was shown to bind nucleotides. It was assumed that bile acids would also be bound and, thus, Al- alginate would be hypocholesterolemic in vivo . The feeding of Al- alginate to rats which were fed a high cholesterol diet produced a marked decrease of serum cholesterol. It is proposed that Al3+ may have a nutritional role if present in conjunction with acidic polysaccharides. Ternary complexes involving lipids may exist in many biological structures.

Thermal activation of O 2 ,59-cyclothymidine 39-phosphate in solution and in the solid state led to the formation of thymidine oligonucleotides containing up to approximately 12 nucleotide units. Only the 39,59 internucleotide diester bonds were formed. This polymerization occurs without the addition of any activating agent or catalyst.

IN contrast to the plausible explanations for proteinoid formation1, there seems to be no satisfactory concept for the genesis of polynucleotide templates in the presumed conditions of the primitive Earth. Only parts of the problem, such as the origin of the bases2,3 and carbohydrates4 and the synthesis of short oligonucleotides5,6, have been subjected to informative experiment. A working hypothesis of the past decade took for granted the availability of common nucleosides, but only in 1970 was a plausible, though inefficient, route to any natural nucleosides proposed7. Some recent evidence suggests, however, that natural nucleosides need not be direct precursors of the corresponding nucleotides and polynucleotides.