Tumor-inhibiting properties of the neutral P-O-ethyl ester of adenosine 3':5'-monophosphate in correlation with its crystal and molecular structure.

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.

Synthesis and properties of some cyclic AMP alkyl phosphotriesters.

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.