Synthesis and pharmacological evaluation of a series of analogs of 1-methylisoguanosine

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Abstract
A series of analogs of the pharmacologically active marine natural product [Tedania digitata] 1-methylisoguanosine was evaluated for biological activity in muscle relaxant, cardiovascular, antiinflammatory and antiallergic tests in rat and mice. Modifications at the 1 position produced the ethyl, n-butyl, n-octyl, and phenyl derivatives, respectively. Substitutions at the 8 position provided the bromo, hydrazino and amino compounds. Modifications at the 5'' position yielded the deoxy, iodo, and phosphate derivatives and the cyclic 3'',5''-phosphate 17. The synthesis of the C-nucleoside analog was achieved from the .beta.-D-ribofuranosylcarboximidic ester. The acylic analog and the .beta.-D-arabinofuranosyl derivative were both synthesized by reaction of methyl isocyanate with the appropriately protected aminocyanoimidazole precursors. 1-Methylxanthosine, isoguanosine and 2-methoxyadenosine (18) were synthesized. At doses up to 100 mg/kg p.o. [per os], the 5''-phosphate, 17 and the O-methylated analog 18 were active in producing muscle relaxation and hypothermia. These compounds possessed antiallergic acitivity and produced dose-dependent falls in mean blood pressure and heart rate as did the 1-ethyl and 1-n-butyl analog. In general, antiinflammatory activity paralleled the other results, except that the 17 was inactive at the dose tested, while the 3,5''-anhydronucleoside was weakly active and displayed antiallergic effects.

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