Synthesis and pharmacological evaluation of a series of analogues of 1-methylisoguanosine.
A series of analogues of the pharmacologically active marine natural product 1-methylisoguanosine (1) was evaluated for biological activity in muscle relaxant, cardiovascular, antiinflammatory, and antiallergic tests. Modifications at the 1 position produced the ethyl, n-butyl, n-octyl, and phenyl derivatives 3-6, respectively. Substitutions at the 8 position provided the bromo, hydrazino and amino compounds 9-11. Modification at the 5' position yielded the deoxy, iodo, and phosphate derivatives 15, 13, and 16, as well as the cyclic 3',5'-phosphate 17. The synthesis of the C-nucleoside analogue 19 was achieved from the beta-D-ribofuranosylcarboximidic ester 20. The acyclic analogue 29 and the beta-D-arabinofuranosyl derivative 35 were both synthesized by reaction of methyl isocyanate with the appropriately protected aminocyanoimidazole precursors 28 and 32. 1-Methylxanthosine (12), isoguanosine (7), and 2-methoxyadenosine (18) were also synthesized. At doses up to 100 mg/kg po, the 5'-phosphate 16, cyclic 3',5'-phosphate 17, and the O-methylated analogue 2-methoxyadenosine 18 were active in producing muscle relaxation and hypothermia. These compounds possessed antiallergic activity and produced dose-dependent falls in mean blood pressure and heart rate as did the 1-ethyl (3) and 1-n-butyl (4) analogues. In general, antiinflammatory activity paralleled the other results, except that the cyclic 3',5'-phosphate 17 was inactive at the dose tested, while the 3,5'-anhydronucleoside 14 was weakly active and displayed antiallergic effects.
D000707:Anaphylaxis / Q000188:drug therapy; D000818:Animals; D000893:Anti-Inflammatory Agents; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006151:Guanosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D051379:Mice; D009125:Muscle Relaxants, Central; D051381:Rats; D013329:Structure-Activity Relationship
D000893:Anti-Inflammatory Agents; D009125:Muscle Relaxants, Central; D006151:Guanosine; C022591:doridosine