Synthesis purine and purine riboside derivatives

Abstract

One of the most unusual purine riboside in nature is isoguanosine. Most of isoguanosine derivatives have been reported to be found in sponge. The new marine natural product doridosine(1-methylisoguanosine) has several biological activities in mammals. Some doridosine analogues, such as 1-ethyl-3-methyl-$N^6$-imino-2-oxo-9-$\beta$-D-ribofuranosylpurine($\underline{2}$), 2-mercaptoadenosine($\underline{3}$), 1-methyl-2-thioadenosine($\underline{4}$), and 1-$\beta$-D-ribofuranosyl-5-alkyl-4-amino-6-oxopyrazolo[3,4-d]pyrimidines($\underline{8a}$,$\underline{8b}$), and acyclic nucleosides of these compounds($\underline{5}$,$\underline{6}$,$\underline{9}$,$\underline{10}$) were prepared and their physical and biological properties were examined. In amino-imino and enol-keto tautomerism, compound $\underline{2}$ is a fixed model compound of 6-imino-2-keto form. Compound $\underline{2}$ was synthesized by several steps started from 5-aminoimidazolo-4-carbamide riboside. Compounds $\underline{3}$ and $\underline{4}$ were prepared from 6-amino-2-mercaptopurine hemisulfate, and compounds $\underline{8a}$, $\underline{8b}$ were synthesized from 5-amino-4-cyanopyrazole via several steps. In the field of biological activity, Compounds $\underline{2}$, $\underline{3}$, and $\underline{4}$ showed coronary vasodilating effects ($\underline{2}$: 36.5\%, $\underline{3}$: 57.5\%, $\underline{4}$: 23.4\%) at 10$\mu$g/heart, and compounds $\underline{3}$ and $\underline{4}$ showed powerful hypotensive effect ($\underline{3}$: 40 mmHg, $\underline{4}$: 50 mmHg fall in 1 mg/kg) which was accompanied by slightly increase in heart rate and respiratory rate. Compound $\underline{4}$ did not show any toxicity on liver within dose of 10 mg/kg. These preliminary results demonstrated that the sulfur analogues of doridosine, $\underline{3}$ and $\underline{4}$ are promising product of a rational drug design.