The antitumor effects of 3’-methyl-adenosine mediated by inhibition of ribonucleotide reductase.

Adenosine derivatives modified at the 1-, 2-, or 3-C-position of the ribose ring by the introduction of a methyl group were evaluated for their antitumor activity. 3'-C-Methyladenosine (3'-Me-Ado) showed the higher cytotoxicity compared to that of other analogues against human myelogenous leukemia K562, human colon carcinoma HT-29, and human breast carcinoma MCF-7 cell lines. Structure-activity relationships study showed that the structure of 3'-Me-Ado is crucial for the activity. The cytotoxicity of 3'-Me-Ado could be explained by its ability to reduce the levels of both intracellular purine and pyrimidine deoxynucleotides through ribonucleotide reductase (RR) inhibition

Antitumor Activity of C-Methyl-beta-D-ribofuranosyladenine Nucleosides Ribonucleotide Reductase Inhibitors

A series of adenosine derivatives substituted at the 1'-, 2'-, or 3'-position of the ribose ring with a methyl group was synthesized and evaluated for antitumor activity. From this study 3'-C-methyladenosine (3'-Me-Ado) emerged as the most active compound, showing activity against human myelogenous leukemia K562, multidrug resistant human leukemia K562IU, human promyelocytic leukemia HL-60, human colon carcinoma HT-29, and human breast carcinoma MCF-7 cell lines with IC50 values ranging from 11 to 38 mu M. Structure-activity relationship studies showed that the structure of 3'-Me-Ado is crucial for the activity. Substitution of a hydrogen atom of the N-6-amino group with a small alkyl or cycloalkyl group, the introduction of a chlorine atom in the 2-position of the purine ring, or the moving of the methyl group from the T-position to other ribose positions brought about a decrease or loss of antitumor activity. The antiproliferative activity of 3'-Me-Ado appears to be related to its ability to deplete both intracellular purine and pyrimidine deoxynucleotides through ribonucleotide reductase inhibition