Antitumor activity of C-methyl-beta-D-ribofuranosyladenine nucleoside ribonucleotide reductase inhibitors.
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| Abstract |
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 IC(50) values ranging from 11 to 38 muM. 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 3'-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.
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| Authors | Palmarisa Franchetti, Loredana Cappellacci, Michela Pasqualini, Riccardo Petrelli, Patrizia Vita, Hiremagalur N Jayaram, Zsuzsanna Horvath, Thomas Szekeres, Mario Grifantini |
| Journal | Journal of medicinal chemistry (J Med Chem) Vol. 48 Issue 15 Pg. 4983-9 (Jul 28 2005) ISSN: 0022-2623 [Print] United States |
| PMID | 16033277 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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