Antitumor activity of C-methyl-β-D-ribofuranosyladenine nucleoside ribonucleotide reductase inhibitors

Palmarisa Franchetti, Loredana Cappellacci, Michela Pasqualini, Riccardo Petrelli, Patrizia Vita, Hiremagalur N. Jayaram, Zsuzsanna Horvath, Thomas Szekeres, Mario Grifantini

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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 IC50 values ranging from 11 to 38 μM. Structure-activity relationship studies showed that the structure of 3′-Me-Ado is crucial for the activity. Substitution of a hydrogen atom of the N6-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.

Original languageEnglish (US)
Pages (from-to)4983-4989
Number of pages7
JournalJournal of Medicinal Chemistry
Volume48
Issue number15
DOIs
StatePublished - Jul 28 2005

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Franchetti, P., Cappellacci, L., Pasqualini, M., Petrelli, R., Vita, P., Jayaram, H. N., Horvath, Z., Szekeres, T., & Grifantini, M. (2005). Antitumor activity of C-methyl-β-D-ribofuranosyladenine nucleoside ribonucleotide reductase inhibitors. Journal of Medicinal Chemistry, 48(15), 4983-4989. https://doi.org/10.1021/jm048944c