Ribose-modified purine nucleosides as ribonucleotide reductase inhibitors. Synthesis, antitumor activity, and molecular modeling of N6- substituted 3′-C-methyladenosine derivatives

Loredana Cappellacci, Palmarisa Franchetti, Patrizia Vita, Riccardo Petrelli, Antonio Lavecchia, Hiremagalur N. Jayaram, Philipp Saiko, Geraldine Graser, Thomas Szekeres, Mario Grifantini

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21 Scopus citations

Abstract

A series of cycloalkyl, bicycloalkyl, aryl, and heteroaryl N 6-substituted derivatives of the antitumor agent 3′-C- methyladenosine (3′-Me-Ado), an inhibitor of the α Rnr1 subunit of mammalian ribonucleotide reductase (RR), were synthesized. The cytotoxicity of these compounds was evaluated against a panel of human leukemia and carcinoma cell lines and compared to that of some corresponding N6-substituted adenosine analogues. N6-cycloalkyl-3′-C-methylribonucleosides 2-7 and N6-phenyl analogue 8 were found to inhibit the proliferation of K562 leukemia cells. N6-(±)-endo-2-norbornyl-3′-C- methyladenosine (7) was found to be the most cytotoxic compound, with GI 50 values slightly higher than that of 3′-Me-Ado against K562 and carcinoma cell lines and 2.7 fold higher cytotoxicity against human promyelocytic leukemia HL-60 cells. The SAR study confirms that an unsubstituted N6-amino group is essential for optimal cytotoxicity of 3′-Me-Ado against both K562 and carcinoma cell lines. Computational studies, carried out on the eukaryotic α subunit (Rnr1) of RR from Saccharomyces cerevisiae were performed to rationalize the observed structure-activity relationships.

Original languageEnglish (US)
Pages (from-to)4260-4269
Number of pages10
JournalJournal of Medicinal Chemistry
Volume51
Issue number14
DOIs
StatePublished - Jul 24 2008

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Cappellacci, L., Franchetti, P., Vita, P., Petrelli, R., Lavecchia, A., Jayaram, H. N., Saiko, P., Graser, G., Szekeres, T., & Grifantini, M. (2008). Ribose-modified purine nucleosides as ribonucleotide reductase inhibitors. Synthesis, antitumor activity, and molecular modeling of N6- substituted 3′-C-methyladenosine derivatives. Journal of Medicinal Chemistry, 51(14), 4260-4269. https://doi.org/10.1021/jm800205c