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

Research output: Contribution to journalArticle

19 Citations (Scopus)

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

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Purine Nucleosides
Ribonucleotide Reductases
Molecular modeling
Ribose
K562 Cells
Derivatives
Cytotoxicity
Leukemia
Cells
Carcinoma
Cell Line
HL-60 Cells
Structure-Activity Relationship
Antineoplastic Agents
Yeast
Adenosine
Saccharomyces cerevisiae
3'-C-methyladenosine

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Ribose-modified purine nucleosides as ribonucleotide reductase inhibitors. Synthesis, antitumor activity, and molecular modeling of N6- substituted 3′-C-methyladenosine derivatives. / Cappellacci, Loredana; Franchetti, Palmarisa; Vita, Patrizia; Petrelli, Riccardo; Lavecchia, Antonio; Jayaram, Hiremagalur N.; Saiko, Philipp; Graser, Geraldine; Szekeres, Thomas; Grifantini, Mario.

In: Journal of Medicinal Chemistry, Vol. 51, No. 14, 24.07.2008, p. 4260-4269.

Research output: Contribution to journalArticle

Cappellacci, L, Franchetti, P, Vita, P, Petrelli, R, Lavecchia, A, Jayaram, HN, 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, vol. 51, no. 14, pp. 4260-4269. https://doi.org/10.1021/jm800205c
Cappellacci, Loredana ; Franchetti, Palmarisa ; Vita, Patrizia ; Petrelli, Riccardo ; Lavecchia, Antonio ; Jayaram, Hiremagalur N. ; Saiko, Philipp ; Graser, Geraldine ; Szekeres, Thomas ; Grifantini, Mario. / Ribose-modified purine nucleosides as ribonucleotide reductase inhibitors. Synthesis, antitumor activity, and molecular modeling of N6- substituted 3′-C-methyladenosine derivatives. In: Journal of Medicinal Chemistry. 2008 ; Vol. 51, No. 14. pp. 4260-4269.
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