Antitumor Activity of C-Methyl-β-d-ribofuranosyladenine Nucleoside Ribonucleotide Reductase Inhibitors
- 28 June 2005
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 48 (15) , 4983-4989
- https://doi.org/10.1021/jm048944c
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.Keywords
This publication has 12 references indexed in Scilit:
- Synthesis, Biological Evaluation, and Molecular Modeling of Ribose-Modified Adenosine Analogues as Adenosine Receptor AgonistsJournal of Medicinal Chemistry, 2005
- Cytotoxicity and cellular differentiation activity of methylenebis(phosphonate) analogs of tiazofurin and mycophenolic acid adenine dinucleotide in human cancer cell linesCancer Letters, 2002
- Nucleosides and Nucleotides. 175. Structural Requirements of the Sugar Moiety for the Antitumor Activities of New Nucleoside Antimetabolites, 1-(3-C-Ethynyl-β-d-ribo-pentofuranosyl)cytosine and -uracilJournal of Medicinal Chemistry, 1998
- Biochemical and antitumor activity of trimidox, a new inhibitor of ribonucleotide reductaseCancer Chemotherapy and Pharmacology, 1994
- Synthesis of 4′-C-MethylnucleosidesBioscience, Biotechnology, and Biochemistry, 1993
- Synthesis and antibacterial activities of C-21 functionalized derivatives of (9R)-9-amino-9-deoxoerythromycins A and BJournal of Medicinal Chemistry, 1991
- Assignment of Anomeric Configuration of D-Ribo-, Arabino-, 2′-Deoxyribo-, and 2′,3′-Dideoxyribonucleosides by Noe Difference SpectroscopyNucleosides, Nucleotides and Nucleic Acids, 1989
- Dog coronary artery adenosine receptor: structure of the N6-alkyl subregionJournal of Medicinal Chemistry, 1985
- A rapid and sensitive high pressure liquid chromatography assay for deoxyribonucleoside triphosphates in cell extractsAnalytical Biochemistry, 1979
- An Example of Alkyne-Alkyne InteractionJournal of the American Chemical Society, 1966