Antitumor Activity of C-Methyl-β-d-ribofuranosyladenine Nucleoside Ribonucleotide Reductase Inhibitors

• Published in: Journal of medicinal chemistry Vol. 48; no. 15; pp. 4983 - 4989
• Main Authors: Franchetti, Palmarisa, Cappellacci, Loredana, Pasqualini, Michela, Petrelli, Riccardo, Vita, Patrizia, Jayaram, Hiremagalur N, Horvath, Zsuzsanna, Szekeres, Thomas, Grifantini, Mario
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 28-07-2005
• Subjects: Adenosine - analogs & derivatives; Adenosine - chemical synthesis; Adenosine - chemistry; Adenosine - pharmacology; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; Cell Line, Tumor; Drug Screening Assays, Antitumor; General aspects; Humans; Medical sciences; Pharmacology. Drug treatments; Ribonucleotide Reductases - antagonists & inhibitors; Structure-Activity Relationship; Antineoplastic agent; Human; Purine nucleoside; Enzyme; Leukemia; Cytotoxicity; Branched compound; In vitro; HL60 cell line; Cell line; Structure activity relation; Colon; Mammary gland; Oxidoreductases; Ribonucleoside; Chemical synthesis; Tumor cell
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm048944c

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 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.