Antitumor activity of C-methyl-beta-D-ribofuranosyladenine nucleoside ribonucleotide reductase inhibitors.
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 IC(50) values ranging from 11 to 38 muM. 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.
Franchetti
Palmarisa
P
Dipartimento di Scienze Chimiche, Università di Camerino, 62032 Camerino, Italy.
Cappellacci
Loredana
L
Pasqualini
Michela
M
Petrelli
Riccardo
R
Vita
Patrizia
P
Jayaram
Hiremagalur N
HN
Horvath
Zsuzsanna
Z
Szekeres
Thomas
T
Grifantini
Mario
M
D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
C502992:3'-C-methyladenosine; D000970:Antineoplastic Agents; D012264:Ribonucleotide Reductases; D000241:Adenosine