Ribose-modified purine nucleosides as ribonucleotide reductase inhibitors. Synthesis, antitumor activity, and molecular modeling of N6-substituted 3'-C-methyladenosine derivatives.
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 alpha 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 N (6)-substituted adenosine analogues. N (6)-cycloalkyl-3'- C-methylribonucleosides 2- 7 and N (6)-phenyl analogue 8 were found to inhibit the proliferation of K562 leukemia cells. N (6)-(+/-)- 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 N (6)-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 alpha subunit (Rnr1) of RR from Saccharomyces cerevisiae were performed to rationalize the observed structure-activity relationships.
Cappellacci
Loredana
L
Dipartimento di Scienze Chimiche, Università di Camerino, 62032 Camerino, Italy,
Franchetti
Palmarisa
P
Vita
Patrizia
P
Petrelli
Riccardo
R
Lavecchia
Antonio
A
Jayaram
Hiremagalur N
HN
Saiko
Philipp
P
Graser
Geraldine
G
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; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*; D012266:Ribose / Q000737:chemistry*; D013329:Structure-Activity Relationship
C502992:3'-C-methyladenosine; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C002230:1-methyladenosine; D012266:Ribose; D012264:Ribonucleotide Reductases; D000241:Adenosine