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

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 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.

From the covalent linkage of drugs to novel inhibitors of ribonucleotide reductase: Synthesis and biological evaluation of valproic esters of 3′-C-methyladenosine

“…18,19 Our previous work on RR inhibitors included the synthesis of 3 0 -C-methyladenosine (3 0 -Me-Ado), a purine ribonucleoside that acts as a mechanism-based inhibitor of the R1 subunit of mammalian RR, and is endowed with significant antitumor activity against a panel of human leukemia and carcinoma cell lines. [20][21][22][23] Interestingly, we found that its cytotoxic and apoptotic activity could be enhanced by combining it with several hydroxamic acid-derived HDAC inhibitors, including the two recently synthesized molecules, MC1864 and MC1879, and the reference compound trichostatin A (TSA). 24 Based on this finding our original aim was to combine 3 0 -Me-Ado with VPA to create a prodrug that would simultaneously deliver both agents into cancer cells for synergistic antitumor activity.…”

Synthesis of Triazole-Linked Analogues of c-di-GMP and Their Interactions with Diguanylate Cyclase

“…Similarly, the protected 5'-azido-5'-deoxy-guanosine 3 was reacted with N 6 -benzoyl-2',3'-O-isopropylidene-5'-O-propargyl-adenosine (9) 34 , to obtain the intermediate 11. The 5'-azido-5'-deoxy-2',3'-O-isopropylidene-adenosine (5) 35 , prepared starting from 2',3'-Oisopropylidene-adenosine (2) [36][37][38][39][40] was clicked with 8 and 9 to furnish the 1,2,3-triazole intermediates 12 and 13, respectively. Compound 10 was first deprotected in acidic conditions and then in saturated ammonium hydroxide solution at 50°C, to give, after purification, the triazolelinked dinucleoside DCI028.…”

Stereoselective Synthesis of Novel Aristeromycin Analogues as Potential Antiviral Agents

“…[13][14][15] Recently, a series of adenosine analogues substituted at the ribose ring with a methyl group have been synthesized and evaluated for antitumor activity. 16 From this study, 3¢-Cmethyladenosine (3¢-Me-Ado, Figure 1) has emerged as an active derivative, and the structure-activity correlation studies have pointed out that its structure is crucial for the antitumor activity. 16 In connection with these facts, we reported in a preliminary communication an original synthetic pathway to the carbasugar analogue, (-)-3¢-methylaristeromycin, with the aim of studying in the near future its biological potential (1, Figure 1).…”

“…16 From this study, 3¢-Cmethyladenosine (3¢-Me-Ado, Figure 1) has emerged as an active derivative, and the structure-activity correlation studies have pointed out that its structure is crucial for the antitumor activity. 16 In connection with these facts, we reported in a preliminary communication an original synthetic pathway to the carbasugar analogue, (-)-3¢-methylaristeromycin, with the aim of studying in the near future its biological potential (1, Figure 1). 17 Modifications of the heterocyclic base moiety of carbocyclic nucleosides may also lead to significant changes in the spectrum of their biological activities.…”