Abstract
7-(2-Thienyl)-7-deazaadenosine (AB61) showed nanomolar cytotoxic activities against various cancer cell lines but only mild (micromolar) activities against normal fibroblasts. The selectivity of AB61 was found to be due to inefficient phosphorylation of AB61 in normal fibroblasts. The phosphorylation of AB61 in the leukemic CCRF-CEM cell line proceeds well and it was shown that AB61 is incorporated into both DNA and RNA, preferentially as a ribonucleotide. It was further confirmed that a triphosphate of AB61 is a substrate for both RNA and DNA polymerases in enzymatic assays. Gene expression analysis suggests that AB61 affects DNA damage pathways and protein translation/folding machinery. Indeed, formation of large 53BP1 foci was observed in nuclei of AB61-treated U2OS-GFP-53BP1 cells indicating DNA damage. Random incorporation of AB61 into RNA blocked its translation in an in vitro assay and reduction of reporter protein expression was also observed in mice after 4-hour treatment with AB61. AB61 also significantly reduced tumor volume in mice bearing SK-OV-3, BT-549, and HT-29 xenografts. The results indicate that AB61 is a promising compound with unique mechanism of action and deserves further development as an anticancer agent. Mol Cancer Ther; 15(5); 922-37. ©2016 AACR.
Highlights
7-(2-Thienyl)-7-deazaadenosine (AB61) showed nanomolar cytotoxic activities against various cancer cell lines but only mild activities against normal fibroblasts
Synthesis of nucleosides and nucleotide analytical standards To obtain analytical standards of AB61-derived metabolites, the nucleotides dAB61-MP and AB61-DP were prepared under standard conditions for Suzuki cross-coupling reaction [11, 29, 30] of the corresponding nucleotide or by phosphorylation of the nucleoside, respectively. [3H]-Labeled AB61 ([3H]AB61) was synthesized by Suzuki cross-coupling reaction of 5-iodotubercidin with 5-chlorothiophene-2-boronic acid followed by tritiation (Fig. 2)
We focused on elucidation of the mechanism of action of a novel 7-deazaadenine analogue, AB61
Summary
7-(2-Thienyl)-7-deazaadenosine (AB61) showed nanomolar cytotoxic activities against various cancer cell lines but only mild (micromolar) activities against normal fibroblasts. Mechanisms of action of naturally occurring 7-deazapurine nucleosides tubercidin, toyocamycin, and sangivamycin (Fig. 1) have been extensively studied. Despite structural similarities, their biochemical and biologic properties show different features for each nucleoside. The most promising derivative among the 7-hetaryl-7-adenosines is a 2-thienyl derivative AB61 (Fig. 1), which is highly cytotoxic against leukemic and solid tumor–derived cell lines and noncytotoxic to normal human fibroblasts [11]. AB61, a New Potent 7-Deazapurine Nucleoside Cytostatic action in CCRF-CEM lymphoblasts showed fast onset of the RNA synthesis inhibition and inhibition of DNA synthesis at higher concentrations. AB61 and its related derivatives were found [17] to be weak inhibitors of human adenosine kinase and AB61 itself was found to be a weak substrate for this enzyme (2%) as compared with adenosine
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