7-(2-Thienyl)-7-Deazaadenosine (AB61), a New Potent Nucleoside Cytostatic with a Complex Mode of Action

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.

N‐Benzyl Substitution of Polyhydroxypyrrolidines: The Way to Selective Inhibitors of Golgi α‐Mannosidase II

“…Both proteins belong to the family of ABC transporters and are involved in the primary and/or acquired multidrug resistance phenomenon. [27] MRC-5 and BJ cell lines were used as a non-tumor control and represent human fibroblasts. The cells were maintained in nunc/corning 80 cm 2 plastic tissue culture flasks and cultured in cell culture medium according to ATCC or Horizon recommendations (DMEM/RPMI 1640 with 5 g/L glucose, 2 m M glutamine, 100 U/mL penicillin, 100 mg/mL streptomycin, 10% fetal calf serum, and NaHCO 3 ).…”

“…The IC 50 value, the drug concentration that is lethal to 50% of the tumor cells, was calculated from the appropriate dose-response curves in Dotmatics software. [27]…”

Thienopyrrolo[2, 3‐d]pyrimidines, New Tricyclic Nucleobase Analogues: Synthesis and Biological Activities

“…These nucleosides also displayed submicromolar anti‐HCV activities, but the methyl, methoxy and methylsulfanyl derivatives were strong nanomolar cytostatics with no/low toxicity to nonmalignant cells showing promising therapeutic index. Preliminary results indicate a different mechanism of action than a previously described related cytostatic 6‐amino‐7‐(2‐thienyl)‐7‐deazapurine ribonucleoside AB61 …”

Pyrrolo[2,3‐d]pyrimidine (7‐deazapurine) as a privileged scaffold in design of antitumor and antiviral nucleosides

“…Direct connection of thiophene and 7‐deazapurine moieties in 7a (known as AB61) is also crucial for the cytotoxic activity, as its analogue 8 with the thienyl group attached via a sulfur atom showed a substantial drop of activity (IC 50 > 20 μM) . The mechanism of action of AB61 ( 7a ) was studied in detail (Fig. ).…”