2'-Deoxy-2'-methylenecytidine and 2'-deoxy-2',2'-difluorocytidine 5'-diphosphates: potent mechanism-based inhibitors of ribonucleotide reductase

Abstract

It has been found that 2'-deoxy-2'-methyleneuridine (MdUrd), 2'-deoxy-2'-methylenecytidine (MdCyd), and 2'-deoxy-2',2'-difluorocytidine (dFdCyd) 5'-diphosphates (MdUDP (1) MdCDP (2) and dFdCDP (3), respectively) function as irreversible inactivators of the Escherichia coli ribonucleoside diphosphate reductase (RDPR). 2 is a much more potent inhibitor than its uridine analogue 1. It is proposed that 2 undergoes abstraction of H3' to give an allylic radical that captures a hydrogen atom and decomposes to an active alkylating furanone species. RDPR also accepts 3 as an alternative substrate analogue and presumably executes an initial abstraction of H3' to initiate formation of a suicide species. Both 2 and 3 give inactivation results that differ from those of previously studied inhibitors. The potent anticancer activities of MdCyd and dFdCyd indicate a significant chemotherapeutic potential. The analogous RDPR of mammalian cells should be regarded as a likely target and/or activating enzyme for these novel mechanism-based inactivators.

Excision of mismatched nucleotides from DNA: a potential mechanism for enhancing DNA replication fidelity by the wild-type p53 protein

“…In fact, we observed that the incubation of ML-1 cells with the nucleoside analog gemcitabine (dFdC) resulted in a signi®cant increase in the number of p53-positive nuclei in ML-1 cells. Gemcitabine has been demonstrated to be incorporated into DNA (Huang, 1991a); it may also cause the incorporation of mismatched deoxynucleotides into DNA because of the imbalance of cellular dNTP pools due to inhibition of ribonucleotide reductase by the drug (Gandhi and Plunkett, 1990;Baker et al, 1991). In the exponentially growing ML-1 cell population, approximately 19% of the cells had a strong p53 stain in their nuclei under normal culture conditions.…”

Gemcitabine-induced CXCL8 expression counteracts its actions by inducing tumor neovascularization

“…dFdCTP directly inhibits DNA polymerase [6], cytidine triphosphate synthetase [7] and deoxycytidylate deaminase [8], and is incorporated into DNA, thereby terminating chain elongation [9]. dFdCDP potently inhibits ribonucleotide reductase (RR), thereby decreasing deoxynucleotide pools [10]. Despite its multiple intracellular targets, the resistance to gemcitabine often ensues [1].…”

Silencing of ribonucleotide reductase subunit M1 potentiates the antitumor activity of gemcitabine in resistant cancer cells

“…3 Gemcitabine diphosphate (dFdCDP) binds to the large subunit M1 of RR (RRM1) and inhibits RR, thereby depleting the cellular deoxynucleotide (dNTP) pools. 4,5 RRM1 has been identified as the key molecule in determining the efficacy of gemcitabine. The overexpression of RRM1 had been repeatedly reported in gemcitabine-resistant cancer cells both in vitro and in vivo, [6][7][8][9][10][11] and RRM1 overexpression through the transfection of a lung cancer cell line led to gemcitabine resistance as well.…”