Structure–activity relationships of β-hydroxyphosphonate nucleoside analogues as cytosolic 5′-nucleotidase II potential inhibitors: Synthesis, in vitro evaluation and molecular modeling studies

Meurillon, Maïa; Márton, Zsuzsanna; Jordheim, Lars Petter; Bejaud, Jérôme; Lionne, Corinne; Dumontet, Charles; Philouze, Christian; Chaloin, Laurent; Peyrottes, Suzanne

doi:10.1016/j.ejmech.2014.02.055

Cited by 21 publications

(30 citation statements)

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“…The cytosolic enzyme cN-II has a preference for IMP and GMP and has also been described as being capable of phosphorylating nucleosides through a phosphotransferase activity [ 7 ]. We have previously shown that this enzyme is involved in the sensitivity of cancer cells to nucleoside analogue-based chemotherapy [ 8 , 9 ], and developed and studied enzymatic inhibitors [ 10 – 14 ]. The clinical relevance of this approach has been confirmed by the observation of hyperactive cN-II mutants in relapsed pediatric acute lymphoblastic leukemia patients associated with a resistance to purine analogues [ 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

The cytosolic 5′-nucleotidase cN-II lowers the adaptability to glucose deprivation in human breast cancer cells

et al. 2017

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The cytosolic 5’-nucleotidase cN-II is a highly conserved enzyme implicated in nucleotide metabolism. Based on recent observations suggesting additional roles not directly associated to its enzymatic activity, we studied human cancer cell models with basal or decreased cN-II expression. We developed cancer cells with stable inhibition of cN-II expression by transfection of shRNA-coding plasmids, and studied their biology. We show that human breast cancer cells MDA-MB-231 with decreased cN-II expression better adapt to the disappearance of glucose in growth medium under normoxic conditions than cells with a baseline expression level. This is associated with enhanced in vivo growth and a lower content of ROS in cells cultivated in absence of glucose due to more efficient mechanisms of elimination of ROS. Conversely, cells with low cN-II expression are more sensitive to glucose deprivation in hypoxic conditions. Overall, our results show that cN-II regulates the cellular response to glucose deprivation through a mechanism related to ROS metabolism and defence.

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Section: Introductionmentioning

confidence: 99%

The cytosolic 5′-nucleotidase cN-II lowers the adaptability to glucose deprivation in human breast cancer cells

et al. 2017

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“…We have identified, synthesized, and evaluated cN-II inhibitors using different approaches and showed that some of them are both cytotoxic per se and sensitize cancer cells to nucleoside analogues [21][22][23]. As it is difficult to evaluate whether the observed biological effect of such inhibitors is due to cN-II inhibition in cells or to off-target effects, we modified cN-II expression in different cell line models by molecular biology and studied the associated modifications in cancer cell biology.…”

Section: Discussionmentioning

confidence: 98%

Determination of the enzymatic activity of cytosolic 5′-nucleotidase cN-II in cancer cells: development of a simple analytical method and related cell line models

et al. 2015

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The cytosolic 5'-nucleotidase (cN-II) has been shown to be involved in the response of cancer cells to cytotoxic agents, and the quantification of its activity in biological samples is of great interest. In this context, we developed and validated an analytical method for determination of cN-II activity in cultured cancer cells. This non-radioactive method, using a Hypercarb column as stationary phase, was validated with a lower limit of quantification of 0.1 μM inosine. We used it to characterize cell line models with modified cN-II expression obtained with stable transfections. We show that the short hairpin RNA (shRNA)-mediated inhibition of cN-II expression in various malignant blood cells is associated with decreased protein expression and enzymatic activity (1.7-6.2-fold) as well as an increased sensitivity to cytotoxic agents (up to 14-fold). On the other hand, expression of green fluorescent protein (GFP)-fused wild type or hyperactive mutant (R367Q) cN-II increased the activity and also decreased the sensitivity to nucleoside analogues. Our results confirm the biological relevance of modulating cN-II in cancer cells, and we present a straightforward validated method for the determination of cN-II activity in cellular samples.

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“…Recently, it was shown that fludarabine was able to interfere with human cN-II as a mixed-inhibitor (Ki 0.5 mM and Ki' 9 mM) [14]. Over the last decade, we have also identified, developed and studied cN-II inhibitors by using virtual screening [15], a substrate analogue-based approach [16][17][18], and finally a fragmentbased drug discovery (FBDD) strategy [19]. All these derivatives behaved as weak to modest cN-II inhibitors with Ki in the millimolar range ( Fig.…”

Section: Introductionmentioning

confidence: 99%

Lead optimization and biological evaluation of fragment-based cN-II inhibitors

Guillon

Rahimova

Preeti

et al. 2019

European Journal of Medicinal Chemistry

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The development of cytosolic 5'-nucleotidase II (cN-II) inhibitors is essential to validate cN-II as a potential target for the reversion of resistance to cytotoxic nucleoside analogues. We previously reported a fragment-based approach combined with molecular modelling, herein, the selected hit-fragments were used again in another computational approach based on the Ilib-diverse (a software enabling to build virtual molecule libraries through fragment based de novo design) program to generate a focused library of potential inhibitors. A molecular scaffold related to a previously identified compound was selected and led to a novel series of compounds. Ten out of nineteen derivatives showed 50 to 75% inhibition on the purified recombinant protein at 200 µM and among them three derivatives (12, 13 and 18) exhibited Ki in the sub-millimolar range (0.84, 2.4 and 0.58 mM, respectively). Despite their only modest potency, the cN-II inhibitors showed synergistic effects when used in combination with cytotoxic purine nucleoside analogues on cancer cells. Therefore, these derivatives represent a family of non-nucleos(t)idic cN-II inhibitors with potential usefulness to overcome cancer drug resistance especially in hematological malignancies in which cN-II activity has been described.

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Structure–activity relationships of β-hydroxyphosphonate nucleoside analogues as cytosolic 5′-nucleotidase II potential inhibitors: Synthesis, in vitro evaluation and molecular modeling studies

Cited by 21 publications

References 42 publications

The cytosolic 5′-nucleotidase cN-II lowers the adaptability to glucose deprivation in human breast cancer cells

The cytosolic 5′-nucleotidase cN-II lowers the adaptability to glucose deprivation in human breast cancer cells

Determination of the enzymatic activity of cytosolic 5′-nucleotidase cN-II in cancer cells: development of a simple analytical method and related cell line models

Lead optimization and biological evaluation of fragment-based cN-II inhibitors

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