A Novel Potent Nicotinamide Phosphoribosyltransferase Inhibitor Synthesized via Click Chemistry

Colombano, Giampiero; Travelli, Cristina; Galli, Ubaldina; Caldarelli, Antonio; Chini, Maria Giovanna; Canonico, Pier Luigi; Sorba, Giovanni; Bifulco, Giuseppe; Tron, Gian Cesare; Genazzani, Armando A.

doi:10.1021/jm9010669

Cited by 90 publications

(73 citation statements)

References 33 publications

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“…Likewise, we had previously shown that SNB-19 and SNB-75, two other cell lines, were sensitive to NADdepleting agents (Colombano et al, 2010). These data, together with the immunohistochemical data showing the presence of NAMPT in these tumors, suggests that these agents might have a role in neuroblastoma therapy.…”

Section: Discussionsupporting

confidence: 68%

“…Viability of cells was measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium assay as described elsewhere (Colombano et al, 2010).…”

Section: Methodsmentioning

confidence: 99%

“…The pellet containing mitochondria were washed and recentrifuged twice and for Western blotting analysis resuspended in buffer B (20 mM Tris, pH 7.5, 100 mM NaCl, 1% Triton, 1 mM DTT, 1 mM PMSF, 0.2 mM sodium orthovanadate, 1 mM NaF). Protein concentration of the subcellular fractions was determined as described previously (Colombano et al, 2010).…”

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confidence: 99%

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Reciprocal Potentiation of the Antitumoral Activities of FK866, an Inhibitor of Nicotinamide Phosphoribosyltransferase, and Etoposide or Cisplatin in Neuroblastoma Cells

Travelli¹,

Drago²,

Maldi

et al. 2011

J Pharmacol Exp Ther

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NAD is an essential coenzyme involved in numerous metabolic pathways. Its principal role is in redox reactions, and as such it is not heavily "consumed" by cells. Yet a number of signaling pathways that bring about its consumption have recently emerged. This has brought about the hypothesis that the enzymes that lead to its biosynthesis may be targets for anticancer therapy. In particular, inhibition of the enzyme nicotinamide phosphoribosyl transferase has been shown to be an effective treatment in a number of preclinical studies, and two lead molecules [N-[4-(1-benzoyl-4-piperidinyl)butyl]-3-(3-pyridinyl)-2E-propenamide (FK866) and (E)-1-[6-(4-chlorophenoxy)hexyl]-2-cyano-3-(pyridin-4-yl)guanidine (CHS 828)] have now entered preclinical trials. Yet, the full potential of these drugs is still unclear. In the present study we have investigated the role of FK866 in neuroblastoma cell lines. We now confirm that FK866 alone in neuroblastoma cells induces autophagy, and its effects are potentiated by chloroquine and antagonized by 3-methyladenine or by down-regulating autophagy-related protein 7. Autophagy, in this model, seems to be crucial for FK866-induced cell death. On the other hand, a striking potentiation of the effects of cisplatin and etoposide is given by cotreatment of cells with ineffective concentrations of FK866 (1 nM). The effect of etoposide on DNA damage is potentiated by FK866 treatment, whereas the effect of FK866 on cytosolic NAD depletion is potentiated by etoposide. Even more strikingly, cotreatment with etoposide/cisplatin and FK866 unmasks an effect on mitochondrial NAD depletion.

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Section: Discussionsupporting

confidence: 68%

“…Viability of cells was measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium assay as described elsewhere (Colombano et al, 2010).…”

Section: Methodsmentioning

confidence: 99%

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Reciprocal Potentiation of the Antitumoral Activities of FK866, an Inhibitor of Nicotinamide Phosphoribosyltransferase, and Etoposide or Cisplatin in Neuroblastoma Cells

Travelli¹,

Drago²,

Maldi

et al. 2011

J Pharmacol Exp Ther

Self Cite

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“…[159] The most promising compound displayed an IC 50 for cytotoxicity in vitro of (3.8 AE 0.3) nm and an IC 50 for nicotinamide adenine dinucleotide (NAD) depletion of (3.0 AE 0.4) nm.…”

Section: Antifungal and Antibacterialsmentioning

confidence: 99%

Click Chemistry: 1,2,3‐Triazoles as Pharmacophores

Agalave

Maujan

Pore

2011

Chemistry An Asian Journal

1,167

508

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The copper(I)-catalyzed 1,2,3-triazole-forming reaction between azides and terminal alkynes has become the gold standard of click chemistry due to its reliability, specificity, and biocompatibility. Applications of click chemistry are increasingly found in all aspects of drug discovery; they range from lead finding through combinatorial chemistry and target-templated in vitro chemistry, to proteomics and DNA research by using bioconjugation reactions. The triazole products are more than just passive linkers; they readily associate with biological targets, through hydrogen-bonding and dipole interactions. The present review will focus mainly on the recent literature for applications of this reaction in the field of medicinal chemistry, in particular on use of the 1,2,3-triazole moiety as pharmacophore.

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“…[4] [5] On the other hand, 1,2,3-triazoles present a great stability under acidic, basic, and oxidative conditions. [6] A number 1,2,3-triazole derivatives show good or excellent anticancer activity.…”

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confidence: 99%

Synthesis and Antitumor Activity of Novel 4,5-Disubstituted Triazole Derivatives

Yuan¹,

Weng²,

Liu³

et al. 2015

Proceedings of the 2015 International Conference on Industrial Technology and Management Science

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A Novel Potent Nicotinamide Phosphoribosyltransferase Inhibitor Synthesized via Click Chemistry

Cited by 90 publications

References 33 publications

Reciprocal Potentiation of the Antitumoral Activities of FK866, an Inhibitor of Nicotinamide Phosphoribosyltransferase, and Etoposide or Cisplatin in Neuroblastoma Cells

Reciprocal Potentiation of the Antitumoral Activities of FK866, an Inhibitor of Nicotinamide Phosphoribosyltransferase, and Etoposide or Cisplatin in Neuroblastoma Cells

Click Chemistry: 1,2,3‐Triazoles as Pharmacophores

Synthesis and Antitumor Activity of Novel 4,5-Disubstituted Triazole Derivatives

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