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Iminosugar-Based Nicotinamide Phosphoribosyltransferase (NAMPT) Inhibitors as Potential Anti-Pancreatic Cancer Agents.

ABSTRACT: The nicotinamide phosphoribosyltransferase (NAMPT) is considered a very promising therapeutic target because it is overexpressed in pancreatic cancer. Although many inhibitors have been prepared and tested, clinical trials have shown that NAMPT inhibition may result in severe haematological toxicity. Therefore, the development of conceptually new inhibitors is an important and challenging task. We synthesized ten β-d-iminoribofuranosides bearing various heterocycle-based chains carbon-linked to the anomeric position starting from non-carbohydrate derivatives. They were then submitted to NAMPT inhibition assays, as well as to pancreatic tumor cells viability and intracellular NAD⁺ depletion evaluation. The biological activity of the compounds was compared to that of the corresponding analogues lacking the carbohydrate unit to assess, for the first time, the contribution of the iminosugar moiety to the properties of these potential antitumor agents.

SUBMITTER: Conforti I

PROVIDER: S-EPMC10222582 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Iminosugar-Based Nicotinamide Phosphoribosyltransferase (NAMPT) Inhibitors as Potential Anti-Pancreatic Cancer Agents.

Conforti Irene I Benzi Andrea A Caffa Irene I Bruzzone Santina S Nencioni Alessio A Marra Alberto A

Pharmaceutics 20230511 5

The nicotinamide phosphoribosyltransferase (NAMPT) is considered a very promising therapeutic target because it is overexpressed in pancreatic cancer. Although many inhibitors have been prepared and tested, clinical trials have shown that NAMPT inhibition may result in severe haematological toxicity. Therefore, the development of conceptually new inhibitors is an important and challenging task. We synthesized ten β-d-iminoribofuranosides bearing various heterocycle-based chains carbon-linked to ...[more]

PMID: 37242714

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Project description:Nicotinamide phosphoribosyltransferase (NAMPT) has crucial roles for myocardial development, cardiomyocyte energy metabolism and cell death/survival by regulating NAD⁺-dependent sirtuin-1 (SIRT1) deacetylase. This study aimed to determine if the single nucleotide polymorphisms (SNPs) of the NAMPT gene may affect the susceptibility and prognosis for patients with dilated cardiomyopathy (DCM) and to describe the association of serum NAMPT levels with clinical features of DCM. Three SNPs (rs61330082, rs2505568, and rs9034) were analyzed by the polymerase chain reaction-restriction fragment length polymorphism method in a case-control study of 394 DCM patients and 395 controls from China. Serum NAMPT levels were measured by enzyme-linked immunosorbent assay kits. The homozygote for the minor allele at rs2505568 and rs9034 could not be detected in this study. Rs9034 T allele and CT genotype were associated with increased DCM risk (OR: 1.63, 95% CI = 1.16-2.27, p = 0.005 and OR: 1.72, 95% CI = 1.20-2.50, p = 0.0027, respectively). Nominally significant decreased DCM risk was found to be associated with the A allele and AT genotype of rs2505568 (OR: 0.48, 95% CI = 0.35-0.67, p < 0.0001 and OR: 0.44, 95% CI = 0.31-0.62, p < 0.0001, respectively), but it should be interpreted with caution because of Hardy-Weinberg disequilibrium in the control group. Of five haplotypes constructed, TAC (rs61330082-rs2505568-rs9034) was a protective haplotype to DCM (OR: 0.22, 95% CI = 0.13-0.39, p = 1.84 × 10(-8)). The Cox multivariate survival analysis indicated that the rs9034 CT genotype (hazard ratio (HR): 0.59, 95% CI = 0.37-0.96, p = 0.03) was an independently multivariate predictor for longer overall survival in DCM patients. Serum NAMPT levels were significantly higher in the DCM group than controls (p < 0.0001) and gradually increased with the increase of New York Heart Association grade in DCM patients. However, there was a lack of association of the three SNPs with serum NAMPT levels. Spearman correlation test revealed that the NAMPT level was positively associated with brain natriuretic peptide (r = 0.56, p = 0.001), left ventricular end-diastolic diameter (r = 0.293, p = 0.011) and left ventricular end-diastolic volume (r = 0.294, p = 0.011). Our study suggested that NAMPT may play an important role in the development of DCM.

Dataset Information

Iminosugar-Based Nicotinamide Phosphoribosyltransferase (NAMPT) Inhibitors as Potential Anti-Pancreatic Cancer Agents.

Publications

Iminosugar-Based Nicotinamide Phosphoribosyltransferase (NAMPT) Inhibitors as Potential Anti-Pancreatic Cancer Agents.

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