Synthesis of a <i>C</i>‐Iminoribofuranoside Analog of the Nicotinamide Phosphoribosyltransferase (NAMPT) Inhibitor FK866

Gillig, Annabelle; Majjigapu, Somi Reddy; Sordat, Bernard; Vogel, Pierre

doi:10.1002/hlca.201100415

Cited by 7 publications

(8 citation statements)

References 56 publications

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“…No pharmacological activity has been reported yet for this compound, but it is likely that the lack of the pyridine ring makes this compound inactive or poorly active. 60 In two recent patents 61 the pyridine moiety has been replaced with heterocycles in which the nitrogen atom of the pyridine is still present. From a medicinal chemistry point of view these compounds can be considered rigid analogues of the 3-vinylpyridine moiety.…”

Section: ■ Medicinal Chemistry Of Nampt Inhibitorsmentioning

confidence: 99%

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Medicinal Chemistry of Nicotinamide Phosphoribosyltransferase (NAMPT) Inhibitors

et al. 2013

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Nicotinamide phoshophoribosyltransferase (NAMPT) plays a key role in the replenishment of the NAD pool in cells. This in turn makes this enzyme an important player in bioenergetics and in the regulation of NAD-using enzymes, such as PARPs and sirtuins. Furthermore, there is now ample evidence that NAMPT is secreted and has a role as a cytokine. An important role of either the intracellular or extracellular form of NAMPT has been shown in cancer, inflammation, and metabolic diseases. The first NAMPT inhibitors (FK866 and CHS828) have already entered clinical trials, and a surge in interest in the synthesis of novel molecules has occurred. The present review summarizes the recent progress in this field.

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Section: ■ Medicinal Chemistry Of Nampt Inhibitorsmentioning

confidence: 99%

“…Recently, a C -iminofuranoside analogue of FK866 has also been prepared ( 8 ). No pharmacological activity has been reported yet for this compound, but it is likely that the lack of the pyridine ring makes this compound inactive or poorly active …”

Section: Medicinal Chemistry Of Nampt Inhibitorsmentioning

confidence: 99%

Medicinal Chemistry of Nicotinamide Phosphoribosyltransferase (NAMPT) Inhibitors

et al. 2013

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“…Eleven years after the synthesis of a single iminosugar-based potential inhibitor of NAMPT reported by Vogel and co-workers [ 13 ], we have described in the present article a straightforward access to chemically stable inhibitors bearing a highly (free hydroxyl derivatives 21 – 25 ) or moderately ( O -methylated derivatives 26 – 30 ) hydrophilic C -iminoribofuranoside moiety. One of them (compound 29 , Figure 10 ) was endowed with good enzyme inhibition activity and quite interesting in cellulo anticancer properties.…”

Section: Discussionmentioning

confidence: 84%

“…In 2012, the conceptually new NAMPT inhibitor 1 was synthetized by Vogel and co-workers [ 13 ] in the aim of mimicking the transition state formed in the glycosylation process catalysed by NAMPT ( Figure 4 ). The compound 1 featured an iminofuranoside unit anomerically C -linked to a moiety closely related to FK866 , the pyridine ring being replaced by a phenyl ring.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2023

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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.

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“…Compounds 1-benzoylpiperidin-4-yl)butyl)isoindoline-1,3-dione ( 1a ) and 2-(4-(4-benzoylpiperazin-1-yl)butyl)isoindoline-1,3-dione ( 1b ) were synthesized according to Gilig et al [ 55 ] with slight modifications.…”

Section: Methodsmentioning

confidence: 99%

Structural Basis of Beneficial Design for Effective Nicotinamide Phosphoribosyltransferase Inhibitors

et al. 2020

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Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) is an attractive therapeutic strategy for targeting cancer metabolism. So far, many potent NAMPT inhibitors have been developed and shown to bind to two unique tunnel-shaped cavities existing adjacent to each active site of a NAMPT homodimer. However, cytotoxicities and resistances to NAMPT inhibitors have become apparent. Therefore, there remains an urgent need to develop effective and safe NAMPT inhibitors. Thus, we designed and synthesized two close structural analogues of NAMPT inhibitors, azaindole–piperidine (3a)- and azaindole–piperazine (3b)-motif compounds, which were modified from the well-known NAMPT inhibitor FK866 (1). Notably, 3a displayed considerably stronger enzyme inhibitory activity and cellular potency than did 3b and 1. The main reason for this phenomenon was revealed to be due to apparent electronic repulsion between the replaced nitrogen atom (N1) of piperazine in 3b and the Nδ atom of His191 in NAMPT by our in silico binding mode analyses. Indeed, 3b had a lower binding affinity score than did 3a and 1, although these inhibitors took similar stable chair conformations in the tunnel region. Taken together, these observations indicate that the electrostatic enthalpy potential rather than entropy effects inside the tunnel cavity has a significant impact on the different binding affinity of 3a from that of 3b in the disparate enzymatic and cellular potencies. Thus, it is better to avoid or minimize interactions with His191 in designing further effective NAMPT inhibitors.

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Synthesis of a C‐Iminoribofuranoside Analog of the Nicotinamide Phosphoribosyltransferase (NAMPT) Inhibitor FK866

Cited by 7 publications

References 56 publications

Medicinal Chemistry of Nicotinamide Phosphoribosyltransferase (NAMPT) Inhibitors

Medicinal Chemistry of Nicotinamide Phosphoribosyltransferase (NAMPT) Inhibitors

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

Structural Basis of Beneficial Design for Effective Nicotinamide Phosphoribosyltransferase Inhibitors

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