Dilazep analogues for the study of equilibrative nucleoside transporters 1 and 2 (ENT1 and ENT2)

Playa, Hilaire C.; Lewis, Timothy A.; Ting, Amal; Suh, Beomseok; Muñoz, Benito; Matuza, Robert; Passer, Brent J.; Schreiber, Stuart L.; Buolamwini, John K.

doi:10.1016/j.bmcl.2014.10.026

Cited by 18 publications

(13 citation statements)

References 15 publications

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“…The bromoazide 3 , in turn, can be obtained by reacting 1,3-dibromopropane ( 4 ) with one equivalent of sodium azide. However, even if the reaction is performed under stoichiometric conditions, it has been found that the desired product cannot be recovered (by chromatography) in yields larger than 50% [ 23 – 25 ]. Indeed, we verified that the reaction affords mixtures containing 3 together with the relevant diazide 5 and the unreacted starting dibromide 4 ( Scheme 3 ), in 46%, 27% and 27% yields, respectively (estimated by 1 H NMR), which is in reasonable agreement with the 2:1:1 ratio expected on the grounds of numerical simulations.…”

Section: Resultsmentioning

confidence: 99%

Polyaminoazide mixtures for the synthesis of pH-responsive calixarene nanosponges

Vincenzo¹,

Piccionello²,

Spinella³

et al. 2019

Beilstein J. Org. Chem.

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Two mixtures of polyaminoazides were synthesized by a nucleophilic displacement strategy providing no separation of the components. The mixtures were adequately characterized by means of combined HR-ESIMS, FTIR and NMR techniques and, despite their complexity, they were successfully used to accomplish the subsequent preparation of pH-sensitive calixarene hyper-reticulated nanosponge materials. The desired responsivity to pH variations of the nanosponges obtained was verified by means of absorption tests on a set of organic pollutant model molecules.

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Section: Resultsmentioning

confidence: 99%

Polyaminoazide mixtures for the synthesis of pH-responsive calixarene nanosponges

Vincenzo¹,

Piccionello²,

Spinella³

et al. 2019

Beilstein J. Org. Chem.

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“…For NBTI, a selective inhibitor of ENT1, a potency value (8.3 ± 0.3) comparable to the radioligand binding data (8.7 ± 0.02) (Supplementary Material; Table S1) as well as previously reported data was found 49 . Dilazep appeared to be approximately 10-fold more potent compared to the literature 49 and the radioligand binding data, which may be explained by the fact that dilazep is a not selective ENT1 and ENT2 inhibitor 50 . The second format also provides information on the inhibitory efficacy of ENT1 inhibitors (i.e.…”

Section: Discussionmentioning

confidence: 64%

Label-free detection of transporter activity via GPCR signalling in living cells: A case for SLC29A1, the equilibrative nucleoside transporter 1

Vlachodimou

IJzerman

Heitman

2019

Sci Rep

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Transporters are important therapeutic but yet understudied targets due to lack of available assays. Here we describe a novel label-free, whole-cell method for the functional assessment of Solute Carrier (SLC) inhibitors. As many SLC substrates are also ligands for G protein-coupled receptors (GPCRs), transporter inhibition may affect GPCR signalling due to a change in extracellular concentration of the substrate/ligand, which can be monitored by an impedance-based label-free assay. For this study, a prototypical SLC/GPCR pair was selected, i.e. the equilibrative nucleoside transporter-1 (SLC29A1/ENT1) and an adenosine receptor (AR), for which adenosine is the substrate/ligand. ENT1 inhibition with three reference compounds was monitored sensitively via AR activation on human osteosarcoma cells. Firstly, the inhibitor addition resulted in an increased apparent potency of adenosine. Secondly, all inhibitors concentration-dependently increased the extracellular adenosine concentration, resulting in an indirect quantitative assessment of their potencies. Additionally, AR activation was abolished by AR antagonists, confirming that the monitored impedance was AR-mediated. In summary, we developed a novel assay as an in vitro model system that reliably assessed the potency of SLC29A1 inhibitors via AR signalling. As such, the method may be applied broadly as it has the potential to study a multitude of SLCs via concomitant GPCR signalling.

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“…A 50% hCNTs-mediated [ 18 F]FLT uptake was observed in MCF7 cells. Experiments were performed in sodium-free choline-containing buffer to block hCNTs because their function depends on the presence of free (33,35). Data in Fig.…”

Section: Discussionmentioning

confidence: 99%

Effect of hypoxia on human equilibrative nucleoside transporters hENT1 and hENT2 in breast cancer

et al. 2019

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Elevated proliferation rates in cancer can be visualized with positron emission tomography (PET) using 39-deoxy-39-L-[ 18 F]fluorothymidine ([ 18 F]FLT). This study investigates whether [ 18 F]FLT transport proteins are regulated through hypoxia. Expression and function of human equilibrative nucleoside transporter (hENT)-1, hENT2, and thymidine kinase 1 (TK1) were studied under normoxic and hypoxic conditions, and assessed with [ 18 F] FLT-PET in estrogen receptor positive (ER + )-MCF7, triple-negative MDA-MB231 breast cancer (BC) cells, and MCF10A cells (human mammary epithelial cells). Functional involvement of hENT2 [ 18 F]FLT transport was demonstrated in all cell lines. In vitro [ 18 F]FLT uptake was higher in MDA-MB231 than in MCF7: 242 6 9 vs. 147 6 18% radioactivity/mg protein after 60 min under normoxia. Hypoxia showed no significant change in radiotracer uptake. Protein analysis revealed increased hENT1 (P < 0.0963) in MDA-MB231. Hypoxia did not change expression of either hENT1, hENT2, or TK1. In vitro inhibition experiments suggested involvement of hENT1, hENT2, and human concentrative nucleoside transporters during [ 18 F]FLT uptake into all cell lines. In vivo PET imaging revealed comparable tumor uptake in MCF7 and MDA-MB231 tumors over 60 min, reaching standardized uptake values of 0.96 6 0.05 vs. 0.89 6 0.08 (n = 3). Higher hENT1 expression in MDA-MB231 seems to drive nucleoside transport, whereas TK1 expression in MCF7 seems responsible for comparable [ 18 F]FLT retention in ER + tumors. Our study demonstrates that hypoxia does not significantly affect nucleoside transport as tested with [ 18 F]

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Dilazep analogues for the study of equilibrative nucleoside transporters 1 and 2 (ENT1 and ENT2)

Cited by 18 publications

References 15 publications

Polyaminoazide mixtures for the synthesis of pH-responsive calixarene nanosponges

Polyaminoazide mixtures for the synthesis of pH-responsive calixarene nanosponges

Label-free detection of transporter activity via GPCR signalling in living cells: A case for SLC29A1, the equilibrative nucleoside transporter 1

Effect of hypoxia on human equilibrative nucleoside transporters hENT1 and hENT2 in breast cancer

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