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. 2021 Nov 30;50(46):17041-17051.
doi: 10.1039/d1dt02298a.

Umbelliferyloxymethyl phosphonate compounds-weakly binding zinc ionophores with neuroprotective properties

Sebastien Guesne  1 , Laura Connole  2 , Stephanie Kim  1 , Majid Motevalli  1 , Lesley Robson  2 , Adina T Michael-Titus  2 , Alice Sullivan  1
Affiliations

Umbelliferyloxymethyl phosphonate compounds-weakly binding zinc ionophores with neuroprotective properties

Sebastien Guesne et al. Dalton Trans. .

Abstract

Umbelliferone is a member of the coumarin family of compounds which are known for diverse pharmacological activity including in targets relevant to Alzheimers disease, AD. The toxicity associated with some forms of the amyloid protein, Aβ, and the role of Zn2+ (and other biometals) dyshomeostasis in this, are of great interest in AD and make metal ionophore capability desirable in so called multi target drug ligands MTDLs. A new series of umbelliferyloxymethyl phosphonic acid diethylester compounds (umbelliferyloxymethyl phosphonates) bearing a phosphonate at the 7-position (compounds 1, 3-6), hydrolysis products 2, 2a and 2b from 1 and analogues 7 and 8 of 1 with 7-O to 7-S and 1-O to 1-NH substitutions, are reported. Single crystal X-ray structures of compounds 1, 2 and 2a were determined. In terms of neuroprotective properties, the compounds 1, 2, 3, 4, 5 and 6 at 1 μM concentration, inhibited the toxicity of Aβ1-42 (Aβ42) in both toxic Amyloid Derived Diffusible Ligand (ADDL) and fibrillar (fibril) forms towards rat hippocampal cells. Compound 7 displayed cytotoxicity and 8 failed to inhibit Aβ42 toxicity. Concerning compound-metal ionophore activity (assessed using chemical experiments), despite weak binding to Zn2+ determined from 31P NMR titration of 1 and 2 by ZnCl2, compounds 1, 3, 4, 5 and 6 demonstrated ionophore assisted partition of Zn2+ from water to octanol at micromolar concentrations with efficacy on a par with or better than the chelator MTDL clioquinol (5-chloro-7-iodo-8-hydroxyquinoline). Partition was assessed using furnace Atomic Absorption Spectroscopy (AAS). In further experiments interaction of compound 1 with Zn2+ or it's pathways was inferred by (i) delayed fluorescence response with added Zn2+ in cells treated with FluoZin-3 and (ii) by suppression of Zn2+ promoted aggregation of Aβ42.

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Conflict of interest statement

There are no conflicts to declare.

Figures

Fig. 1
Fig. 1. (a) umbelliferone (b) umbelliferyloxymethyl phosphonic acid diethylester (c) ethylphosphonic acid umbelliferyl ester.
Fig. 2
Fig. 2. Chemical structure of compounds 1, 2, 2a, 2b, 3, 4, 5, 6, 7 and 8.
Fig. 3
Fig. 3. ORTEP image of compound 1 showing modelled disorder in one ethyl ester group.
Fig. 4
Fig. 4. Chain structure in 2 with intermolecular PO⋯HO–P hydrogen bonding and showing modelled disorder of the ethyl ester group.
Fig. 5
Fig. 5. X-ray structure of 2a trisodium 3-[4-(ethoxy-phosphonatomethoxy)-2-phenolato]-but-2-enoate trihydrate. Left: showing Na+–O–P, Na+–O–C and Na+−OH2 bonding. Right: the extended hydrogen bonded chain structure.
Fig. 6
Fig. 6. MTT assays on hippocampal cell viability (a) effect of compounds after 72 h incubation. Data (n = 3) are expressed as mean ± SEM and analysed using a one-way ANOVA. Effect of compounds on ADDL (b) and fibril (c)-induced cytotoxicity after 72 h incubation. Data (n = 3) are expressed as mean ± SEM and analysed using a one-way ANOVA with a Newman–Keuls multiple comparison post-hoc test (***P < 0.05 vs. vehicle; ###P < 0.05 vs. ADDL or Fibril.
Fig. 7
Fig. 7. Percentage aqueous metal partitioned after 24 h in 1 : 1 aqueous–octanol (a) with 4 μM 1 for 1 : Zn2+ ratios 0.5–8. (b) with 1 μM compound and 0.25 μM Zn2+. The mean value for the media control (Zn2+ in 1 : 1 aqueous–octanol) is shown in (b) and was subtracted from compound data. Data (n = 3) are expressed as mean ± SD analysed using one way ANOVA and post hoc comparison: # P < 0.05 vs.4.
Fig. 8
Fig. 8. Effect of compound 1 on stimulated Zn2+ signaling by FluoZin-3. Fluorescence (Ex/Em 494/516) was measured at 2 min intervals for 60 min with addition of ZnCl2 (30 μM) at 6 min. Average baseline values were recorded for the first 6 min for each treatment and used to normalize fluorescence at all time points. The data (n = 3) are analysed using a two-way ANOVA with Bonferroni post-hoc test (*P < 0.05 vs. vehicle).
Fig. 9
Fig. 9. SEMs after treatment Aβ42 (5 μM) as follows (a) constant agitation 72 hours pH 7.4 @ 37 °C (b) as in (a) including 5 μM Zn2+ (c) as in (a) including Zn2+ (5 μM) and compound 1 μM 1. Bar = 100 nm. Magnification 49 000×.
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