Issue 46, 2021

Umbelliferyloxymethyl phosphonate compounds-weakly binding zinc ionophores with neuroprotective properties

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.

Graphical abstract: Umbelliferyloxymethyl phosphonate compounds-weakly binding zinc ionophores with neuroprotective properties

Supplementary files

Article information

Article type
Paper
Submitted
11 iyl 2021
Accepted
04 noy 2021
First published
04 noy 2021
This article is Open Access
Creative Commons BY license

Dalton Trans., 2021,50, 17041-17051

Umbelliferyloxymethyl phosphonate compounds-weakly binding zinc ionophores with neuroprotective properties

S. Guesne, L. Connole, S. Kim, M. Motevalli, L. Robson, A. T. Michael-Titus and A. Sullivan, Dalton Trans., 2021, 50, 17041 DOI: 10.1039/D1DT02298A

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