Investigation of plant-derived phenolic compounds as plasma membrane Ca2+-ATPase inhibitors with potential cardiovascular activity
✍ Scribed by Basil D. Roufogalis; Qian Li; Van H. Tran; Eleanor P.W. Kable; Colin C. Duke
- Publisher
- John Wiley and Sons
- Year
- 1999
- Tongue
- English
- Weight
- 242 KB
- Volume
- 46
- Category
- Article
- ISSN
- 0272-4391
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✦ Synopsis
Various flavonoids and alkylphenols have been reported to inhibit the Ca 2+ -ATPase of plasma membrane (PM) and sarcoplasmic reticulum Ca 2+ -ATPase. This article describes the development of phenolic inhibitors of PM Ca 2+ -ATPase as potential cardiovascular agents. The new inhibitors were obtained from the screening of alkylphenols, alkylresorcinols, and phenolic constituents of medicinal plants, followed by synthesis of analogues and analysis of their structure-activity relationships. Alkylphenols were found to inhibit the PM Ca 2+ -ATPase, with 2-nonylphenol being the most potent compound (IC 50 = 30 µM) among a series of synthetic phenols. Several bis-resorcinols were isolated from the Australian plants Grevillea robusta and Grevillea striata, including two novel compounds which were identified as 1-(1,3-dihydroxy-4methylphenyl)-14-(1,3-dihydroxyphenyl)tetradec-8-Z-ene (grebustol-A) and norstriatol-B. Among these bisresorcinols, striatol was found to be the most potent inhibitor of PM Ca 2+ -ATPase, with an IC 50 value of 16 µM. Analogues of bis-phenols and bis-resorcinols were synthesised and investigated for Ca 2+ -ATPase inhibitory activity. It was found that 2,2′-(decane-1,10-diyl)bisphenol (decanediyl-bisphenol) was the most potent inhibitor (IC 50 = 10 µM). The synthetic bis-phenols and alkylphenols were shown to inhibit the PM Ca 2+ -ATPase in a concentration-and structure-dependent fashion. The inhibitory activity of decanediylbisphenol was also demonstrated in reconstituted purified Ca 2+ -ATPase from human erythrocyte plasma membrane and in intact red blood cells and smooth muscle cells. The mechanism of action of these inhibitors, however, is not fully understood but presumably, due to their high lipophilic nature, they would interact with the hydrophobic interior or at the lipid-protein interface, thereby perturbing the Ca 2+ -ATPase enzyme function. The inhibition was independent of calmodulin stimulation. The inhibition of Ca 2+ -ATPase was selective relative to the Na + ,K + -ATPase and Mg 2+ -ATPase in the same membrane preparations. These results indicate that bis-phenolic compounds may be useful in studying the function of PM Ca 2+ -ATPase and regulation of intracellular Ca 2+ , and may have potential cardiovascular activities. Drug Dev. Res. 46:235-249, 1999.