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Title: Calcium antagonist and antiperoxidant properties of some hindered phenols.
Authors: Sgaragli, GIAN PIETRO
Valoti, Massimo
Gorelli, Beatrice
Fusi, Fabio 
Palmi, Mitri
Mantovani, Piero
Keywords: 2,6‐di‐t‐butyl‐4‐methylphenol (BHT), 2‐t‐butyl‐4‐methoxyphenol (BHA), antioxidant, calcium antagonist, Phenol derivatives
Issue Date: 1993
Project: None 
1. The calcium antagonist and antioxidant activities of certain synthetic and natural phenols, related to BHA (2-t-butyl-4-methoxyphenol), were evaluated in rat ileal longitudinal muscle and in lipid peroxidation models respectively. 2. Compounds with a phenol or a phenol derivative moiety, with the exception of 2,2'-dihydroxy-3,-3'-di-t-butyl-5,5'-dimethoxydiphenyl (di-BHA), inhibited in a concentration-dependent manner the BaCl 2-induced contraction of muscle incubated in a Ca 2+-free medium. Calculated pIC 50 (M) values ranged between 3.32 (probucol) and 4.96 [3,5-di-t-butyl-4-hydroxyanisole (di-t-BHA)], with intermediate activity shown by khellin < gossypol < guercetin < 3-t-butylanisole < BHA < nordihydroguaiaretic acid (NDGA) < 2,6-di-t-butyl-4-methylphenol (BHT) and papaverine. 3. The Ca 2+ channel activator Bay K 8644 overcame the inhibition sustained by nifedipine, BHA and BHT, while only partially reversing that of papaverine. 4. BHA, BHT, nifedipine and papaverine also inhibited in a concentration-dependent fashion CaCl 2 contractions of muscle depolarized by a K +-rich medium. This inhibition appeared to be inversely affected by the Ca 2+-concentration used. 5. The inhibitory effects of nifedipine, papaverine, BHA and BHT were no longer present when muscle contraction was elicited in skinned fibres by 5 μM Ca 2+ or 500 μM Ba 2+, suggesting a plasmalemmal involvement of target sites in spasmolysis. 6. Comparative antioxidant capability was assessed in two peroxyl radical scavenging assay systems. These were based either on the oxidation of linoleic and initiated by a heat labile azo compound or on lipid peroxidation of rat liver microsomes promoted by Fe 2+ ions. Across both model systems, di-t-BHA, NDGA, BHT, di-BHA,BHA and quercetin ranked as the most potent inhibitors of lipid oxidation, with calculated pIC 50 (M) values ranging between 7.4 and 5.7. 7. Of the 32 compounds studied only 15 phenolic derivatives exhibited both antispasmogenic and antioxidant activity. Within this subgroup a linear and significant correlation was found between antispasmogenic activity and antioxidation. These bifunctional compounds were characterized by the presence of at least one hydroxyl group on the aromatic ring and a highly lipophilic area in the molecule. 8. Di-t-BHA is proposed as a lead reference compound for future synthesis of new antioxidants combining two potentially useful properties in the prevention of tissue damage after ischaemia-reperfusion injury.
ISSN: 0007-1188
DOI: 10.1111/j.1476-5381.1993.tb13819.x
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