Succinobucol’s New Coat — Conjugation with Steroids to Alter Its Drug Effect and Bioavailability

Molecules

Ondřej Jurček¹  Satu Ikonen¹  Lucie Buřičová¹  Martina Wimmerová¹  Zdeněk Wimmer¹  Pavel Drašar¹  Jan Horníček¹  Adéla Galandáková¹  Jitka Ulrichová¹ 

[1] ¹Department of Chemistry, FI-40014, University of Jyväskylä, P.O. Box 35, Finland

关键词: succinobucol;    phytosterol;    atherosclerosis;    cholesterol;    probucol;   

DOI  :  10.3390/molecules16119404

来源: mdpi

【 摘 要 】

Synthesis, detailed structural characterization (X-ray, NMR, MS, IR, elemental analysis), and studies of toxicity, antioxidant activity and bioavailability of unique potent anti-atherosclerotic succinobucol-steroid conjugates are reported. The conjugates consist of, on one side, the therapeutically important drug succinobucol ([4-{2,6-di-tert-butyl-4-[(1-{[3-tert-butyl-4-hydroxy-5-(propan-2-yl)phenyl]sulfanyl}ethyl)sulfanyl]phenoxy}-4-oxo-butanoic acid]) possessing an antioxidant and anti-inflammatory activity, and on the other side, plant stanol/sterols (stigmastanol, β-sitosterol and stigmasterol) possessing an ability to lower the blood cholesterol level. A cholesterol-succinobucol prodrug was also prepared in order to enhance the absorption of succinobucol through the intestinal membrane into the organism and to target the drug into the place of lipid metabolism—The enterohepatic circulation system. Their low toxicity towards mice fibroblasts at maximal concentrations, their antioxidant activity, comparable or even higher than that of ascorbic acid as determined by direct quenching of the DPPH radical, and their potential for significantly altering total and LDL cholesterol levels, suggest that these conjugates merit further studies in the treatment of cardiovascular or other related diseases. A brief discussion of succinobucol’s ability to quench the radicals, supported with a computational model of the electrostatic potential mapped on the electron density surface of the drug, is also presented.

【 授权许可】

CC BY   
This is an open access article distributed under the Creative Commons Attribution License (CC BY) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.