Sulfated Oligomers of Tyrosol: Toward a New Class of Bioinspired Nonsaccharidic Anticoagulants.
Maria Laura AlfieriLucia PanzellaBárbara DuarteSalomé Gonçalves-MonteiroFranklim MarquesManuela MoratoMarta Correia da SilvaLuisella VerottaAlessandra NapolitanoPublished in: Biomacromolecules (2021)
Sulfated phenolic polymers have extensively been investigated as anticoagulant agents in view of their higher bioavailability and resistance to degradation compared to heparins, allowing for increased half-lives. In this frame, we report herein the preparation of sulfated derivatives of tyrosol, one of the most representative phenolic constituents of extra virgin olive oil, by different approaches. Mild sulfation of OligoTyr, a mixture of tyrosol oligomers, that has been reported to possess antioxidant properties and osteogenic activity, afforded OligoTyrS I in good yields. Elemental analysis, NMR, and MALDI-MS investigation provided evidence for an almost complete sulfation at the OH on the phenylethyl chain, leaving the phenolic OH free. Peroxidase/H2O2 oxidation of tyrosol sulfated at the alcoholic group (TyrS) also provided sulfated tyrosol oligomers (OligoTyrS II) that showed on structural analysis highly varied structural features arising likely from the addition of oxygen, derived from water or hydrogen peroxide, to the intermediate quinone methides and substantial involvement of the phenolic OH group in the oligomerization. In line with these characteristics, OligoTyrS I proved to be more active than OligoTyrS II as antioxidant in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) and ferric reducing/antioxidant power (FRAP) assays and as anticoagulant in the classical clotting times, mainly in prolonging the activated partial thromboplastin time (APTT). After intraperitoneal administration in mice, OligoTyrS I was also able to significantly decrease the weight of an induced thrombus. Data from chromogenic coagulation assays showed that the anticoagulant effect of OligoTyrS I was not dependent on antithrombin or factor Xa and thrombin direct inhibition. These results clearly highlight how some structural facets of even closely related phenol polymers may be critical in dictating the anticoagulant activity, providing the key for the rationale design of active synthetic nonsaccharidic anticoagulant agents alternative to heparin.
Keyphrases
- hydrogen peroxide
- venous thromboembolism
- atrial fibrillation
- oxidative stress
- mass spectrometry
- anti inflammatory
- nitric oxide
- high throughput
- mesenchymal stem cells
- multiple sclerosis
- body mass index
- multidrug resistant
- electronic health record
- drug induced
- big data
- type diabetes
- metabolic syndrome
- high resolution
- endothelial cells
- ms ms
- liquid chromatography
- artificial intelligence
- body weight
- iron deficiency
- structure activity relationship
- adipose tissue
- deep learning