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Title page for ETD etd-12182007-154611

Type of Document Dissertation
Author Serwa, Remigiusz Adam
Author's Email Address remigiusz.a.serwa@vanderbilt.edu
URN etd-12182007-154611
Title Synthesis and antioxidant properties of vitamin B6 derivatives; and ù-alkynylated fatty acids as substrates for preparation of modified phospholipids, novel probes for evaluating lipid-protein interactions
Degree PhD
Department Chemistry
Advisory Committee
Advisor Name Title
Ned A. Porter Committee Chair
Brain O. Bachmann Committee Member
David E. Cliffel Committee Member
Eva Harth Committee Member
Terry P. Lybrand Committee Member
  • Lipids --Peroxidation
  • Vitamin B6 -- Derivatives
  • lipid peroxidation
  • lipid derived electrophiles
  • lipid-protein adducts
  • pyridinols
  • alkynylated fatty acids
  • antioxidants
  • Antioxidants -- Synthesis
  • Phospholipids -- Synthesis
Date of Defense 2008-12-18
Availability unrestricted
Development of a methodology for an efficient multi-gram scale preparation of 2-amino-5-pyridinols and subsequent investigation of the antioxidant properties of these compounds were executed. The key compound, 2-amino-3,4,6-trimethylpyridin-5-ol hydrochloride, was obtained from naturally occurring pyridoxyl hydrochloride in four steps. p-Alkylamino derivatives of the key precursor were prepared via N,O-diacylation followed by borane-tetrahydrofuran reduction, whereas p-dialkylaminopyridinols were synthesized utilizing one-pot reductive-alkylation methodology. Important properties of these compounds were subsequently evaluated in aqueous buffer, in non-polar organic solvent, as well as in a liposomal suspension. 2-Amino-5-pyridinols were considered stable under aerated conditions. However, in addition to peroxyl radical scavenging, they tended to autoxidize in aqueous media in the presence of radical initiators. In aqueous media, the autoxidizability of antioxidants depended exclusively on their stereoelectronic properties, whereas in liposomal

suspensions, distribution of radical scavengers between an aqueous and a lipid phase was an additional factor.

In addition to the studies conducted on pyridinols, synthesis and oxidizability studies were performed on omega-alkynylated polyunsaturated fatty acids. The modified linoleate and arachidonate have been prepared utilizing a general protocol that could be applied to synthesize other terminally modified lipids. The prepared ù-alkynylated fatty acids have been shown to behave similarly to their native analogues. Upon chemical or enzymatic transformations, they were converted into hydroperoxide and bicyclic peroxide products that further decompose to yield reactive electrophiles. Formation of selected reactive species, such as omega-alkynylated 4-hydroxynonenal, cyclopentenone isoprostanes and isoketals, was confirmed on the basis of adduction studies to model peptides or proteins.

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