Bioorganic studies using retinoid analogs

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  • Wada Akimori
    Department of Organic Chemistry for Life Science, Kobe Pharmaceutical University

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  • ビタミンA誘導体を用いた生物有機化学的研究
  • ビタミン A ユウドウタイ オ モチイタ セイブツ ユウキ カガクテキ ケンキュウ

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Abstract

Marked developments in vitamin A research over the past decade have advanced our understanding of the fundamental roles of this vitamin and its physiological significance in living cells. The present research was focused on using retinoid analogs to investigate the function of vitamin A. To reveal the conformation of chromophores in retinal proteins, various retinal analogs were synthesized, and their interaction with an apoprotein was investigated. The circular dichroism spectra of a novel rhodopsin analog consisting of a 11-cis-8,18-alkanoretinal and bovine opsin showed that the torsional angle around the C6-C7 single bond of the retinal in bovine rhodopsin was remarkably similar to that of 8,18-propanoretinal. Comparisons of the interactions of several all-trans-8,16-ethanoretinals and all-trans-8,18-ethanoretinal with the apoprotein in phoborhodopsin revealed that the retinal was incorporated into the protein as the 6s-trans conformation. Furthermore, the fine structure of the ultraviolet/visible absorption spectrum in native phoborhodopsin was found to be affected by the co-planarity of the conjugated polyene structure of the chromophore. Next, through stereoselective synthesis of retinoid isomers, 11-cis-retinal was successfully synthesized using the tricarbonyliron complex. The same methodology was applied to synthesize various 9-substituted 11-cis-retinals to investigate their interactions with bovine opsin. Subsequently, all-trans- and 9-cis-retinoic acids, which are ligands of retinoic acid receptors (all-trans-isomer) and retinoid X receptors (9-cis-isomer), were synthesized from enol triflate and trienyl- or tetraenyl-stannylester in a cesium fluoride-promoted Stille coupling reaction. Using this method, various 9-cis-retinoic acid analogs were also synthesized by replacing the trimethylcyclohexene ring with a cyclic terpenoid moiety and their biological activity was assessed.

Journal

  • VITAMINS

    VITAMINS 88 (2), 72-81, 2014

    THE VITAMIN SOCIETY OF JAPAN

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