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Synthetic Studies on Novel Facially Amphiphilic Sesquiterpenoid- and 11β-Steroid-Amino Acid Conjugates and Transition Metal Mediated Steroid-Amino Acid Derived Biometallosurfactants

  • Author / Creator
    Pandya, Keyur
  • Sesquiterpenoid- and steroid-amino acid conjugates demonstrate a broad array of interesting biological properties, as the different segments of the conjugate function collectively to regulate conformation, recognition, transport and solubility. The current project involved developing a facile methodology to synthesize metabolically stable facially amphiphilic conjugates by appending either amino acids (chapter 2) or cationic metal ligand-amino acid complexes (chapter 3) as hydrophilic segments on steroid progesterone and sesquiterpene amorpha-4,11-diene scaffolds. Aminosteroids and C-11 substituted steroids have attracted long lasting interest due to their diverse pharmacological properties. As the stereoselective C- 11β functionalization of a steroid imposes severe steric hindrance due to the C-18 and C-19 angular methyl groups, access to 11β-aminoprogesterone is a challenge. Chapter 2 describes stereoselective syntheses of a new family of aminosteroids: 11β-aminoprogesterone (11β-NH2-Pro) (76) and its derivatives, including its glycine 77 and L-/D- alanine- 78/79 based conjugates, by nucleophilic substitution or reductive amination. Additionally, a synthesis of the 12-amorpha-4,11-dienyl- (S)-glycine (80) conjugate is also discussed. Biological testing of the aminoprogesterone derivatives revealed that some of them selectively inhibit 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), similar to that of their structural analogue 11β-hydroxyprogesterone. Moreover, two compounds, 11β-azidoprogesterone (81) and 11β-N-(o-nosyl)- aminoprogesterone (93), which did not significantly inhibit 11β-HSDs, had antagonist properties on the mineralocorticoid receptor (MR). The 11β- aminoprogesterone derivatives form the basis for the further development of improved modulators of corticosteroid action for treatment of electrolyte disturbances and chronic inflammatory disorders. Chapter 3 discusses the efforts towards developing a new class of amidoglutarate-tethered cationic cobalt(III) based biometallosurfactant complexes Λ-α-Co[(S,S-picbipyrro-amidoglutarate)(11β-NH-Pro-Gly)]2+ (138) and Λ-α- Co[(picenMe2-amidoglutarate)(11β-NH-Pro-Gly)]2+ (139) bearing chiral rigid or achiral non-rigid N4-tetradentate and N,O-bidentate ligand derived from the steroid-based N-substituted amino acid N-(11β-NH-Pro)-Gly (77). However, no desired complexation was realized. Subsequently, model studies identifying the critical impeding factors of complexation suggested that unfavorable steric interactions between N-substituted alkyl group of amino acids and the pyridyl rings of N4-tetradentate ligands caused the complexation to fail. The synthesized cis-α-Co[N4Cl2]+ (161, 171-174) and Λ-α-Co[N4(AA)]2+ (185, 186, 190-192) complexes were characterized by comparing their 1H-NMR and CD spectral features to their structural analogues for which X-ray crystallographic studies have been reported.

  • Subjects / Keywords
  • Graduation date
    2014-06
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/R3M03Z55T
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
    English
  • Institution
    University of Alberta
  • Degree level
    Doctoral
  • Department
    • Department of Chemistry
  • Supervisor / co-supervisor and their department(s)
    • Vederas, John C.(Department of Chemistry)
  • Examining committee members and their departments
    • Klobukowski, Mariusz (Department of Chemistry)
    • Hof, Fraser (Department of Chemistry, University of Victoria)
    • McMullen, Lynn (Department of Agricultural, Food & Nutritional Science)
    • Campbell, Robert E. (Department of Chemistry)
    • Clive, Derrick L. J. (Department of Chemistry)