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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 Open Access


Other title
Cobalt(III) hexadentate amino acid complexes
amorpha-4,11-diene-based amino acid conjugate
Artemisinic-based amino acid hybrid
Steroid-amino acid conjugates
11β-Hydroxysteroid dehydrogenase (11β-HSD) inhibitors
Sesquiterpenoid-amino acid conjugate
Selective 11β-HSD2 inhibitors for hyperkalemia treatment
Mineralocorticoid receptor antagonist (MRA)
11β-Aminoprogesterone derivatives
Type of item
Degree grantor
University of Alberta
Author or creator
Pandya, Keyur
Supervisor and department
Vederas, John C.(Department of Chemistry)
Examining committee member and department
Hof, Fraser (Department of Chemistry, University of Victoria)
Klobukowski, Mariusz (Department of Chemistry)
McMullen, Lynn (Department of Agricultural, Food & Nutritional Science)
Campbell, Robert E. (Department of Chemistry)
Clive, Derrick L. J. (Department of Chemistry)
Department of Chemistry

Date accepted
Graduation date
Doctor of Philosophy
Degree level
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.
This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for the purpose of private, scholarly or scientific research. 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.
Citation for previous publication
Pandya, K.; Dietrich, D.; Seibert, J.; Vederas, J. C.; Odermatt, A., Synthesis of sterically encumbered 11β -aminoprogesterone derivatives and evaluation as 11β-hydroxysteroid dehydrogenase inhibitors and mineralocorticoid receptor antagonists. Bioorg. Med. Chem. 2013, 21, 6274-6281.Pandya, K.; Dietrich, D.; Vederas, J. C., A Facile Synthesis and Biological Evaluations of New Family of Amino-steroids: 11β-aminoprogesterone Derivatives, Poster, 245th ACS National Meeting, 2013, New Orleans, LA, USA

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