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

Abstract

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.