Structural, Thermoanalytical and Molecular Modeling Studies on N-(3-hydroxypropyl) 3α,12α-Dihydroxy-5β-cholan-24-amide and Its Monohydrates

Abstract

Abstract:The synthetic method for preparing N-(3-hydroxypropyl) 3α,12α-dihydroxy-5β-cholan-24-amide can lead to formation of at least three different crystal forms -an anhydrous compound and two monohydrates. The structural and thermal properties of these forms have been characterized by 13 C-CP/MAS-NMR and IR spectroscopy, thermogravimetry, differential scanning calorimetry and by powder and single crystal x-ray crystallography. In addition, theoretical 13 C-NMR chemical shift calculations were also performed for the anhydrous compound and for the first monohydrate, starting from single crystal structures and the structures of these species have now been verified. The first monohydrate, C 27 H 47 NO 4 · H 2 O, crystallizes in orthorhombic space group P2 1 2 1 2 1 with cell parameters: a = 7.1148(2), b = 18.1775(5), c = 20.1813(6), Z = 4.

Structural studies on lithocholyl-N-(2-aminoethyl)amide in the solid state

“…To the best of our knowledge, only a few studies on polymorphism of bile acid derivatives by SS NMR have been published [19][20][21]. The distinct resonances are clearly visible in cases of methyl groups CH 3 -18 and CH 3 -21, which do not overlap with the other resonances.…”

“…For instance, N-substituted amides of lithocholic acid and derivatives of 3a-hydroxy-24-amino-5b-cholane have shown in vitro activity against Gram positive strains and mycetes [14]. Bile acids and steroids exhibit variable crystal structures, solvates, and co-crystals [15][16][17][18][19][20][21][22]. Although structural studies of systems involving bile acid derivatives have long been a challenge due to their complex and supramolecular nature, papers dealing with single crystal X-ray diffraction characterization of crystalline host-guest assemblies of steroidal and related molecules have been published.…”

Marine Bile Natural Products as Agonists of the TGR5 Receptor

“…Another mammalian bile compound in common use is the endogenous secondary bile acid 4 , which is derived from primary bile acids, such as chenodeoxycholic acid or cholic acid, following colonic microbe conversion. − It is one of the seven most common bile acids present within the human digestive system and acts as an emulsifier of ingested fat within the human intestine, as well as being commonly used as a solubilizing agent for lipophilic compounds, such as phosphatidylcholine. , 4 is the major constituent of the traditional Chinese medicine known as “Niu Huang” (derived from ox gallstones), while the synthetic form of 4 is also marketed in injections for cosmetic procedures to reduce localized fat accumulations . The chemical structure of 4 is 3α,12α-dihydroxy-5β-cholan-24-oic acid …”

“…Of several bile acids studied, 4 is among the most potent agonists of TGR5 receptors, with only lithocholic acid exhibiting higher potency in luciferase-based binding experiments . This effect was also reported by Mobraten et al (2015) for TGR5 activation in the U937 human monocyte line . In contrast, 4 has been shown to be a weak agonist of the FXR receptor. , …”

3α-Hydroxy-N-(3-hydroxypropyl)-5β-cholan-24-amide

“…However, in gelation studies these properties were found to be too weak for utilization in any purposes. Although single crystals of analogous deoxycholic (DCA, 3α,12α-dihydroxy-5β-cholan-24-oic acid) and chenodeoxycholic (CDCA, 3α,7α-dihydroxy-5β-cholan-24-oic acid) acid amide derivatives were easily obtained during gelation tests (Valkonen et al, 2004;Valkonen et al, 2007;, the crystals of the title compound were very thin needles and far too small for crystallographic data collection. Methanol, which is unacceptably good solvent for the title compound and analogues in gel formation (Valkonen et al, 2004), showed to be a good solvent for growing of reasonable size crystals of the title compound for X-ray diffraction studies.…”