Elina Sievänen

Recent advances in steroidal supramolecular gels

During the last decade or two the interest towards small molecules capable of self-assembly leading to gelation has increased intensively. The investigation of these supramolecular gels aims not only at understanding the fundamental processes underlying gel formation but also at development of new materials with a myriad of applications. Steroids are widely-spread natural products with a large and rigid steroidal nucleus combined with derivatizable functional groups leading to an adjustable polarity profile, which makes them attractive building blocks when designing novel low molecular weight gelators. Due to their unique properties, steroid-based supramolecular gels may find use in applications ranging from materials science and nanoelectronics to their application as reaction media or as sensing and responsive materials. Moreover, biomaterials based on steroidal gels may find use in biomedicine, drug delivery, regenerative medicine, and tissue engineering. This article summarizes the most recent advances in the field of steroidal supramolecular gels in terms of steroid-derived hydro- and organogels, metallogels, two-component gels, and stimuli-responsive gels. Furthermore, the potential applications of the systems are discussed.

Exploitation of bile acid transport systems in prodrug design.

The enterohepatic circulation of bile acids is one of the most efficient recycling routes in the human body. It is a complex process involving numerous transport proteins, which serve to transport bile acids from the small intestine into portal circulation, from the portal circulation into the hepatocyte, from the hepatocyte into the bile, and from the gall bladder to the small intestine. The tremendous transport capacity and organ specificity of enterohepatic circulation combined with versatile derivatization possibilities, rigid steroidal backbone, enantiomeric purity, availability, and low cost have made bile acids attractive tools in designing pharmacological hybrid molecules and prodrugs with the view of improving intestinal absorption, increasing the metabolic stability of pharmaceuticals, specifically targeting drugs to organs involved in enterohepatic circulation, as well as sustaining therapeutically reasonable systemic concentrations of active agents. This article briefly describes bile acid transport proteins involved in enterohepatic circulation, summarizes the key factors affecting on the transport by these proteins, and reviews the use of bile acids and their derivatives in designing prodrugs capable of exploiting the bile acid transport system.

Bile acid alkylamide derivatives as low molecular weight organogelators: Systematic gelation studies and qualitative structural analysis of the systems

A series of amino- and hydroxyalkyl amides of bile acids have been synthesized and characterized by Fourier transform infrared spectroscopy (FTIR), (1)H and (13)C nuclear magnetic resonance spectroscopy (NMR), as well as electrospray ionization mass spectrometry (ESI-MS) measurements. The ability of the synthesized molecules to promote gel formation was systematically investigated. Out of 396 combinations formed by 11 compounds and 36 different solvents, 22 gel-containing systems were obtained with 1% (w/v) gelator concentration. Apart from one exception, the gelator compounds were lithocholic acid derivatives. This challenges the general trend of bile acid-based physical gelators, according to which the gelation ability of lithocholic acid derivatives is poor. A correlation between the values of Kamlet-Taft parameters and solvent preferences for gelators was observed. The morphologies of the solid and gel structures studied with scanning electron microscopy (SEM) showed variability from fibers to spherical microscale aggregates, the latter of which are unique among bile acid-based organogels. The gels exhibited more complex behavior than was previously established with bile acid derivatives, judging by the microscale diversity present in gelating and non-gelating systems and the tendency for polymorphism. This study underlines the importance of both the molecular and colloidal scale aspects of the gelation phenomenon.

Bile acid–amino acid ester conjugates: gelation, structural properties, and thermoreversible solid to solid phase transition

Design, synthesis, and gelation properties of three novel biocompatible bile acid–L-methionine methyl ester conjugates are presented. Two of the conjugates have been shown to undergo self-assembly leading to organogelation in certain aromatic solvents. The properties of these gels have been investigated by conventional methods typical for molecular gel studies along with 13C CPMAS NMR spectroscopic studies of the native gel. In addition, properties in solid and solution states for all three compounds have been investigated, and single crystal X-ray structures of all compounds determined. Furthermore, powder X-ray diffraction studies have revealed that compound 1 undergoes a dynamic and reversible conformational change in the solid state when cooling from ambient temperature to −150 °C. The powder X-ray diffraction data of the room-temperature conformer has been utilized to unambiguously determine the structure at room temperature.

Synthesis, Characterization, and Saccharide Binding Studies of Bile Acid − Porphyrin Conjugates

Synthesis and characterization of bile acid-porphyrin conjugates (BAPs) are reported. Binding of saccharides with BAPs in aqueous methanol was studied by monitoring changes in the visible absorption spectral of the porphyrin-moieties. Although these studies clearly showed absorbance changes, suggesting quite high if non-selective binding, the mass spectral studies do not unambiguously support these results.

Bile acid-cysteamine conjugates: structural properties, gelation, and toxicity evaluation.

Design, synthesis, and characterization of six novel bile acid-cysteamine conjugates together with investigation of their structural studies, gelation properties, and preliminary toxicity evaluation, are reported. Solid state properties of selected compounds were studied by means of X-ray diffraction and (13)C CPMAS NMR spectroscopy. N-(2-thioethyl)-3α,7α,12α-trihydroxy-5β-cholan-24-amide was shown to exhibit (pseudo)polymorphism, and a single crystal structure of its non-stoichiometric hydrate is reported herein. Cholyl and dehydrocholyl derivatives bearing three functionalities in their steroidal backbone were shown to undergo self-assembly leading to gelation in certain organic solvents. Preliminary morphology studies of the formed gels by scanning electron microscopy (SEM) were performed. The standard model mouse fibroblast cell line together with the MTT and NR tests were utilized for evaluating the toxicity of the prepared compounds. Lithocholyl, ursodeoxycholyl, and dehydrocholyl derivatives turned out to be relatively non-toxic in the conditions studied.

Novel Porphyrin-cholic Acid Conjugates as Receptors for Biologically Important Anions

A series of novel receptors showing high binding affinity in aqueous media for biologically important anions are reported. These naturally chromophoric porphyrin-based receptors contain cholic acids connected via quaternary alkyl ammonium amido linkages.

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

The synthetic method for preparing N-(3-hydroxypropyl) 3 alpha,12 alpha-dihydroxy-5 beta-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 13C-CP/MAS-NMR and IR spectroscopy, thermo- gravimetry, differential scanning calorimetry and by powder and single crystal x-ray crystallography. In addition, theoretical 13C-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, C27H47NO4 x H2O, 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.

Dissolution behavior of co-amorphous amino acid-indomethacin mixtures: The ability of amino acids to stabilize the supersaturated state of indomethacin

Graphical abstract Figure. No caption available. Abstract Arginine, phenylalanine, and tryptophan have been previously shown to improve the solid‐state stability of amorphous indomethacin. The present study investigates the ability of these amino acids to prolong the supersaturation of indomethacin in both aqueous and biorelevant conditions either when freely in solution or when formulated as co‐amorphous mixtures. The co‐amorphous amino acid‐indomethacin mixtures (molar ratio 1:1) and amorphous indomethacin were prepared by cryomilling. Dissolution and precipitation tests were performed in buffer solutions (pH 5 and 6.5) and in Fed and Fasted State Simulated Intestinal Fluids (FeSSIF and FaSSIF, respectively). Precipitation tests were conducted with the solvent shift method. The supersaturation stability of indomethacin and the precipitation inhibitory effect of amino acids were evaluated by calculating the supersaturation factor and the excipient gain factor, respectively. Biorelevant media exerted a significant effect on indomethacin solubility but had little effect on the supersaturation stability. Arginine had the most significant impact on the dissolution properties of indomethacin, but also phenylalanine and tryptophan stabilized supersaturation in some media when formulated as co‐amorphous mixtures with indomethacin. Only arginine stabilized supersaturation without co‐amorphization, an effect only observed in media of pH 6.5. The unique behavior of the arginine‐indomethacin mixture was further demonstrated by the abrupt formation of a precipitate, when an excess physical mixture of arginine and indomethacin was added to FeSSIF (pH 6.5). The solid‐state investigation of this precipitate indicated that it probably consisted of crystalline arginine‐indomethacin salt with possibly some residual crystalline starting materials. Abbreviations: AA: amino acid; ACN: acetonitrile; ARG: arginine; AUC: area under the curve; CA: co‐amorphous; DMSO: dimethyl sulfoxide; DS: degree of supersaturation; DSC: differential scanning calorimetry; EGF: excipient gain factor; FaSSIF: fasted state simulated intestinal fluid; FeSSIF: fed state simulated intestinal fluid; FTIR: Fourier transform infrared spectroscopy; HPLC: high performance liquid chromatography; IND: indomethacin; PHE: phenylalanine; PM: physical mixture; SF: supersaturation factor; ssNMR: solid‐state nuclear magnetic resonance spectroscopy; TFA: trifluoro acetic acid; Tg: glass transition temperature; Tm: melting temperature; TRP: tryptophan; XRPD: X‐ray powder Diffractometry.

First bisphosphonate hydrogelators: potential composers of biocompatible gels

Recently, investigation of hydrogels has gained ever increasing attention mostly because of their biomedical and pharmaceutical properties, and novel hydrogelators are constantly studied to find functional applications. Bisphosphonates (BPs) are well-known compounds applicable in different fields but are mostly used in clinics as drugs for bone-related diseases. In this study, a novel class of BP-hydrogelators together with a BP-organogelator was found, and the gelating abilities of the compounds were studied. Several techniques to analyze the structure and the properties of the formed gels were used, including solid state 13C and 31P CPMAS and solution state NMR spectroscopy, IR spectroscopy, PXRD, thermoanalysis, as well as SEM.