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Contrary to our previous report in which a Pd-catalyzed three-component reaction of a steroid alkynol, trimethyl orthoformate, and salicylaldehyde exclusively produced chroman ketals, the same reaction employing 2,5-dihydroxysalicylaldehyde led to a mixture of a chroman ketal and a spiroketal. Provided that both courses of the reaction imply a 4 + 2 inverse demand cycloaddition between an o-quinone methide and an enol ether, density functional theory calculations revealed that the chroman ketal/spiroketal selectivity is governed by both, the rate of the formation of the o-quinone methide and the isomerization of the initially produced exocyclic enol ether─that led to the spiroketal─to its endocyclic partner that produces the chroman ketal. Remarkably, Lewis catalysis is central to the observed reactivity, and the availability of plausible catalytic species controls the overall chemoselectivity. The methodology herein applied and scrutinized enriches the palette of reactions, leading to increased molecular complexity, as demonstrated in the obtained products, whose antioxidant activity and detailed NMR characterization are presented.

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Four hybrid steroid dimers were obtained by BF3·Et2O-catalyzed aldol condensation of acetylated steroid sapogenins with 2-formyl-estradiol diacetate. The structures of the obtained dimers were unambiguously established by NMR. The hybrid dimers 9a (IC50 18.37 µM) and 9c (IC50 9.4 µM) with the 5α configuration at the A/B rings junction showed the higher cytotoxicity against HeLa, with selectivity index of 4.36 and 11.8 respectively. The presence of a carbonyl function at position C-12 produced the highest cytotoxic effect, which is in line with our previous reports.

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Five new brassinosteroid analogues were synthetized from 3ß-acetoxy-23,24-dinorchol-4-en-22-oic acid. All the obtained compound showed significant activity in the Rice Lamina Inclination Test. Interestingly the effects of the methyl ester of 3ß-hydroxy-6-oxo-23,24-dinorcholan-22-oic acid (14) at concentrations of 1 × 10-7 and 1 × 10-6 M proved to be higher than those produced by brassinolide. In silico Molecular Docking and Induced fit docking (IFD) simulations for the compounds with the highest biological activity data were carried out to investigate the binding mode interactions into the brassinolide-binding groove which revealed that the compound 14 had high binding energy values and a good affinity.

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The dimeric steroid SMR-3, featuring a 1,4-phenyldiboronic ester flanked by two pregnan-triol frameworks, was synthesized to explore the intramolecular dynamics of its central component. The structural data from single-crystal X-ray diffraction studies and the Hirshfeld analyses indicate small steric effects around the aromatic ring that should favor the intended motion. However, solid-state NMR data obtained through VT 13C{1H} CPMAS and 2H spin-echo experiments, using the deuterated analogue SMR-3D4, revealed that this component is rigid even at temperatures where other reported steroidal molecular rotors experience fast rotation (85 °C). A combination of classical molecular dynamics, molecular mechanics, and correlated ab initio calculations allowed us to distinguish the steric and electronic factors that restrict the potential motion in this compound. The experimental and computational data reveal that electronic components dominate the behavior and are responsible for the high rotational barrier in the SMR-3 crystal.

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23E-diacetoxybenzylidenespirostanes underwent rearrangement when treated with HCl in CH2Cl2/CH3OH. The course of the rearrangement depends on the substitution pattern in the phenyl ring. While compounds bearing an acetoxy group at the ortho position produced spirochromenes, the partners with no substituent at the ortho position led to spiroindenes. All the rearranged compounds exhibited moderate antioxidant activity.

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The synthesis and characterization of a dimer in which two nuclei of 3ß-acetoxy-19-hydroxyandrost-5-en-17-one are linked by the fluorescent 1,4-bis(phenylethynyl)phenylene bridge attached to the oxygenated functions at positions C-19 of each steroid fragment is described. The compound was obtained in five steps and 23 % overall yield and showed a strong blue emission with a quantum yield of 0.66.

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This work describes the synthesis and aggregation behavior of a dimeric bile acid derivative in which two steroid cores are bridged by a p-di(phenylethynyl)phenylene fluorophore. The studied compound contains three key characteristics: (a) restricted conformational equilibrium in solution, (b) efficient fluorescence conferred by the bridge, and (c) medium responsiveness encoded in the steroid fragments. The incorporation of the three components afforded a compound that generates nano- and micrometric spherical particles with aggregation-responsive fluorescence emission. The observed self-assembly process of the featured molecule was induced by the gradual addition of water to the tetrahydrofuran (THF) solution. This aggregation led to significant changes in fluorescence that went from two bands at λem values of 370 and 390 nm in pure THF to a new spectrum with two maxima at λem values of 395 and 418 nm at high water contents, without a decrease in emission. The observed changes can be ascribed to weakly coupled aggregation, a hypothesis supported by multiscale molecular modeling, which sheds light on the mechanism of the self-assembly of this unconventional amphiphile.

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NaBH3CN reduction of symmetric dimers in which two steroid units are linked by a 1,4-dimethylidenebenzene moiety followed two different courses: (a) hydrogenation of the benzylic double bond and (b) reductive F ring opening of the side chain. While courses a and b led to symmetrical dimers, the combination of both pathways produced an unsymmetrical dimer that bears different side chains in each half. The exhaustive NMR characterization of all obtained compounds is presented.

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Irradiation of dichloroethane solutions of different bile acids with diacetoxy(iodobenzene) and iodine followed by treatment of the resulting raw mixture with MCPBA led to the 41-50% yields of the corresponding dehomologated alcohols in an uncomplicated one-pot protocol that can be completed in less than one day of work.

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A series of hybrid dimers having orthogonal steroidal cores bridged by a chroman ketal moiety were obtained by Pd-catalyzed three-component reactions of steroid alkynols, 2-formylestradiol 17-monoacetate, and methyl orthoformate, via ortho-quinone methide intermediates. One of the obtained L-shaped scaffolds showed an inefficient crystal packing featuring large channels within the crystal array. Monte Carlo simulations indicate that these voids preferentially allocate n-hexane, opening the way to explore further applications of similar organic crystalline materials as selective hosts for small molecules.

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Palladium-catalyzed cross-coupling of bile acids with 2-furanylboronic acid produced steroid furanyl ketones in low yields. Unambiguous assignments of the NMR signals were made with the aid of combined 1D and 2D NMR techniques.

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Two diastereomeric crystalline steroid dimers were obtained by acid-catalyzed double acetalization of (20S)-5α-pregnan-3ß,16ß,20-triol 3-monoacetate with terephtalaldehyde. These compounds were characterized by NMR in solution, MS, single-crystal X-ray diffraction, and variable-temperature solid-state NMR by 13C cross-polarization magic angle spinning (CPMAS). While the phenylene rotator in the SR diastereomer remains static even at 373 K, the RR isomer shows a slow rotational process of the phenylene ring at temperatures above room temperature and thus may be considered the first crystalline steroid molecular rotor without the alkyne axle.

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Nine cytotoxic [5/7] and [6/6] benzannulated steroid spiroketals were synthesized by palladium catalyzed spiroketalization of 5α and 5ß-alkynediols derived from testosterone, diosgenin and cholesterol. The regioselectivity of the spiroketalization reaction is decisively influenced by the α or ß-orientation of the hydroxyl group at C-5. NMR and single crystal X-ray diffraction corroborated the structure of the obtained compounds. Compounds bearing a cholestane skeleton exhibited higher cytotoxicity against U251 and T47D cells, and the BrdU incorporation assay suggests that the synthesized spiroketals inhibit cell proliferation.

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A study of the reactivity of 25R and 25S 23E-benzylidene spirostanes that includes epoxidation, catalytic hydrogenation as well as Lewis or Brønsted acid-catalyzed rearrangements is described. Exhaustive NMR characterization of the obtained compounds is presented. Additionally the structures of some of the obtained compounds were confirmed by single crystal X-Ray Diffraction studies.

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BF3·Et2O-catalyzed double aldol condensation between acetylated steroid sapogenins and terephtalaldehyde led to acetylated dimeric spirostanols linked through a 1,4-dimethylidenebenzene moiety in moderate to good yields. The E configurations of the introduced double bonds were corroborated by NOE experiments. Saponification of the dimeric steroids led to the corresponding dimeric spirostanols.

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A novel steroid molecular rotor was obtained in four steps from the naturally occurring spirostane sapogenin diosgenin. The structural and dynamic characterization was carried out by solution NMR, VT X-ray diffraction, solid state 13C CPMAS, and solid state 2H NMR experiments. They allowed the identification of a fast dynamic process with a frequency of 14 MHz at room temperature, featuring a barrier to rotation Ea = 7.87 kcal mol-1. The gathered experimental evidence indicated the presence of a hydrogen bond that becomes stronger as the temperature lowers. This interaction was characterized using theoretical calculations, based on topological analyses of the electronic density and energies. In addition, combining theoretical calculations with experimental measurements, it was possible to propose a partition to Ea (∼8 kcal/mol) into three contributions, that are the cost of the intrinsic rotation (∼2 kcal/mol), the hydrogen bond interaction (∼2 kcal/mol), and the packing effects (∼2-3 kcal/mol). The findings from the present work highlight the relevance of the individual components in the function of molecular machines in the solid state.

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Treatment of steroid sapogenins with H2O2 in CF3COOH for 15min followed by reflux in CH3OH/H2O afforded good yields of pregnan-3ß,16ß,20-triol 3-monoacetates. When the hydrolysis step was carried out with KOH in refluxing methanol excellent yields pregnantriols were obtained. The resulting compounds were characterized by their melting points and NMR spectral data. An X-ray diffraction analysis of compound 3a confirmed the proposed structure and provided detailed information about the bond lengths, bond angles and conformation.

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BF3·Et2O-catalyzed aldol condensation of steroid sapogenins with 2-formyl-estradiol diacetate afforded two novel classes of steroid dimers in which an estrogenic core is attached to the spirostanic side chain of an steroid sapogenin through an exocyclic double bond in position C-23, or through a spiro centre in C-22.

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Benzylidenespirostanols were prepared by two-step synthesis including BF3·Et2O-catalyzed aldol condensation of several acetylated steroid sapogenins with benzaldehyde followed by saponification. The obtained compounds showed moderate cytotoxicity against three cancer cell lines (T-lymphoblastic leukemia cell line CEM, breast carcinoma cell line MCF7 and cervical carcinoma cell line HeLa) and normal human fibroblasts (BJ). The most active of the five tested substances was 3c (lowest IC50 for MCF7 cells 19.9±0.1µM) without any selectivity towards human cancer and normal cells, respectively.

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Crystalline derivatives of side chain modified bile acids were efficiently prepared from the naturally occurring steroids by palladium-catalyzed cross coupling reaction as a key step. The solvent-free crystalline bile acids derivatives 2b-e are readily accessed by slow evaporation from selected solvents. A variety of steroidal scaffolds were found and elucidated by SXRD studies. The crystal packing of the title compounds are dominated by hydrogen-bonding interactions established between differently positioned acetyl protecting groups, which in the case of 2b and 2e take advantage of the facial amphiphilicity producing two novel steroidal supramolecular self-assemblies combining π-π and strong facial interactions. Thus, these crystalline arrays of side chain modified bile acids represent promising scaffolds for research and implementation in biomolecular materials or inclusion phenomena.

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