Search

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.

Four hybrid steroid dimers were obtained by BF 3 ·Et 2 O-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 (IC 50 18.37 μM) and 9c (IC 50 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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Five new brassinosteroid analogues were synthetized from 3β-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 3β-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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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 13 C{ 1 H } CPMAS and 2 H spin-echo experiments, using the deuterated analogue SMR-3D 4 , 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.

23E-diacetoxybenzylidenespirostanes underwent rearrangement when treated with HCl in CH 2 Cl 2 /CH 3 OH. 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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The synthesis and characterization of a dimer in which two nuclei of 3β-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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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 λ em values of 370 and 390 nm in pure THF to a new spectrum with two maxima at λ em 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.

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., (Copyright © 2021 Elsevier Inc. All rights reserved.)

NaBH 3 CN 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., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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.

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., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Two diastereomeric crystalline steroid dimers were obtained by acid-catalyzed double acetalization of (20S)-5α-pregnan-3β,16β,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 13 C 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.

Nine cytotoxic [5/7] and [6/6] benzannulated steroid spiroketals were synthesized by palladium catalyzed spiroketalization of 5α and 5β-alkynediols derived from testosterone, diosgenin and cholesterol. The regioselectivity of the spiroketalization reaction is decisively influenced by the α or β-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.

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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

BF 3 ·Et 2 O-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., (Copyright © 2018 Elsevier Inc. All rights reserved.)

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 13 C CPMAS, and solid state 2 H 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.

BF 3 ·Et 2 O-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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Benzylidenespirostanols were prepared by two-step synthesis including BF 3 ·Et 2 O-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 IC 50 for MCF7 cells 19.9±0.1µM) without any selectivity towards human cancer and normal cells, respectively., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Treatment of steroid sapogenins with H 2 O 2 in CF 3 COOH for 15min followed by reflux in CH 3 OH/H 2 O afforded good yields of pregnan-3β,16β,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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

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., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Treatment of 3-oxo-5β-steroids with diacetoxyiodobenzene/KOH triggered a fast and regioselective Favorskii rearrangement that exclusively led to 3β-methoxycarbonyl-5β-4-norsteroids in good yields. The outcome of the reaction indicates that although both Cyclopropanone and Semi-benzylic pathways are possible, in the case of 3-oxo-5β-steroids, only the last participates. Unambiguous characterization of the products was achieved by NMR and X-ray Diffraction studies., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Two dimeric steroidal terephthalates derived from epimeric 4,5-seco-cholest-3-yn-5-ols were prepared starting from cholesterol in a five-step synthetic sequence. X-ray crystallography shows that the obtained compounds display novel supramolecular networks in the solid state in which the facial hydrophobicity of the steroidal skeletons plays an important role. Unambiguous NMR characterization of the obtained dimers is also provided., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Palladium-catalyzed cross coupling of 4-methoxycarbonyl phenyboronic acid with acetylated bile acids in which the carboxyl functions was activated by formation of a mixed anhydride with pivalic anhydride afforded the cross coupled compounds, which were converted in novel side chain modified bile acids by one pot carbonyl reduction/removal of the protecting acetyl groups by Wolff-Kishner reduction. Unambiguous assignments of the NMR signals and crystal characterization of the heretofore unknown compounds are provided., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Tandem aldol condensation between steroid sapogenins and hydroxylated benzaldehydes afforded steroidal spirochromenes. Compounds that bear a phenolic hydroxyl group at position C-6', obtained by a reaction with 2,5-dihydroxybenzaldehyde, showed approximately 80% of maximal radical scavenging activity in the 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) assay at 288 nM. In contrast, the starting steroid sapogenins and the spirochromenes without a phenolic group in the side chain proved to be inactive., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Palladium-catalyzed cross coupling of phenyboronic acid with acetylated bile acids in which the carboxyl functions have been activated by formation of a mixed anhydride with pivalic anhydride afforded moderate to good yield of 24-phenyl-24-oxo-steroids. Unambiguous assignments of the NMR signals were made with the aid of combined 1D and 2D NMR techniques. X-ray diffraction studies confirmed the obtained structures., (Copyright © 2013 Elsevier Inc. All rights reserved.)

F-ring opening in spirostanes with the 16β,22:22,25-diepoxy-23-acetoxymethyl-24-methyl side chain produces a Δ(22)-intermediate with an allylic acetoxy group. For this reason the reactivity profile of these compounds deviates from that observed in other naturally occurring or synthetic spirostanes and furospirostanes., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Two unnatural steroid sapogenins bearing a furospirostane side chain were prepared starting from the readily available spirostane sapogenins, tigogenin and diosgenin following a synthetic protocol that included: (i) introduction of a carbonyl group at position C-23, (ii) diacetoxyiodobenzene-induced F-ring contraction and (iii) LiAlH4 reduction of the newly emerged methoxycarbonyl moiety. The structures of the new compounds were corroborated by NMR and X-ray studies., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The naturally occurring dinorcholanic lactone vespertilin and two other non-natural derivatives bearing the 5α-hydroxy-6-oxo moiety were synthesized starting from the readily available steroid sapogenin diosgenin. The obtained compounds showed plant growth promoting activity in the bean's second internode elongation assay., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Treatment of 12-oxosteroids with PhI(OAc)(2) and KOH in refluxing methanol triggers a quasi-Favorskii C-ring contraction leading to the corresponding 11α-alcoxycarbonyl-C-norsteroids in moderate yields. This constitutes the first one-step synthetic alternative to C-norsteroids starting from 12-oxosteroids., (Copyright © 2012 Elsevier Inc. All rights reserved.)

This review article is a tribute to the numerous chemists whose relentless effort for the last quarter of a century resulted in the isolation, identification, and finally the chemical synthesis of a family of bis-steroidal pyrazine alkaloids of marine origin. In the task of defeating cancer, the search for bioactive substances among the naturally occurring compounds is, without any doubt, a preferential approach. The remarkable contribution of Petitt, Fusetani, and their coworkers allowed to discover this family of marine alkaloids that emerge as potential therapeutic anticancer agents, although there is still a long way to go. The challenging and dangerous task of collecting living organisms from deep-waters was followed by a laborious isolation, elucidation of the complicated structures and biological tests. The outcome of this paramount effort was the identification of 45 compounds that stand, to date, as some of the most potent anticancer agents. The intriguing structures of the isolated alkaloids drew the attention of synthetic chemists, valiant enough to undertake the challenging task of synthesizing some of the most active members of the family. Fuchs, Heathcock, Winterfeldt, Suarez, Shair, and their associates pioneered in the establishment of feasible synthetic routes for the preparation of some of the naturally occurring compounds and a large number of synthetic analogs, allowing to establish SAR criteria that have guided the design of new synthetic analogs. Numerous analogs have been prepared to investigate the mechanism of action of bis-steroidal pyrazines, e.g. cephalostatin analogs bearing a strained spiroketal moiety. However, the mechanism of action and the biological target of these compounds remain far from being understood. Therefore, the rational design of simpler, yet highly active analogs seems at the current stage elusive. It is still 1 to clear why these compounds need to be dimeric to show high biological activity. Furthermore, it is not known whether the central pyrazine ring is simply a linker or has some additional function. This could be tested by examining the biological activity of steroidal dimers with other linkers, e.g. with a benzene ring. Such analogs have been actually prepared but without functional groups necessary for biological activity. The clinical trials of cephalostatins have got stuck due to a shortage of material. There is an urgent need to provide highly active, yet not too complex analogs, which could be available in substantial amounts for advanced pharmacological studies.

Treatment of steroid sapogenins with benzaldehyde and BF(3)·Et(2)O cleanly produces E-23(23')-benzylidenspirostanes in good yields in a reaction pathway which consists on an aldol reaction followed by a dehydration step. The obtained E-23(23')-benzylidenspirostanes can be easily converted to dinorcholanic lactones by treatment with CrO(3) in acetic acid. The synthetic sequence to dinorcholanic lactones is compatible with the presence of double bonds and carbonyl groups in the steroid framework., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Three polyhydroxylated ketones bearing the 5α-hydroxy-6-oxo moiety were obtained from cholesterol. Two of them show plant growth promoting activity in the bean's second internode bioassay. The obtained results indicate that the presence of the 5α-hydroxy-6-oxo moiety may be capable to induce plant growth promotion even the absence oxygenated functions in the side chain., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Brønsted and Lewis acid-catalysed reactions of the 23-methoxycarbonyl furospirostanic side chain are described. While bromination, deuteration and BF(3)·Et(2)O/AcOH treatment involve regioselective F-ring opening with exclusive participation of Δ(22)-furostenic intermediates, BF(3)·Et(2)O/Ac(2)O treatment leads to irreversible E- or F-ring cleavage., (Copyright © 2011 Elsevier Inc. All rights reserved.)

During reactions of 23-oxosapogenins and the corresponding isomeric 22-oxo-23-spiroketals with MCPBA in the presence of BF(3)·Et(2)O, equilibration occurs between the ketones. The Baeyer-Villiger type oxidation is followed by fragmentation to the dinorcholanic lactones and 3-methylbutyrolactone. The mechanistic aspects of these reactions in the 25R and 25S series are discussed., (Copyright © 2010 Elsevier Inc. All rights reserved.)

In addition to a previous report, the reaction of tigogenin acetate with ICl in refluxing CHCl(3) produced the hitherto unknown 23R-iodotigogenin acetate, bearing an axial iodine atom at C-23 and its already reported 23S-epimer. The same treatment of sarsasapogenin acetate led to a single diasteromer characterized as 23S-iodosarsasapogenin acetate. A full characterization of the obtained compound including (1)H, (13)C NMR, MS and X-ray diffraction is provided.

The Beckmann rearrangement of the syn and anti isomers of the spirocyclic oxime derived from a 16beta,23:23,26-diepoxy-5beta-cholestan-22-one was studied. Whereas the anti isomer always follows the Beckmann fragmentation course, the syn isomer, depending on the reaction conditions, follows the normal Beckmann rearrangement course and/or the isomerization to the anti isomer followed by the fragmentation course.

A detailed analysis of the course of the reaction of steroid sapogenins with NaNO(2) and BF(3).Et(2)O in acetic acid is presented and some evidences on the involved mechanism are provided. Two new products of the studied reaction were isolated and unambiguously characterized with the aid of NMR and single crystal X-ray diffraction.

The full assignments of the (1)H and (13)C NMR signals of steroids bearing the 16beta,23:23,26-diepoxy side chain are provided. Differentiation of the diasterotopic H-26 pair was achieved with the aid of NOESY experiments. The main substituent and steric effects associated with this moiety and their influence on the chemical shifts of the neighboring atoms are discussed.

Two furostanic analogues of brassinosteroids bearing the 5alpha-hydroxy-6-oxo moiety were synthesized and their biological activity studied using the bean second internode elongation test. One of the compounds produced significant stimulation at doses of 2.5 and 5ng/plant.

A convenient, one-pot procedure for the synthesis of 1-benzoyl-2(S)-substituted-5-iodo-2,3-dihydro-4(H)-pyrimidin-4-ones by tandem decarboxylation/beta-iodination of the corresponding 6-carboxy-perhydropyrimidin-4-ones was developed. In addition, several 1-benzoyl-2(S)-substituted-5-bromo-2,3-dihydro-4(H)-pyrimidin-4-ones were readily prepared by bromination of 1-benzoyl-2(S)-substituted-2,3-dihydro-4(H)-pyrimidin-4-ones. Subsequently, Sonogashira coupling of the halogenated heterocyclic enones with various terminal alkynes produced 1-benzoyl-2(S)-isopropyl-5-alkynyl-2,3-dihydro-4(H)-pyrimidin-4-ones in good yields. Hydrogenation of the unsaturated C-C moieties in the Sonogashira products followed by acid hydrolysis afforded highly enantioenriched alpha-substituted beta-amino acids.

The synthesis, spectroscopic characterization, and biologic activity of two bioactive spirostanic analogues of the naturally occurring brassinosteroid castasterone are described.