RESUMEN
Cyclopropanation reactions between C60 and different malonates decorated with monosaccharides and steroids using the Bingel-Hirsch methodology have allowed the obtention of a new family of hybrid compounds in good yields. A complete set of instrumental techniques has allowed us to fully characterize the hybrid derivatives and to determine the chemical structure of monocycloadducts. Besides, the proposed structures were investigated by cyclic voltammetry, which evidenced the exclusive reductive pattern of fullerene Bingel-type monoadducts. Theoretical calculations at the DFT-D3(BJ)/PBE 6-311G(d,p) level of the synthesized conjugates predict the most stable conformation and determine the factors that control the hybrid molecules' geometry. Some parameters such as polarity, lipophilicity, polar surface area, hydrophilicity index, and solvent-accessible surface area were also estimated, predicting its potential permeability and capability as cell membrane penetrators. Additionally, a molecular docking simulation has been carried out using the main protease of SARS-CoV-2 (Mpro) as the receptor, thus paving the way to study the potential application of these hybrids in biomedicine.
RESUMEN
The reaction of C60 with pregnen-20-carboxaldehyde, a biologically active synthetic steroid, by using a 1,3-dipolar cycloaddition reaction (Prato's protocol) results in the formation of pyrrolidine rings bearing a new stereogenic center on the C2 of the five-membered ring. The formation of the fullerene-steroid hybrids proceeds with preference for the Re face of the 1,3-dipole, with formation of a diastereomeric mixture in 73:15 ratio. The investigation of the chiroptical properties of these conjugates allowed determining the absolute configuration of the new fulleropyrrolidines. In addition, a thorough spectroscopical study permitted to determine the structure of the two mono-cycloadducts. The electrochemical properties of the new hybrids were also evaluated by cyclic voltammetry, both systems exhibit three quasi-reversible reduction waves which are cathodically shifted in regard to the parent C60. Theoretical calculations help supporting the experimental data. A conformational study combining semiempirical methods and density functional theory has predicted the most stable diastereomer. On the basis of this agreement, a possible reaction mechanism is presented. Additionally, a molecular docking simulation has been carried out using the HIV-1 protease as receptor, thus paving the way to study the possible application of these stereoisomers in biomedicine.
RESUMEN
The diastereoselective synthesis of cis and trans steroid-fulleropyrrolidines hybrids by reaction of N-metalated azomethine ylides [Cu(II) or Ag(I)] with the appropriate chiral ligand and C60 is described. The experimental findings reveal that the azomethine ylide stabilized by an allylic group cycloadds to [60]fullerene in an efficient manner and with a good diastereomeric excess. Furthermore, the new generated stereocenters are fully controlled by the catalytic systems used without being influenced by the chirality of the steroid. Interestingly, by this synthetic methodology the each one of the four possible stereoisomers have efficiently been obtained and characterized by CD spectra.
RESUMEN
New [60]fullerene-steroid conjugates (4-6) have been synthesized by 1,3-dipolar cycloaddition and Bingel-Hirsch cyclopropanation reactions from suitably functionalized epiandrosterone and [60]fullerene. Since a new stereocenter is created in the formation of the Prato monoaduct, two different diastereomers were isolated by HPLC (4, 5) whose absolute configurations were assigned according to the highly reliable "sector rule" on fullerenes. A further reaction of the malonate-containing diastereomer 5 with a second C60 molecule has afforded dumbbell fullerene 6 in which the two fullerene units are covalently connected through an epiandrosterone moiety. The new compounds have been spectroscopically characterized and their redox potentials, determined by cyclic voltametry, reveal three reversible reduction waves for hybrids 4 and 5, whereas these signals are split in dumbbell 6. Theoretical calculations at semiempirical (AM1) and single point B3LYP/6-31G(d) levels have predicted the most stable conformations for the hybrid compounds (4-6), showing the importance of the chlorine atom on the D ring of the steroid. Furthermore, TDDFT calculations have allowed assignments of the experimentally determined circular dichroism (CD) of the [60]fullerene-steroid hybrids based on the sign and position of the Cotton effects, despite the exceptionally large systems under study.
Asunto(s)
Fulerenos/química , Esteroides/química , Cromatografía Líquida de Alta Presión , Dicroismo Circular , Espectroscopía de Resonancia Magnética , Modelos Teóricos , Conformación Molecular , EstereoisomerismoRESUMEN
The design and synthesis of fullerene-steroid hybrids by using Prato's protocol has afforded new fullerene derivatives endowed with epiandrosterone, an important naturally occurring steroid hormone. Since the formation of the pyrrolidine ring resulting from the 1,3-dipolar cyloaddition reaction takes place with generation of a new stereogenic center on the C2 of the five-membered ring, the reaction proceeds with formation of a diastereomeric mixture [compounds 6 and 7 in 70:30 ratio, 8 and 9 in 26:74 ratio (HPLC)] in which the formation of the major diasteroisomers 6 and 9 is consistent with an electrophilic attack of [60]fullerene on the Re face of the azomethine ylide directed by the steroidic unit. The chiroptical properties of these conjugates reveal typical Cotton effects in CD spectra that have been used to assign the absolute configuration of the new fulleropyrrolidines. The electrochemical study of the new compounds reveals the presence of four quasi-reversible reduction waves which are cathodically shifted in comparison with the parent C60, thus ascertaining the proposed structures.
Asunto(s)
Fulerenos/química , Esteroides/química , Ciclización , Modelos Moleculares , Estructura Molecular , Teoría Cuántica , EstereoisomerismoRESUMEN
Invited for this month's cover are the collaborating groups of Dr. Margarita Suárez at Universidad de La Habana, Cuba, and Dr. Nazario Martín at Universidad Complutense de Madrid, Spain, together with groups at other institutions worldwide. The Front Cover shows a representation of the H2 @C60 hybrid molecule with a dehydroepiandrosterone moiety interacting with the active site of the SARS Cov-2. Read the full text of the article at 10.1002/cplu.202000770.
RESUMEN
We report the synthesis and characterization of a fullerene-steroid hybrid that contains H2 @C60 and a dehydroepiandrosterone moiety synthesized by a cyclopropanation reaction with 76 % yield. Theoretical calculations at the DFT-D3(BJ)/PBE 6-311G(d,p) level predict the most stable conformation and that the saturation of a double bond is the main factor causing the upfield shielding of the signal appearing at -3.13â ppm, which corresponds to the H2 located inside the fullerene cage. Relevant stereoelectronic parameters were also investigated and reinforce the idea that electronic interactions must be considered to develop studies on chemical-biological interactions. A molecular docking simulation predicted that the binding energy values for the protease-hybrid complexes were -9.9 kcal/mol and -13.5 kcal/mol for PLpro and 3CLpro respectively, indicating the potential use of the synthesized steroid-H2 @C60 as anti-SARS-Cov-2 agent.
Asunto(s)
Androsterona/química , Antivirales/química , Fulerenos/química , Simulación del Acoplamiento Molecular , SARS-CoV-2/metabolismo , Antivirales/metabolismo , Sitios de Unión , COVID-19/patología , COVID-19/virología , Proteasas 3C de Coronavirus/química , Proteasas 3C de Coronavirus/metabolismo , Proteasas Similares a la Papaína de Coronavirus/química , Proteasas Similares a la Papaína de Coronavirus/metabolismo , Teoría Funcional de la Densidad , Humanos , Unión Proteica , SARS-CoV-2/aislamiento & purificación , Electricidad Estática , TermodinámicaRESUMEN
Two new functionalized steroids containing both chloro and formyl substituents in ring A, and intended as precursors for the synthesis of hybrid systems, have been synthesized from ketosteroid precursors. 3-Chloro-2-formyl-17,17-dimethyl-18-nor-5α-androstane-2,13-diene, (I), and methyl 3-chloro-4-formyl-12-oxo-5ß-cholan-3-ene-24-oate, C26H37ClO4, (IV), have been synthesized using Vilsmeier reactions with 17ß-hydroxy-17α-methyl-5α-androstan-3-one and methyl 3,13-dioxo-5ß-cholan-24-oate, respectively. These products have been fully characterized using IR spectroscopy, 1H and 13C NMR spectroscopy, and high-resolution mass spectrometry, and in the case of (IV), a single-crystal X-ray diffraction study. Crystal structures have also been determined for the known analogues 3-chloro-2-formyl-17-oxo-5α-androst-2-ene, C20H27ClO2, (II), 3-chloro-2-formyl-5α-cholest-2-ene, C28H45ClO, (III), and the absolute and relative configurations are assigned for all four compounds (I)-(IV): when the fusion between rings A and B is trans, 3-chloro-2-formyl products are formed, but when this ring fusion is cis, a 3-chloro-4-formyl product results. The formation of (I) involves not only chloroformylation at ring A, but also dehydration and the 1,2 migration of a methyl group at ring D. In each of (II), (III) and (IV), rings B and C adopt almost perfect chair conformations, while ring A adopts a half-chair conformation. Ring D adopts an envelope conformation in each of (II) and (III), albeit differently folded in the two compounds, while in (IV), it adopts a half-chair conformation. A single C-H...O hydrogen bond links the molecules of (II) into C(6) chains which are linked into sheets by means of carbonyl-carbonyl interactions. The molecules of (IV) are linked into simple C(7) chains, again by a single C-H...O hydrogen bond, but there are no direction-specific interactions in (III) that are structurally significant.