RESUMEN
Alkyltitanium alkoxides generally serve as nucleophiles in reactions with carbonyl compounds and cross-coupling. Their application as reductants is known but remains underdeveloped. Here, we report that irradiation with visible light makes these organometallic compounds efficient reducing agents for the dehalogenation of 1,2- and 1,3-haloalcohols. This reaction was utilized for the reduction of epoxides and sulfonates, which proceeded through a sequence of the in situ halohydrin formation and photochemical dehalogenation. Ester, amide, nitrile, alkyne, and remote bromide groups were stable under the reaction conditions.
RESUMEN
Synthesis of 21,22-cyclosteroids has been achieved starting from pregnenolone acetate. The key transformation was the Kulinkovich reaction of 17-vinyl steroids with esters. The resulting cyclopropanols were further subjected to three-membered ring-opening under various conditions including to base-, palladium or visible light-promoted isomerization and cross-coupling reaction. A number of steroidal Δ2-6-ketones and 3ß-hydroxy-Δ5-enes with functional groups at C-21 - C-23 have been synthesized via the 21,22-cyclosteroids. The antiproliferative and antihormonal activity of the obtained compounds on the cell lines of prostate (22Rv1) and breast (MCF-7) cancer was studied. The androgen receptor activity was assessed by reporter assay when the expression of signalling proteins was evaluated by immunoblotting. (20S,22R)-22-Acetoxy-21,22-cyclo-5α-cholest-5-ene with the moderate antiandrogenic potency revealed IC50 values of 18.4 ± 1.2 and 14.6 ± 1.4 µM against MCF-7 and 22Rv1 cells, respectively, and its effects on the expression of AR-V7, cyclin D1 and BCL2 were explored.
Asunto(s)
Antineoplásicos , Cicloesteroides , Humanos , Masculino , Línea Celular Tumoral , Proliferación Celular , Cicloesteroides/química , Cicloesteroides/farmacología , Imidazoles , Pregnenolona , Receptores Androgénicos/metabolismo , Esteroides , Neoplasias de la Mama/tratamiento farmacológico , Antineoplásicos/química , Antineoplásicos/farmacologíaRESUMEN
Here, we report that alkyltitanium alkoxides generated in situ from Grignard reagents and Ti(OiPr)4 undergo a photocatalyst-free nickel-catalyzed cross-coupling with organic halides upon irradiation with blue light. Mechanistic studies suggested that the reaction proceeds through radical intermediates formed by photochemical decomposition of the alkyltitanium reagents. Various aryl, heteroaryl, and vinyl halides were efficiently alkylated under the reported conditions, including those containing ester and amide groups.
RESUMEN
Readily available from esters or ketones, cyclopropanols are inclined to undergo diverse ring-opening transformations. Their one-electron oxidation is a conventional way to ß-carbonyl radicals. However, despite this fact, their application as a coupling partner in dual photoredox and nickel-catalyzed reactions with organic halides remains underdeveloped. Here, we report that the Ti(OiPr)4 additive enables this elusive cross-coupling with aryl and alkenyl bromides leading to ß-substituted ketones.
RESUMEN
Mycobacterium tuberculosis (Mtb) infection is among top ten causes of death worldwide, and the number of drug-resistant strains is increasing. The direct interception of human immune signaling molecules by Mtb remains elusive, limiting drug discovery. Oxysterols and secosteroids regulate both innate and adaptive immune responses. Here we report a functional, structural, and bioinformatics study of Mtb enzymes initiating cholesterol catabolism and demonstrated their interrelation with human immunity. We show that these enzymes metabolize human immune oxysterol messengers. Rv2266 - the most potent among them - can also metabolize vitamin D3 (VD3) derivatives. High-resolution structures show common patterns of sterols binding and reveal a site for oxidative attack during catalysis. Finally, we designed a compound that binds and inhibits three studied proteins. The compound shows activity against Mtb H37Rv residing in macrophages. Our findings contribute to molecular understanding of suppression of immunity and suggest that Mtb has its own transformation system resembling the human phase I drug-metabolizing system.
Asunto(s)
Metabolismo Energético , Interacciones Huésped-Patógeno , Mycobacterium tuberculosis/inmunología , Tuberculosis/inmunología , Tuberculosis/metabolismo , 3-Hidroxiesteroide Deshidrogenasas/química , 3-Hidroxiesteroide Deshidrogenasas/metabolismo , Catálisis , Sistema Enzimático del Citocromo P-450/química , Sistema Enzimático del Citocromo P-450/metabolismo , Activación Enzimática , Interacciones Huésped-Patógeno/inmunología , Humanos , Inmunidad , Isoenzimas , Modelos Moleculares , Oxiesteroles/química , Oxiesteroles/metabolismo , Proteínas Recombinantes , Relación Estructura-Actividad , Tuberculosis/microbiologíaRESUMEN
A photochemical approach to 18-nor-17ß-hydroxymethyl-17α-methylandrost-13-ene unit of the long-term metabolites of 17-methylated androgenic anabolic steroids (AAS) is reported. It is based on a visible light-promoted radical decarboxylative alkynylation of steroidal redox-active ester. The developed method was used in synthesis of the long-term metabolite of AAS oxymesterone.
Asunto(s)
Anabolizantes/síntesis química , Androstenos/síntesis química , Esteroides/síntesis química , Anabolizantes/química , Anabolizantes/metabolismo , Androstenos/química , Androstenos/metabolismo , Luz , Conformación Molecular , Procesos Fotoquímicos , Estereoisomerismo , Esteroides/química , Esteroides/metabolismoRESUMEN
Enantioselective synthesis of C23-C28 subunit of campestane steroids based on catalytic methods is reported. The synthesis was started from (S)-2-isopropyl-4-nitrobutan-1-ol, which is easily accessible by the reaction between isovaleraldehyde and nitroethylene catalyzed by only 2% of (S)-trimethylsilyldiphenylprolinol. Removal of one "extra" carbon from the nitroalcohol was achieved by Ni-catalyzed hydrodecarboxylation of the redox-active ester intermediate. The synthesized C23-C28 fragment was attached to a steroidal core by Julia-Kocienski reaction of a steroidal aldehyde with metallated C23-C28 sulfone. The obtained product of olefination was easily transformed to a precursor of campesterol and (Z)-22-dehydrocampesterol.
Asunto(s)
Pirrolidinas/química , Esteroides/síntesis química , Catálisis , Conformación Molecular , Estereoisomerismo , Esteroides/químicaRESUMEN
Late stage CH functionalization is a powerful tool for modification of natural compounds. Herein we report that the rhodium-catalyzed reaction of brassinosteroids with aryloxysulfonamides proceeds regio- and stereoselectively at C15 position. The derivative obtained from 24-epibrassinolide was easily transformed to the conjugate with a BODIPY dye bearing unaffected functional groups of the native brassinosteroid.
Asunto(s)
Brasinoesteroides/química , Compuestos de Boro/química , Catálisis , Rodio/química , EstereoisomerismoRESUMEN
A number of isoxazole, 1,2,3-triazole, tetrazole, and 1,2,4-oxadiazole derivatives of [17(20)E]-21-norpregnene comprising 3ß-hydroxy-5-ene and 3-oxo-4-ene fragments were prepared. Among the key steps for the synthesis of isoxazoles, 1,2,3-triazoles, and tetrazoles were (i) 1,3-dipolar cycloaddition of nitrile oxides or azides to acetylenes or nitriles and ii) dehydration of 17ß-hydroxy-17α-methylene-azoles to [17(20)E]-21-norpregnene derivatives. 1,2,4-Oxadiazoles were prepared through the formation of acetimidamides. Potency of the synthesized compounds to inhibit CYP17A1 and to suppress growth of prostate carcinoma cells was investigated. Among the new azole derivatives, four compounds were found possessing high anti-proliferative activity.
Asunto(s)
Antineoplásicos/farmacología , Azoles/farmacología , Norpregnadienos/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Antineoplásicos/síntesis química , Antineoplásicos/uso terapéutico , Azoles/síntesis química , Azoles/química , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Masculino , Estructura Molecular , Norpregnadienos/síntesis química , Norpregnadienos/uso terapéutico , Células PC-3 , Neoplasias de la Próstata/patología , Células Tumorales CultivadasRESUMEN
Alkenes bearing a stereocenter in the allylic position were found to undergo Kulinkovich hydroxycyclopropanation with good diastereoselectivity. For the isomerization of the resulting cyclopropanols to diastereomerically enriched α-methyl ketones, a new mild regioselective method has been developed. A sequence of stereoselective cyclopropanation and cyclopropanol ring opening was successfully employed for the construction of the C20 stereocenter in steroids.
RESUMEN
Effects exerted by heavy isotope substitution in biopolymers on the functioning of whole organisms have not been investigated. We report on the decrease of permissive temperature of nematodes fed with bacteria containing 5,5-D2-lysine. We synthesized 5,5-dideuterolysine and, taking advantage of lysine being an essential amino acid, showed that C. elegans with modified lysine poorly develop from larvae into fertile adult hermaphrodites. This effect occurs only at high temperature within the permissible range for C. elegans (25 °C) and completely vanishes at 15 °C. The only known metabolic involvement of C5 in lysine is in post-translational modification through lysyl hydoxylases. Indeed, siRNA experiments showed that deficiency of let-268/plod lysyl-hydroxylase/glycosydase further amplifies the isotope effect making it apparent even at 20 °C, whereas control siRNAs as well as another lysyl-hydroxylase (psr-1/jmjdD) siRNA do not. We report for the first time that a site-specific deuteration may strongly affect the development of the whole animal organism especially under the conditions of deficiency of the corresponding enzyme. These findings provide the basis for our ongoing efforts to employ isotope effects for fine tuning of metabolic pathways to mitigate pathological processes.
Asunto(s)
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/genética , Deuterio/metabolismo , Escherichia coli/metabolismo , Lisina/metabolismo , Procolágeno-Lisina 2-Oxoglutarato 5-Dioxigenasa/deficiencia , Animales , Caenorhabditis elegans/crecimiento & desarrollo , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/antagonistas & inhibidores , Proteínas de Caenorhabditis elegans/genética , Ingestión de Alimentos , Escherichia coli/química , Regulación del Desarrollo de la Expresión Génica , Larva/genética , Larva/crecimiento & desarrollo , Larva/metabolismo , Lisina/síntesis química , Procolágeno-Lisina 2-Oxoglutarato 5-Dioxigenasa/antagonistas & inhibidores , Procolágeno-Lisina 2-Oxoglutarato 5-Dioxigenasa/genética , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Relación Estructura-Actividad , TemperaturaRESUMEN
Palladium-catalyzed C-H acetoxylation has been proposed as a key transformation in the first chemical synthesis of steroids bearing a unique 17ß-hydroxymethyl-17α-methyl-18-nor-13-ene D-fragment. This C-H functionalization step was crucial for inverting the configuration at the quaternary stereocenter of a readily available synthetic intermediate. The developed approach was applied to prepare the metandienone metabolite needed as a reference substance in anti-doping analysis to control the abuse of this androgenic anabolic steroid.
Asunto(s)
Anabolizantes/química , Metandrostenolona/análogos & derivados , Norandrostanos/síntesis química , Anabolizantes/síntesis química , Catálisis , Técnicas de Química Sintética/métodos , Metandrostenolona/síntesis química , Norandrostanos/química , Oxidación-Reducción , Paladio/química , EstereoisomerismoRESUMEN
The aim of this work was to prepare 24-epicryptolide and 22-dehydro-24-epibrassinolide as possible metabolites of 24-epibrassinolide. The main synthetic problem to be solved was the differentiation of functional groups in brassinosteroids. Distinguishing 2α,3α-diol function from another diol group in 24-epibrassinolide was achieved via selective hydrolysis of 2α,3α-cyclic carbonate or via regioselective reaction of boric acid with the functional groups in the side chain. The hydroxyl at C-23 was more reactive than the 22-OH in the oxidation with bromine in the presence of bis(tributyltin) oxide and in the benzylation reaction that resulted in the predominant formation of the corresponding α-hydroxy ketone derivatives with the ratio ranging from 4:1 to 1.5:1.
Asunto(s)
Brasinoesteroides/química , Cetonas/química , Esteroides Heterocíclicos/química , Esteroides/química , Esteroides/síntesis química , Ácidos Bóricos/química , Técnicas de Química Sintética , Hidrólisis , Oxidación-Reducción , EstereoisomerismoRESUMEN
A new synthetic route to 22S-hydroxy-24R-methyl steroids has been developed and applied for the preparation of cathasterone, (22S)-hydroxycampesterol, and 6-deoxocathasterone, which are precursors in the early stages of the biosynthesis of brassinolide. The construction of the steroid side chain with the correct stereochemistry at C-24 is based on the use of Claisen rearrangement. The introduction of the 22-hydroxyl group has been achieved by epoxidation of the Δ(22)-double bond, nucleophilic opening of the intermediate mesyl epoxide with sodium sulfide, and desulfurization of the formed tetrahydrothiophenes with Raney nickel.
Asunto(s)
Brasinoesteroides/química , Esteroides Heterocíclicos/química , Esteroides/química , Compuestos Epoxi/química , Espectroscopía de Resonancia Magnética , Espectrometría de MasasRESUMEN
Lysyl oxidase (LOX) is implicated in several extracellular matrix related disorders, including fibrosis and cancer. Methods of inhibition of LOX in vivo include antibodies, copper sequestration and toxic small molecules such as ß-aminopropionitrile. Here, we propose a novel approach to modulation of LOX activity based on the kinetic isotope effect (KIE). We show that 6,6-d(2)-lysine is oxidised by LOX at substantially lower rate, with apparent deuterium effect on V(max)/K(m) as high as 4.35 ± 0.22. Lys is an essential nutrient, so dietary ingestion of D(2)Lys and its incorporation via normal Lys turnover suggests new approaches to mitigating LOX-associated pathologies.