RESUMEN

Conventional chemotherapy, especially with natural anticancer drugs, usually suffers from poor bioavailability and low tumor accumulation. To address these limitations, we developed a novel approach for modifying natural products in which amphiphilic hydroxamic acid hybrids based on a natural product: isoalantolactone (IAL) were rationally designed. Compound 18 is identified as a highly potent dual signal transducer and activator of transcription 3 (STAT3)/histone deacetylases (HDAC) inhibitor and induces autophagy and apoptosis. 18 exhibits higher antitumor potency than IAL and the hydroxamic acid SAHA in vitro and in vivo. Furthermore, 18 self-assembled in water to form nanoparticles (18 NPs), which facilitated the accumulation of drugs in tumor tissues and promoted their cellular uptake, resulting in superior anticancer efficacy compared to free 18. Compared to drug-drug conjugates, hydroxamic acid hybrids have a smaller molecular weight and can synergize with various anticancer drugs. Overall, these findings indicate that 18 utilizing nanomedicines and dual-target drugs provide an efficient strategy for the rational design of dual-target drugs and the modification of natural products.

Asunto(s)

Antineoplásicos , Apoptosis , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores de Histona Desacetilasas , Ácidos Hidroxámicos , Nanopartículas , Factor de Transcripción STAT3 , Factor de Transcripción STAT3/antagonistas & inhibidores , Factor de Transcripción STAT3/metabolismo , Humanos , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/farmacología , Ácidos Hidroxámicos/síntesis química , Nanopartículas/química , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Animales , Apoptosis/efectos de los fármacos , Relación Estructura-Actividad , Proliferación Celular/efectos de los fármacos , Ratones , Estructura Molecular , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Histona Desacetilasas/metabolismo , Lactonas/química , Lactonas/farmacología , Lactonas/síntesis química

RESUMEN

Polyene cyclizations are among the most complex and challenging transformations in biology. In a single reaction step, multiple carbon-carbon bonds, ring systems and stereogenic centres are constituted from simple, acyclic precursors1-3. Simultaneously achieving this kind of precise control over product distribution and stereochemistry poses a formidable task for chemists. In particular, the polyene cyclization of (3E,7E)-homofarnesol to the valuable naturally occurring ambergris odorant (-)-ambrox is recognized as a longstanding challenge in chemical synthesis1,4-7. Here we report a diastereoselective and enantioselective synthesis of (-)-ambrox and the sesquiterpene lactone natural product (+)-sclareolide by a catalytic asymmetric polyene cyclization by using a highly Brønsted-acidic and confined imidodiphosphorimidate catalyst in the presence of fluorinated alcohols. Several experiments, including deuterium-labelling studies, suggest that the reaction predominantly proceeds through a concerted pathway in line with the Stork-Eschenmoser hypothesis8-10. Mechanistic studies show the importance of the enzyme-like microenvironment of the imidodiphosphorimidate catalyst for attaining exceptionally high selectivities, previously thought to be achievable only in enzyme-catalysed polyene cyclizations.

Asunto(s)

Catálisis , Ciclización , Diterpenos , Farnesol , Furanos , Naftalenos , Polienos , Alcoholes/química , Productos Biológicos/síntesis química , Productos Biológicos/química , Diterpenos/síntesis química , Diterpenos/química , Farnesol/análogos & derivados , Farnesol/química , Flúor/química , Furanos/síntesis química , Furanos/química , Lactonas/química , Lactonas/síntesis química , Naftalenos/síntesis química , Naftalenos/química , Polienos/química , Estereoisomerismo

RESUMEN

In recent years, researchers have often encountered the significance of the aberrant metabolism of tumor cells in the pathogenesis of malignant neoplasms. This phenomenon, known as the Warburg effect, provides a number of advantages in the survival of neoplastic cells, and its application is considered a potential strategy in the search for antitumor agents. With the aim of developing a promising platform for designing antitumor therapeutics, we synthesized a library of conjugates of 3,5-bis(arylidene)-4-piperidone and sesquiterpene lactones. To gain insight into the determinants of the biological activity of the prepared compounds, we showed that the conjugates of 3,5-bis(arylidene)-4-piperidone and sesquiterpene lactones, which are cytotoxic agents, demonstrate selective activity toward a number of tumor cell lines with glycolysis-inhibiting ability. Moreover, the results of molecular and in silico screening allowed us to identify these compounds as potential inhibitors of the pyruvate kinase M2 oncoprotein, which is the rate-determining enzyme of glycolysis. Thus, the results of our work indicate that the synthesized conjugates of 3,5-bis(arylidene)-4-piperidone and sesquiterpene lactones can be considered a promising platform for designing selective cytotoxic agents against the glycolysis process, which opens new possibilities for researchers involved in the search for antitumor therapeutics among compounds containing piperidone platforms.

Asunto(s)

Antineoplásicos , Lactonas , Piperidonas , Sesquiterpenos , Humanos , Sesquiterpenos/farmacología , Sesquiterpenos/química , Lactonas/química , Lactonas/farmacología , Lactonas/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Línea Celular Tumoral , Piperidonas/farmacología , Piperidonas/química , Glucólisis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Simulación del Acoplamiento Molecular , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Ensayos de Selección de Medicamentos Antitumorales

RESUMEN

Native chemical ligation (NCL) represents a cornerstone strategy in accessing synthetic peptides and proteins, remaining one of the most efficacious methodologies in this domain. The fundamental requisites for achieving a proficient NCL reaction involve chemoselective coupling between a C-terminal thioester peptide and a thiol-bearing N-terminal peptide. However, achieving coupling at sterically congested residues remains challenging. In addition, while most NCLs proceed without epimerization, ß-branched (e.g., Ile, Thr, Val) and Pro-derived C-terminal thioesters react slowly and can be susceptible to significant epimerization and hydrolysis. Herein, we report an epimerization-free NCL reaction via ß-lactone-mediated native chemical ligation which constructs sterically congested Thr residues. The constrained ring from the ß-lactone allows rapid peptide ligation without detectable epimerization. The method has a broad side-chain tolerance and was applied to the preparation of cyclic peptides and polypeptidyl thioester, which could be difficult to obtained otherwise.

Asunto(s)

Lactonas , Péptidos , Lactonas/química , Lactonas/síntesis química , Estructura Molecular , Péptidos/química , Péptidos/síntesis química , Péptidos Cíclicos/química , Péptidos Cíclicos/síntesis química

RESUMEN

Ecklonialactones, Eiseniachlorides, and Egregiachlorides are synthesized in living organisms via the lipoxygenase-mediated oxidation of polyunsaturated fatty acids. Originally isolated and identified from brown seaweed (Ecklonia stolonifera, Eisenia bicyclis, and Egregia menziesii), and later replicated on milligram scale through chemical synthesis, the full biological activities of these compounds remain to be elucidated. To bridge this gap in knowledge, we propose a unified methodology to synthesize the 14-membered macrocyclic structures of Ecklonialactones, Eiseniachlorides and analogs using a versatile and convergent approach. This study delineates the synthesis of Ecklonialactone A, B, C, D, and Eiseniachlorides A and B, as well as ent-Ecklonialactone B, 16-epi-Ecklonialactone B and 12,13-diepi-Ecklonialactone B.

Asunto(s)

Lactonas , Lactonas/química , Lactonas/síntesis química , Phaeophyceae/química , Oxidación-Reducción , Algas Marinas/química , Estereoisomerismo , Ácidos Grasos Insaturados/química , Ácidos Grasos Insaturados/síntesis química , Estructura Molecular

RESUMEN

Strigolactones (SLs) have potential to be used in sustainable agriculture to mitigate various stresses that plants have to deal with. The natural SLs, as well as the synthetic analogs, are difficult to obtain in sufficient amounts for practical applications. At the same time, fluorescent SLs would be useful for the mechanistic understanding of their effects based on bio-imaging or spectroscopic techniques. In this study, new fluorescent SL mimics containing a substituted 1,8-naphthalimide ring system connected through an ether link to a bioactive furan-2-one moiety were prepared. The structural, spectroscopic, and biological activity of the new SL mimics on phytopathogens were investigated and compared with previously synthetized fluorescent SL mimics. The chemical group at the C-6 position of the naphthalimide ring influences the fluorescence parameters. All SL mimics showed effects similar to GR24 on phytopathogens, indicating their suitability for practical applications. The pattern of the biological activity depended on the fungal species, SL mimic and concentration, and hyphal order. This dependence is probably related to the specificity of each fungal receptor-SL mimic interaction, which will have to be analyzed in-depth. Based on the biological properties and spectroscopic particularities, one SL mimic could be a good candidate for microscopic and spectroscopic investigations.

Asunto(s)

Lactonas , Naftalimidas , Naftalimidas/química , Naftalimidas/síntesis química , Naftalimidas/farmacología , Lactonas/química , Lactonas/farmacología , Lactonas/síntesis química , Estructura Molecular , Ascomicetos , Colorantes Fluorescentes/química , Colorantes Fluorescentes/síntesis química , Rhizoctonia/efectos de los fármacos , Compuestos Heterocíclicos con 3 Anillos

RESUMEN

Pyruvate kinase isoform 2 (PKM2) is closely related to the regulation of Th17/Treg balance, which is considered to be an effective strategy for UC therapy. Parthenolide (PTL), a natural product, only possesses moderate PKM2-activating activity. Thus, five series of PTL derivatives are designed and synthesized to improve PKM2-activated activities and anti-UC abilities. Through detailed structure optimization, B4 demonstrates potent T-cell anti-proliferation activity (IC50 = 0.43 µM) and excellent PKM2-activated ability (AC50 = 0.144 µM). Subsequently, through mass spectrometry analysis, B4 is identified to interact with Cys423 of PKM2 via covalent-bond. Molecular docking and molecular dynamic simulation results reveal that the trifluoromethoxy of B4 forms a stronger hydrophobic interaction with Ala401, Pro402, and Ile403. In addition, B4 has a significant effect only on Th17 cell differentiation, thereby regulating the Th17/Treg balance. The effect of B4 on Th17/Treg imbalance can be attributed to inhibition of PKM2 dimer translocation and suppression of glucose metabolism. Finally, B4 can notably ameliorate the symptoms of dextran sulfate sodium (DSS)-induced colitis in mouse model in vivo. Thus, B4 is confirmed as a potent PKM2 activator, and has the potential to develop as a novel anti-UC agent.

Asunto(s)

Colitis Ulcerosa , Diseño de Fármacos , Lactonas , Piruvato Quinasa , Sesquiterpenos , Sesquiterpenos/farmacología , Sesquiterpenos/química , Sesquiterpenos/síntesis química , Animales , Ratones , Piruvato Quinasa/metabolismo , Piruvato Quinasa/antagonistas & inhibidores , Lactonas/farmacología , Lactonas/química , Lactonas/síntesis química , Relación Estructura-Actividad , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/inducido químicamente , Humanos , Estructura Molecular , Proliferación Celular/efectos de los fármacos , Ratones Endogámicos C57BL , Relación Dosis-Respuesta a Droga , Masculino , Sulfato de Dextran , Simulación del Acoplamiento Molecular , Hormonas Tiroideas/metabolismo , Células Th17/efectos de los fármacos , Proteínas de Unión a Hormona Tiroide

RESUMEN

Toward human immunodeficiency virus type-1 (HIV-1) cure, cells latently infected with HIV-1 must be eliminated from people living with HIV-1. We previously developed a protein kinase C (PKC) activator, diacylglycerol (DAG)-lactone derivative 3, with high HIV-1 latency-reversing activity, based on YSE028 (2) as a lead compound and found that the activity was correlated with binding affinity for PKC and stability against esterase-mediated hydrolysis. Here, we synthesized new DAG-lactone derivatives not only containing a tertiary ester group or an isoxazole surrogate but also several symmetric alkylidene moieties to improve HIV-1 latency reversing activity. Compound 9a, with a dimethyl group at the α-position of the ester group, exerted twice higher HIV-1 latency reversing activity than compound 3, and compound 26, with the isoxazole moiety, was significantly active. In addition, DAG-lactone derivatives with moderate hydrophobicity and potent biostability showed high biological activity.

Asunto(s)

Fármacos Anti-VIH , VIH-1 , Lactonas , Latencia del Virus , Humanos , VIH-1/efectos de los fármacos , VIH-1/fisiología , Latencia del Virus/efectos de los fármacos , Lactonas/farmacología , Lactonas/química , Lactonas/síntesis química , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/química , Fármacos Anti-VIH/síntesis química , Diglicéridos/química , Diglicéridos/farmacología , Diglicéridos/síntesis química , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Proteína Quinasa C/metabolismo , Proteína Quinasa C/antagonistas & inhibidores

RESUMEN

Synthesis of the A/D/E-ring core compounds of maoecrystal V was achieved. The key Diels-Alder reactions between tricyclic α-methylene lactones and Kitahara-Danishefsky dienes afforded the spirocyclic core compounds in a regioselective and stereoselective manner.

Asunto(s)

Lactonas , Estereoisomerismo , Lactonas/química , Lactonas/síntesis química , Reacción de Cicloadición , Técnicas de Química Sintética , Diterpenos/síntesis química , Diterpenos/química , Compuestos de Espiro/química , Compuestos de Espiro/síntesis química , Estructura Molecular

RESUMEN

Herein, the first total synthesis of natural 13-hydroxy-14-deoxyoxacyclododecindione along with the revision of the proposed configuration is reported. This natural product, initially discovered in 2018, belongs to the oxacyclododecindione family, renowned for their remarkable anti-inflammatory and antifibrotic activities. The synthetic route involves an esterification/Friedel-Crafts-acylation approach and uses various triol fragments. It allows the preparation of different stereoisomers, including the (revised) natural product, two threo-derivatives, and two Z-isomers of the endocyclic C═C double bond. Furthermore, a late-stage inversion of the C-13 stereocenter could transform the originally proposed structure into the revised natural product. With this comprehensive set of compounds and the previously prepared (13R,14S,15R)-isomer, deeper insights into their structural properties and biological activities were obtained. A detailed analysis of the final macrolactones using spectroscopy (NMR, IR, UV-vis) and X-ray crystallography gave new insights such as the significance of the optical rotation for the elucidation of their configuration and the light-induced E/Z double-bond photoisomerization. The pharmacological potential of the compounds was underlined by remarkably low IC50 values in biological assays addressing the inhibition of cellular inflammatory responses.

Asunto(s)

Antiinflamatorios , Macrólidos , Humanos , Antiinflamatorios/farmacología , Antiinflamatorios/síntesis química , Antiinflamatorios/química , Productos Biológicos/farmacología , Productos Biológicos/química , Productos Biológicos/síntesis química , Lactonas/farmacología , Lactonas/química , Lactonas/síntesis química , Estructura Molecular , Estereoisomerismo , Macrólidos/química , Macrólidos/farmacología

RESUMEN

A general method for chemo- and diastereoselective modification of anticancer natural product arglabin with nitrogen- and carbon-centered pronucleophiles under the influence of nucleophilic phosphine catalysts was developed. The locked s-cis-geometry of α-methylene-γ-butyrolactone moiety of arglabin favors for the additional stabilization of the zwitterionic intermediate by electrostatic interaction between phosphonium and enolate oxygen centers, leading to the unprecedentedly high efficiency of the phosphine-catalyzed Michael additions to this sesquiterpene lactone. Using n-Bu3P as the catalyst, pyrazole, phthalimide, 2-oxazolidinone, 4-quinazolinone, uracil, thymine, cytosine, and adenine adducts of arglabin were obtained. The n-Bu3P-catalyzed reaction of arglabin with active methylene compounds resulted in the predominant formation of bisadducts bearing a new quaternary carbon center. All synthesized Michael adducts and previously obtained phosphorylated arglabin derivatives were evaluated in vitro against eleven cancer and two normal cell lines, and the results were compared to those of natural arglabin and its dimethylamino hydrochloride salt currently used as anticancer drugs. 2-Oxazolidinone, uracil, diethyl malonate, dibenzyl phosphonate, and diethyl cyanomethylphosphonate derivatives of arglabin exhibited more potent antiproliferative activity towards several cancer cell lines and lower cytotoxicity towards normal cell lines in comparison to the reference compounds, indicating the feasibility of the developed methodology for the design of novel anticancer drugs with better therapeutic potential.

Asunto(s)

Antineoplásicos , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Lactonas , Fosfinas , Humanos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Fosfinas/química , Fosfinas/farmacología , Fosfinas/síntesis química , Catálisis , Lactonas/química , Lactonas/farmacología , Lactonas/síntesis química , Proliferación Celular/efectos de los fármacos , Relación Estructura-Actividad , Estructura Molecular , Línea Celular Tumoral , Sesquiterpenos/química , Sesquiterpenos/farmacología , Sesquiterpenos/síntesis química , Sesquiterpenos de Guayano/química , Sesquiterpenos de Guayano/farmacología , Sesquiterpenos de Guayano/síntesis química , Relación Dosis-Respuesta a Droga

RESUMEN

Dimeric naphthopyranones are known to be biologically active, however, for the corresponding monomeric naphthopyranones this information is still elusive. Here the first enantioselective total synthesis of semi-viriditoxic acid as well as the synthesis of semi-viriditoxin and derivatives is reported. The key intermediate in the synthesis of naphthopyranones is an α,ß-unsaturated δ-lactone, which we synthesized in two different ways (Ghosez-cyclization and Grubbs ring-closing metathesis), while the domino-Michael-Dieckmann reaction of the α,ß-unsaturated δ-lactone with an orsellinic acid derivative is the key reaction. A structure-activity relationship study was performed measuring the cytotoxicity in Burkitt B lymphoma cells (Ramos). The dimeric structure was found to be crucial for biological activity: Only the dimeric naphthopyranones showed cytotoxic and apoptotic activity, whereas the monomers did not display any activity at all.

Asunto(s)

Antineoplásicos , Linfoma de Burkitt , Relación Estructura-Actividad , Línea Celular Tumoral , Humanos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Linfoma de Burkitt/tratamiento farmacológico , Linfoma de Burkitt/patología , Estereoisomerismo , Apoptosis/efectos de los fármacos , Lactonas/química , Lactonas/farmacología , Lactonas/síntesis química , Ciclización

RESUMEN

Neurotrophic factors have been shown to potentially be beneficial for the treatment of neurodegenerative diseases such as Alzheimer's disease, because endogenous neurotrophic factors (NGF, BDNF) have been recognized to play critical roles in the promotion of neurogenesis, differentiation, and neuroprotection throughout the development of the central nervous system. However, high-molecular-weight proteins are unable to cross the blood-brain barrier and are easily decomposed under physiological conditions. Thus, small molecules that can mimic the functions of neurotrophic factors are promising alternatives for the treatment of neurodegenerative disease. Since 1990, the author has been involved in searching for natural products with typical neurotrophic properties that can cause neurogenesis, enhance neurite outgrowth, and protect against neuronal death by using three cellular systems (PC12, rat cortical neurons, and MEB5 cells). Through these research activities on neurotrophic natural products, the author has tried to induce a paradigm shift from the discipline of natural products chemistry to science disciplines. This review focuses on our independent synthetic studies of the neurotrophic natural products discovered in the plants. The following synthetic elaborations are described: syntheses of dimeric isocuparane-type sesquiterpenes mastigophorenes A and B, macrocyclic bis-bibenzyls plagiochins A-D and cavicularin through a Pd-catalyzed Stille-Kelly reaction; the formal synthesis of merrilactone A and jiadifenin, which are seco-prezizaane-type sesquiterpenes, through intramolecular Pd-catalyzed Mizoroki-Heck and Tsuji-Trost reactions; and finally the first enantioselective synthesis of neovibsanin B, a vibsane-type diterpene, through a Pd-catalyzed cyclic carbopalladation-carbonyl tandem reaction.

Asunto(s)

Productos Biológicos/síntesis química , Factores de Crecimiento Nervioso/síntesis química , Animales , Productos Biológicos/química , Productos Biológicos/farmacología , Productos Biológicos/uso terapéutico , Barrera Hematoencefálica/metabolismo , Hidrocarburos Aromáticos con Puentes/síntesis química , Ciclopentanos/síntesis química , Diterpenos/síntesis química , Lactonas/síntesis química , Ratones , Peso Molecular , Factores de Crecimiento Nervioso/química , Factores de Crecimiento Nervioso/farmacología , Factores de Crecimiento Nervioso/uso terapéutico , Enfermedades Neurodegenerativas/tratamiento farmacológico , Fenómenos Químicos Orgánicos , Ratas , Sesquiterpenos/síntesis química , Estereoisomerismo

RESUMEN

Aliphatic polyesters are the most common type of biodegradable synthetic polymer used in many pharmaceutical applications nowadays. This report describes the ring-opening polymerization (ROP) of l-lactide (L-LA), ε-caprolactone (CL) and glycolide (Gly) in the presence of a simple, inexpensive and convenient PEG200-BiOct3 catalytic system. The chemical structures of the obtained copolymers were characterized by 1H- or 13C-NMR. GPC was used to estimate the average molecular weight of the resulting polyesters, whereas TGA and DSC were employed to determine the thermal properties of polymeric products. The effects of temperature, reaction time, and catalyst content on the polymerization process were investigated. Importantly, the obtained polyesters were not cyto- or genotoxic, which is significant in terms of the potential for medical applications (e.g., for drug delivery systems). As a result of transesterification, the copolymers obtained had a random distribution of comonomer units along the polymer chain. The thermal analysis indicated an amorphous nature of poly(l-lactide-co-ε-caprolactone) (PLACL) and a low degree of crystallinity of poly(ε-caprolactone-co-glycolide) (PCLGA, Xc = 15.1%), in accordance with the microstructures with random distributions and short sequences of comonomer units (l = 1.02-2.82). Significant differences in reactivity were observed among comonomers, confirming preferential ring opening of L-LA during the copolymerization process.

Asunto(s)

Bismuto/química , Caproatos/química , Dioxanos/química , Lactonas/química , Ácido Poliglicólico/química , Polimerizacion , Caproatos/síntesis química , Catálisis , Dioxanos/síntesis química , Lactonas/síntesis química , Poliésteres/síntesis química , Poliésteres/química , Ácido Poliglicólico/síntesis química , Temperatura

RESUMEN

Function-oriented molecular editing of the polycyclic scaffold of securinine led to the preparation of a library of simplified analogs that have been evaluated for their cytotoxicity potential against HCT116 and HL60 human cell lines. Chemical diversity at the C14 position (securinine numbering) was generated through the site-selective γ-iodination followed by Pd-catalyzed Sonogashira and Suzuki-Miyaura reactions. To explain the selectivity in the iodination step, a reaction mechanism has been proposed. Surprisingly, the piperidine ring (ring A) of the securinine skeleton has been found to be irrelevant for the cytotoxic activity. Based on this finding, the pharmacophoric core of securinine could be simplified to the key BCD motif. The nature of the substituent at the nitrogen can vary from a methyl or an isobutyl group to a benzyl or a carbamate moiety. Interestingly, the N-benzyl substituted simplified analog exhibited the same cytotoxic activity as the parent compound securinine. This functional group tolerance paves the way for the installation of reactive handles for the synthesis of molecular probes for target identification.

Asunto(s)

Antineoplásicos/farmacología , Azepinas/farmacología , Compuestos Heterocíclicos de Anillo en Puente/farmacología , Lactonas/farmacología , Piperidinas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Azepinas/síntesis química , Azepinas/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Teoría Funcional de la Densidad , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HCT116 , Células HL-60 , Compuestos Heterocíclicos de Anillo en Puente/síntesis química , Compuestos Heterocíclicos de Anillo en Puente/química , Humanos , Lactonas/síntesis química , Lactonas/química , Conformación Molecular , Piperidinas/síntesis química , Piperidinas/química , Relación Estructura-Actividad , Células Tumorales Cultivadas

RESUMEN

A strategy to control the diastereoselectivity of bond formation at a prochiral attached-ring bridgehead is reported. An unusual stereodivergent Michael reaction relies on basic vs. Lewis acidic conditions and non-covalent interactions to control re- vs. si- facial selectivity en route to fully substituted attached-rings. This divergency reflects differential engagement of one rotational isomer of the attached-ring system. The successful synthesis of an erythro subtarget diastereomer ultimately leads to a short formal synthesis of merrilactone A.

Asunto(s)

Lactonas/síntesis química , Sesquiterpenos/síntesis química , Ciclización , Lactonas/química , Estructura Molecular , Sesquiterpenos/química , Estereoisomerismo

RESUMEN

In the last two years, nucleosides analogues, a class of well-established bioactive compounds, have been the subject of renewed interest from the scientific community thanks to their antiviral activity. The COVID-19 global pandemic, indeed, spread light on the antiviral drug Remdesivir, an adenine C-nucleoside analogue. This new attention of the medical community on Remdesivir prompts the medicinal chemists to investigate once again C-nucleosides. One of the essential building blocks to synthetize these compounds is the D-(+)-ribono-1,4-lactone, but some mechanistic aspects linked to the use of different carbohydrate protecting groups remain unclear. Here, we present our investigations on the use of benzylidene as a ribonolactone protecting group useful in the synthesis of C-purine nucleosides analogues. A detailed 1D and 2D NMR structural study of the obtained compounds under different reaction conditions is presented. In addition, a molecular modeling study at the B3LYP/6-31G* level of theory with the SM8 solvation model for CHCl3 and DMSO to support the obtained results is used. This study allows for clarifying mechanistic aspects as the side reactions and structural rearrangements liked to the use of the benzylidene protecting group.

Asunto(s)

Compuestos de Bencilideno/química , Lactonas/química , Nucleósidos/síntesis química , Ribosa/análogos & derivados , Adenina/análogos & derivados , Antivirales/química , COVID-19/prevención & control , Humanos , Lactonas/síntesis química , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Nucleósidos/metabolismo , Nucleósidos de Purina , Ribosa/síntesis química , Ribosa/química , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/metabolismo , SARS-CoV-2/patogenicidad , Estereoisomerismo , Tratamiento Farmacológico de COVID-19

RESUMEN

Chiral amines can be made by insertion of a carbene into an N-H bond using two-catalyst systems that combine a transition metal-based carbene-transfer catalyst and a chiral proton-transfer catalyst to enforce stereocontrol. Haem proteins can effect carbene N-H insertion, but asymmetric protonation in an active site replete with proton sources is challenging. Here we describe engineered cytochrome P450 enzymes that catalyse carbene N-H insertion to prepare biologically relevant α-amino lactones with high activity and enantioselectivity (up to 32,100 total turnovers, >99% yield and 98% e.e.). These enzymes serve as dual-function catalysts, inducing carbene transfer and promoting the subsequent proton transfer with excellent stereoselectivity in a single active site. Computational studies uncover the detailed mechanism of this new-to-nature enzymatic reaction and explain how active-site residues accelerate this transformation and provide stereocontrol.

Asunto(s)

Aminas/síntesis química , Sistema Enzimático del Citocromo P-450/química , Biocatálisis , Dominio Catalítico , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Lactonas/síntesis química , Lactonas/metabolismo , Conformación Molecular , Simulación de Dinámica Molecular , Mutación , Unión Proteica , Ingeniería de Proteínas , Estereoisomerismo

RESUMEN

The first total syntheses of isocorniculatolide B, corniculatolide B, and corniculatolide C, consisting of isomeric corniculatolide skeletons, have been accomplished in a divergent manner. The key features of the synthesis involve the construction of diaryl ether linkages by nucleophilic aromatic substitution, installation of a C14-substituted alkyl side chain via a sequence of Baeyer-Villiger reaction and Claisen rearrangement, and efficient construction of corniculatolide and isocorniculatolide frameworks, including 17-membered (exterior) macrolactone skeletons from a versatile diaryl ether intermediate by Mitsunobu macrolactonization. Moreover, we prepared the structural congeners of isomeric corniculatolides via diverted total synthesis approach including desmethyl analogues and related dimeric macrolides. The anti-inflammatory activities of the synthesized natural products, analogues and synthetic intermediates were also investigated. In particular, corniculatolide B significantly inhibited the protein expression of COX-2 and the mRNA expressions of TNF-α, IL-1ß and IL-6 by inhibiting of NF-κB signaling in intestinal epithelial cells induced by lipopolysaccharide treatment. It also significantly inhibited the promoter activity and the phosphorylation of subunits p50 and p65 of NF-κB to the same extent as Bay 11-7082, a potent IκB kinase inhibitor. These results suggest that corniculatolide B might have therapeutic potential in inflammatory bowel disease via NF-κB signaling pathway.

Asunto(s)

Antiinflamatorios no Esteroideos/farmacología , Lactonas/farmacología , Macrólidos/farmacología , FN-kappa B/antagonistas & inhibidores , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Línea Celular , Relación Dosis-Respuesta a Droga , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Lactonas/síntesis química , Macrólidos/síntesis química , Estructura Molecular , FN-kappa B/metabolismo , Ratas , Relación Estructura-Actividad

RESUMEN

A straightforward synthesis of (+)-trans-(4S,5R)- and (+)-cis-(4R,5R)-whisky lactones starting from d-(+)-mannitol has been reported here in fewer number of efficient steps compared to existing literature processes involving d-mannitol as the chiral pool starting material. Chiron approach directly translated chirality of d-mannitol to one of the two chiral centers in these target molecules. Toward this end, stereoisomerically pure trans- and cis-iodomethyl-γ-lactones were formed in the penultimate step. These two acted as versatile advanced common intermediates as they were also converted to the (+)-trans-(4S,5R)- and (+)-cis-(4R,5R)-cognac lactones, respectively. To the best of our knowledge, till date no synthesis of cognac lactones starting from d-mannitol has been reported. All these lactones are identified as the key aroma components of aged alcoholic beverages.

Asunto(s)

4-Butirolactona/química , Bebidas Alcohólicas/análisis , Lactonas/síntesis química , Manitol/química , 4-Butirolactona/análogos & derivados , Lactonas/química , Estructura Molecular , Estereoisomerismo