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1.
J Nat Prod ; 87(4): 869-875, 2024 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-38427968

RESUMO

Cannabidiol (CBD), a prominent phytocannabinoid found in various Cannabis chemotypes, is under extensive investigation for its therapeutic potential. Moreover, because it is nonpsychoactive, it can also be utilized as a functional ingredient in foods and supplements in certain countries, depending on its legal status. From a chemical reactivity point of view, CBD can undergo conversion into different structurally related compounds both during storage and after the consumption of CBD-based products. The analytical determination of these compounds is of paramount concern due to potential toxicity and the risk of losing the active ingredient (CBD) title. Consequently, the complete stereoselective total synthesis of representative CBD-derived compounds has become a matter of great interest. The synthesis of pure CBD-derived compounds, achievable in a few synthetic steps, is essential for preparing analytical standards and facilitating biological studies. This paper details the transformation of the readily available CBD into Δ8-THC, Δ9-THC, Δ8-iso-THC, CBE, HCDN, CBDQ, Δ6-iso-CBD, and 1,8-cineol cannabinoid (CCB). The described protocols were executed without the extensive use of protecting groups, avoiding tedious purifications, and ensuring complete control over the structural features.


Assuntos
Canabidiol , Canabinoides , Canabinoides/síntese química , Canabinoides/química , Canabidiol/química , Canabidiol/síntese química , Estrutura Molecular , Cannabis/química , Estereoisomerismo
2.
Angew Chem Int Ed Engl ; 63(10): e202318557, 2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38189576

RESUMO

Chiral perovskites possess a huge applicative potential in several areas of optoelectronics and spintronics. The development of novel lead-free perovskites with tunable properties is a key topic of current research. Herein, we report a novel lead-free chiral perovskite, namely (R/S-)ClMBA2 SnI4 (ClMBA=1-(4-chlorophenyl)ethanamine) and the corresponding racemic system. ClMBA2 SnI4 samples exhibit a low band gap (2.12 eV) together with broad emission extending in the red region of the spectrum (∼1.7 eV). Chirality transfer from the organic ligand induces chiroptical activity in the 465-530 nm range. Density functional theory calculations show a Rashba type band splitting for the chiral samples and no band splitting for the racemic isomer. Self-trapped exciton formation is at the origin of the large Stokes shift in the emission. Careful correlation with analogous lead and lead-free 2D chiral perovskites confirms the role of the symmetry-breaking distortions in the inorganic layers associated with the ligands as the source of the observed chiroptical properties providing also preliminary structure-property correlation in 2D chiral perovskites.

3.
mSphere ; 7(6): e0036922, 2022 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-36377880

RESUMO

Tuberculosis (TB) still poses a global menace as one of the deadliest infectious diseases. A quarter of the human population is indeed latently infected with Mycobacterium tuberculosis. People with latent infection have a 5 to 10% lifetime risk of becoming ill with TB, representing a reservoir for TB active infection. This is a worrisome problem to overcome in the case of relapse; unfortunately, few drugs are effective against nonreplicating M. tuberculosis cells. Novel strategies to combat TB, including its latent form, are urgently needed. In response to the lack of new effective drugs and after screening about 500 original chemical molecules, we selected a compound, 11726172, that is endowed with potent antitubercular activity against M. tuberculosis both in vitro and in vivo and importantly also against dormant nonculturable bacilli. We also investigated the mechanism of action of 11726172 by applying a multidisciplinary approach, including transcriptomic, labeled metabolomic, biochemical, and microbiological procedures. Our results represent an important step forward in the development of a new antitubercular compound with a novel mechanism of action active against latent bacilli. IMPORTANCE The discontinuation of TB services due to COVID-19 causes concern about a future resurgence of TB, also considering that latent infection affects a high number of people worldwide. To combat this situation, the identification of antitubercular compounds targeting Mycobacterium tuberculosis through novel mechanisms of action is necessary. These compounds should be active against not only replicating bacteria cells but also nonreplicating cells to limit the reservoir of latently infected people on which the bacterium can rely to spread after reactivation.


Assuntos
COVID-19 , Tuberculose Latente , Mycobacterium tuberculosis , Tuberculose , Humanos , Antituberculosos/farmacologia , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia
4.
J Org Chem ; 87(15): 9497-9506, 2022 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-35820228

RESUMO

Properly substituted tetrahydrofuran (THF) rings are important building blocks in the synthesis of many natural metabolites. Having reliable procedures to control the stereoselectivity at the THF core while decorating it with different substituents is a fundamental requirement to achieve and fulfill the complexity of nature. We recently reported a new chemical approach to control the stereochemistry in the alkylation and arylation of furanoside derivatives by using a rhenium(V) complex to form an intermediate oxo-carbenium species able to react with proper soft nucleophiles. Here, we describe theoretical calculations, performed at the DFT B3LYP level, to disclose the important mechanistic features which regulate the entire catalytic cycle of the reaction of mono- and disubstituted furanosides with allyltrimethylsilane catalyzed by Re(O)Cl3(OPPh3)(Me2S). Moreover, the key factors governing the allylation step were investigated, confirming that the stereoselectivity, which is independent of the anomeric configuration of starting acetal, mainly arises from the orientation of the substituent at C-4, with only marginal contribution of the substituent at C-5. Finally, puckering Cremer-Pople parameters were used to take trace of the structural modifications throughout the catalytic cycle.


Assuntos
Rênio , Catálise , Rênio/química
5.
J Nat Prod ; 84(11): 2858-2865, 2021 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-34668704

RESUMO

Cannabis is a plant with an astonishing ability to biosynthesize cannabinoids, and more than 100 molecules belonging to this class have been isolated. Among them in recent years cannabidiol (CBD) has received the interest of pharmacology as the major nonpsychotropic cannabinoid with many potential clinical applications. Although the reactivity of CBD has been widely investigated, only little attention has been given to the possible photodegradation of this cannabinoid, and the data available in the literature are outdated and, in some cases, conflicting. The aim of the present work is providing a characterization of the photochemical behavior of CBD in organic solvents, through a detailed GC-MS analyses, isolation, and NMR characterization of the photoproducts obtained.


Assuntos
Canabidiol/química , Fotólise , Cromatografia Gasosa-Espectrometria de Massas , Espectroscopia de Ressonância Magnética
6.
J Org Chem ; 86(11): 7672-7686, 2021 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-34033490

RESUMO

A novel approach for the formation of anomeric carbon-functionalized furanoside systems was accomplished through the employment of an oxo-rhenium catalyst. The transformation boasts a broad range of nucleophiles including allylsilanes, enol ethers, and aromatics in addition to sulfur, nitrogen, and hydride donors, able to react with an oxocarbenium ion intermediate derived from furanosidic structures. The excellent stereoselectivities observed followed the Woerpel model, ultimately providing 1,3-cis-1,4-trans systems. In the case of electron-rich aromatic nucleophiles, an equilibration occurs at the anomeric center with the selective formation of 1,3-trans-1,4-cis systems. This anomalous result was rationalized through density functional theory calculations. Different oxocarbenium ions such as those derived from dihydroisobenzofuran, pyrrolidine, and oxazolidine heterocycles can also be used as a substrate for the oxo-Re-mediated allylation reaction.


Assuntos
Rênio , Álcoois , Catálise , Éteres , Glicosilação
7.
J Med Chem ; 63(13): 7066-7080, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32530281

RESUMO

The Mg2+-dependent Mycobacterium tuberculosis salicylate synthase (MbtI) is a key enzyme involved in the biosynthesis of siderophores. Because iron is essential for the survival and pathogenicity of the microorganism, this protein constitutes an attractive target for antitubercular therapy, also considering the absence of homologous enzymes in mammals. An extension of the structure-activity relationships of our furan-based candidates allowed us to disclose the most potent competitive inhibitor known to date (10, Ki = 4 µM), which also proved effective on mycobacterial cultures. By structural studies, we characterized its unexpected Mg2+-independent binding mode. We also investigated the role of the Mg2+ cofactor in catalysis, analyzing the first crystal structure of the MbtI-Mg2+-salicylate ternary complex. Overall, these results pave the way for the development of novel antituberculars through the rational design of improved MbtI inhibitors.


Assuntos
Desenho de Fármacos , Liases/química , Liases/metabolismo , Magnésio/metabolismo , Mycobacterium tuberculosis/enzimologia , Cristalografia por Raios X , Modelos Moleculares , Conformação Proteica , Relação Estrutura-Atividade
8.
Front Microbiol ; 11: 562, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32318042

RESUMO

There is an urgent need for new antimicrobials to treat the opportunistic Gram-negative Burkholderia cenocepacia, which represents a problematic challenge for cystic fibrosis patients. Recently, a benzothiadiazole derivative, C109, was shown to be effective against the infections caused by B. cenocepacia and other Gram-negative and-positive bacteria. C109 has a promising cellular target, the cell division protein FtsZ, and a recently developed PEGylated formulation make it an attractive molecule to counteract Burkholderia infections. However, the ability of efflux pumps to extrude it out of the cell represents a limitation for its use. Here, more than 50 derivatives of C109 were synthesized and tested against Gram-negative species and the Gram-positive Staphylococcus aureus. In addition, their activity was evaluated on the purified FtsZ protein. The chemical, metabolic and cellular stability of C109 has been assayed using different biological systems, including quantitative single-cell imaging. However, no further improvement on C109 was achieved, and the role of efflux in resistance was further confirmed. Also, a novel nitroreductase that can inactivate the compound was characterized, but it does not appear to play a role in natural resistance. All these data allowed a deep characterization of the compound, which will contribute to a further improvement of its properties.

9.
Chemistry ; 25(44): 10323-10327, 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31215707

RESUMO

The development of efficient and mild methods for the synthesis of organofluorine compounds is of foremost interest in various fields of chemistry. A direct pyrimidine-based selective meta-C-H perfluoroalkenylation of arenes involving several commercially available perfluoroolefins is described. The synthetic versatility of the protocol is demonstrated by an extensive substrate scope including different benzylsulfonyl, alkylarene and phenylacetic acid scaffolds. The generality of this methodology including the meta-C-H perfluoroalkenylation of Ibuprofen, the facile cleavage of the directing group and gram-scale reactions are presented.

11.
ACS Omega ; 3(7): 7621-7629, 2018 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-30087920

RESUMO

Nitrosocarbonyl mesitylene intermediate undergoes an ene reaction with cinnamyl alcohol affording the corresponding 5-hydroxy-isoxazolidine in fair yields. The synthesized 5-acetoxy-isoxazolidine serves as synthon for the preparation of 6-chloropurine N,O-nucleoside analogues, according to the Vorbrüggen reaction. The compounds were evaluated for their metabolic and apoptotic activity, and their structure-activity relationship is discussed.

12.
Chemistry ; 24(62): 16516-16520, 2018 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-30136746

RESUMO

Bioactive 2-benzazepines were accessed in an atom- and step-economical manner through a versatile palladium-catalyzed C-H activation strategy. The C-H arylation required low catalyst loading and a mild base, which was reflected by a broad scope and high functional-group tolerance. The benzotriazolodiazepinones were identified as new heat shock protein 90 (Hsp90) inhibiting lead compounds, with considerable potential for anti-cancer applications.

13.
Angew Chem Int Ed Engl ; 57(27): 8250-8254, 2018 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-29704310

RESUMO

Using the previously designed biphenyl-2-ylphosphine ligand, featuring a remote tertiary amino group, the first gold-catalyzed intermolecular hydroalkenylation of alkynes has been developed. Synthetically valuable conjugated dienyl alcohols are formed in moderate to good yields. A range of alkenyltrifluoroborates are allowed as the alkenyl donor, and no erosion of alkene geometry and/or the propargylic configuration are detected. DFT calculations confirm the critical role of the remote basic group in the ligand as a general-base catalyst for promoting this novel gold catalysis with good efficiency.


Assuntos
Alcinos/química , Ouro/química , Propanóis/química , Aminas/química , Catálise , Teoria da Densidade Funcional , Ligantes , Conformação Molecular , Estereoisomerismo
14.
Org Biomol Chem ; 16(14): 2393-2396, 2018 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-29560484

RESUMO

A practical methodology for the synthesis of key intermediates for isoprostane, neuroprostane and dihomo-isoprostane preparation has been described. The key strategy involved a three stage C-12 stereocenter inversion of the configuration of a Corey lactone, commercially available in an enantiopure form. The key intermediate was then used to prepare 17-E2c-dihomo-isoprostane and 17-F2c-dihomo-isoprostane.

15.
Chemistry ; 23(38): 9009-9013, 2017 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-28547785

RESUMO

The decomposition of N-tosylhydrazones is a safe and convenient method for the generation of donor carbenes. However, alkynyl carbenes cannot be isolated by this route because they readily undergo intramolecular cyclization to pyrazoles as soon as formed from alkynyl N-tosylhydrazones. Here, the use of alkynyl N-nosylhydrazones for the in situ generation of alkynyl carbenes and their coupling reaction with boronic acids under metal-free conditions is reported, giving rise to a wide array of di- and trisubstituted allenes. Preliminary mechanistic investigations demonstrated that γ-protodeboration of propargyl boric acid was responsible for the initial allene formation. This methodology based on the nosyl group allows for novel transformations that involve an alkynylcarbene transient species.

16.
Neonatology ; 112(1): 1-8, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28142140

RESUMO

BACKGROUND: Perinatal hypoxic-ischemic brain damage is a major cause of acute mortality and chronic neurological morbidity in infants and children. Oxidative stress due to free radical formation and the initiation of abnormal oxidative reactions appears to play a key role. Docosahexanoic acid (DHA), a main component of brain membrane phospholipids, may act as a neuroprotectant after hypoxia-ischemia by regulating multiple molecular pathways and gene expression. OBJECTIVES: The aims of this study were to test the hypothesis that DHA provides significant protection against lipoperoxidation damage in the cerebral cortex and hippocampus in a neonatal piglet model of severe hypoxia-reoxygenation. METHODS: Newborn piglets, Noroc (LYLD), were subjected to severe global hypoxia. One group was resuscitated with ambient air (21% group, n = 11) and another also received 5 mg/kg of DHA 4 h after the end of hypoxia (21% DHA group, n = 10). After 9.5 h, tissues from the prefrontal cortex and hippocampus were sampled and the levels of isoprostanes, neuroprostanes, neurofurans, and F2-dihomo-isoprostanes were determined by the liquid chromatography triple quadrupole mass spectrometry technique. RESULTS: Lipid peroxidation biomarkers were significantly lower in both the cortex and hippocampus in the DHA-treated group compared with the untreated group. CONCLUSIONS: The present study demonstrates that DHA administration after severe hypoxia in newborn piglets has an antioxidative effect in the brain, suggesting a protective potential of DHA if given after injuries to the brain.


Assuntos
Antioxidantes/farmacologia , Asfixia Neonatal/tratamento farmacológico , Ácidos Docosa-Hexaenoicos/farmacologia , Hipocampo/efeitos dos fármacos , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Asfixia Neonatal/metabolismo , Asfixia Neonatal/patologia , Biomarcadores/metabolismo , Modelos Animais de Doenças , Furanos/metabolismo , Hipocampo/metabolismo , Hipocampo/patologia , Hipóxia-Isquemia Encefálica/metabolismo , Hipóxia-Isquemia Encefálica/patologia , Isoprostanos/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Neuroprostanos/metabolismo , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Sus scrofa
17.
Chem Biodivers ; 14(3)2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27982513

RESUMO

Accompanied by other rare compounds, a new iridoid dimer, named kurdnestorianoside (1), showing an unprecedented secologanol configuration, has been isolated for the first time from the Kurdish medicinal plant Pterocephalus nestorianus, which is used in Kurdistan for treating oral diseases and inflammation. The structure of 1 was established from 1D- and 2D-NMR spectroscopic data. Kaempferol 3-O-[3,6-di-O-(E)-p-coumaroyl]-ß-d-glucopyranoside (7) showed a remarkable antiproliferative activity against several human tumor cell lines.


Assuntos
Antineoplásicos Fitogênicos/química , Dipsacaceae/química , Iridoides/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/toxicidade , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dipsacaceae/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Flores/química , Flores/metabolismo , Humanos , Iridoides/isolamento & purificação , Iridoides/toxicidade , Quempferóis/química , Quempferóis/isolamento & purificação , Quempferóis/toxicidade , Espectroscopia de Ressonância Magnética , Plantas Medicinais/química , Plantas Medicinais/metabolismo
18.
Chem Biodivers ; 14(5)2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-27982523

RESUMO

Two new sterols 1 and 2 and five known ones 3 - 7 were isolated for the first time from the fruiting bodies of Cortinarius glaucopus. Their structures were established by 1- and 2D-NMR spectra and HR-FABS-MS. The relative configuration of 1 was firmly determined by comparison of the observed 1 H-1 H couplings and NOESY correlations, with those predicted for the computed geometries of the conformers. Calculations were performed by means of DFT with the B3LYP functional at 6-31 + G(d,p) level of theory, in CHCl3 as the solvent. The structures of the new ergosterol derivatives, called glaucoposterol A (1) and B (2), were thus established as (3S,5R,7R,10R,13R,17R,20S,22R,23R,24R)-5,6-epoxy-3,7,23-trihydroxystrophast-8-en-14-one and (22E,3S,5S,9S,10R,13R,17R,20R,24R)-3,5-dihydroxyergosta-6,8(14),22-trien-15-one, respectively. Moreover, the configuration of known strophasterol C (3) was determined as (3S,5R,6S,7R,10R,13R,17R,20S,22S,24R). Glaucoposterol A (1) and strophasterol C (3) represent the second finding in nature of steroids with the rare strophastane skeleton.


Assuntos
Cortinarius/química , Ergosterol/química , Ergosterol/isolamento & purificação , Basidiomycota , Fracionamento Químico , Ergosterol/análogos & derivados , Carpóforos/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Fitosteróis/química , Fitosteróis/isolamento & purificação , Estereoisomerismo
19.
Free Radic Biol Med ; 103: 146-154, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27988338

RESUMO

Whereas the anti-inflammatory properties and mechanisms of action of long chain ω3 PUFAs have been abundantly investigated, research gaps remain regarding the respective contribution and mechanisms of action of their oxygenated metabolites collectively known as oxylipins. We conducted a dose-dependent and comparative study in human primary macrophages aiming to compare the anti-inflammatory activity of two types of DHA-derived oxylipins including the well-described protectins (NPD1 and PDX), formed through lipoxygenase pathway and the neuroprostanes (14-A4t- and 4-F4t-NeuroP) formed through free-radical mediated oxygenation and expected to be new anti-inflammatory mediators. Considering the potential ability of these DHA-derived oxylipins to bind PPARs and knowing the central role of these transcription factors in the regulation of macrophage inflammatory response, we performed transactivation assays to compare the ability of protectins and neuroprostanes to activate PPARs. All molecules significantly reduced mRNA levels of cytokines such as IL-6 and TNF-α, however not at the same doses. NPD1 showed the most effect at 0.1µM (-14.9%, p<0.05 for IL-6 and -26.7%, p<0.05 for TNF-α) while the three other molecules had greater effects at 10µM, with the strongest result due to the cyclopentenone neuroprostane, 14-A4t-NeuroP (-49.8%, p<0.001 and -40.8%, p<0.001, respectively). Part of the anti-inflammatory properties of the DHA-derived oxylipins investigated could be linked to their activation of PPARs. Indeed, all tested oxylipins significantly activated PPARγ, with 14-A4t-NeuroP leading to the strongest activation, and NPD1 and PDX also activated PPARα. In conclusion, our results show that neuroprostanes and more especially cyclopentenone neuroprostanes have potent anti-inflammatory activities similar or even more pronounced than protectins supporting that neuroprostanes should be considered as important contributors to the anti-inflammatory effects of DHA.


Assuntos
Anti-Inflamatórios/farmacologia , Ácidos Docosa-Hexaenoicos/farmacologia , Macrófagos/imunologia , Neuroprostanos/farmacologia , Oxilipinas/farmacologia , Animais , Células COS , Células Cultivadas , Chlorocebus aethiops , Citocinas/genética , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Expressão Gênica/efeitos dos fármacos , Humanos , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo
20.
Talanta ; 147: 322-7, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26592614

RESUMO

Benzotriazoles (BTRs), benzothiazoles (BTs) and benzenesulfonamides (BSAs), compounds largely used in industrial and household applications, are ubiquitous emerging contaminants. In this work a novel, straightforward procedure for the simultaneous determination of two BTRs (1H-benzotriazole, 5-methyl-1H-benzotriazole), three BTs (benzothiazole, 2-hydroxybenzothiazole, 2-methylthiobenzothiazole) and two BSAs (benzenesulfonamide, toluenesulfonamide) in soil has been developed. The target analytes were extracted from soil by a single low-pressurized microwave-assisted extraction (MAE) cycle (120°C, 10min) and quantified by high-performance liquid chromatography with UV detection. For all the seven analytes, quantitative extraction yields (72-119%, n=4) were observed from recovery tests on soil samples (1g) spiked with 5, 10 and 50mg kg(-1), using 4mL water-methanol (85:15) as extracting solution. For the lower concentrations levels (100, 250 and 500µg kg(-1)), the analytes were extracted from soil samples (2-3g) using 6mL methanol, and the extract was pre-concentrated by evaporation before analysis; recoveries in the range 70-117% were obtained (n=4). Suitable intra-day and inter-day precision were observed, with values of relative standard deviation generally below 6% and 11% (n=4), respectively. Linearity was evaluated in the concentration range 0.5-10mg L(-1) by matrix-matched standards, obtaining r(2)>0.9996. The experimental method quantification limit (MQL) was 100µg kg(-1). The entire procedure has been successfully applied to the analysis of real impacted soil samples.

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