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1.
Chem Commun (Camb) ; 57(74): 9390-9393, 2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34528958

RESUMO

Herein, a highly regioselective alkylation of propargylic carbonates for trisubstituted allenes with alkyl 1,4-dihydropyridine derivatives (1,4-DHPs) is developed via a photoredox/nickel dual-catalyzed process, which represents the first direct approach to access alkylated allene products without alkyl organometallic reagents. This method features a broad substrate scope and mild conditions. A hypothetical mechanism with an alkyl radical and an allenyl Ni(III) species is proposed. Benzylation products were also obtained to be the complement building blocks for the potential synthesis of pharmaceuticals.


Assuntos
Alcadienos/síntese química , Carbonatos/química , Níquel/química , Alcadienos/química , Alquilação , Catálise , Estrutura Molecular , Oxirredução , Processos Fotoquímicos , Estereoisomerismo
2.
J Org Chem ; 86(15): 10889-10902, 2021 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-34259003

RESUMO

Benzofused seven-membered heterocycles such as 1,4-benzo[e]diazepines (1,4-BZDs) and 1,4-benzo[e]oxazepines (1,4-BZOs) were efficiently synthesized by Rh-catalyzed hydrofunctionalization of internal alkynes and allenes in good to excellent yields. The asymmetric hydroamination of (aminomethyl)anilines gave rise to 3-vinyl-1,4-BZDs with excellent enantioselectivities. Orthogonal N-deprotection of 1,4-BZDs allowed an easy entry to an advanced pyrrolobenzodiazepine metabolite of the V2-receptor antagonist Lixivaptan.


Assuntos
Ródio , Alcadienos , Alcinos , Benzodiazepinas , Catálise , Estereoisomerismo
3.
Int J Mol Sci ; 22(14)2021 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-34299042

RESUMO

Diarylpentanoid (DAP), an analog that was structurally modified from a naturally occurring curcumin, has shown to enhance anticancer efficacy compared to its parent compound in various cancers. This study aims to determine the cytotoxicity, antiproliferative, and apoptotic activity of diarylpentanoid MS13 on two subtypes of non-small cell lung cancer (NSCLC) cells: squamous cell carcinoma (NCI-H520) and adenocarcinoma (NCI-H23). Gene expression analysis was performed using Nanostring PanCancer Pathways Panel to determine significant signaling pathways and targeted genes in these treated cells. Cytotoxicity screening revealed that MS13 exhibited greater inhibitory effect in NCI-H520 and NCI-H23 cells compared to curcumin. MS13 induced anti-proliferative activity in both cells in a dose- and time-dependent manner. Morphological analysis revealed that a significant number of MS13-treated cells exhibited apoptosis. A significant increase in caspase-3 activity and decrease in Bcl-2 protein concentration was noted in both MS13-treated cells in a time- and dose-dependent manner. A total of 77 and 47 differential expressed genes (DEGs) were regulated in MS13 treated-NCI-H520 and NCI-H23 cells, respectively. Among the DEGs, 22 were mutually expressed in both NCI-H520 and NCI-H23 cells in response to MS13 treatment. The top DEGs modulated by MS13 in NCI-H520-DUSP4, CDKN1A, GADD45G, NGFR, and EPHA2-and NCI-H23 cells-HGF, MET, COL5A2, MCM7, and GNG4-were highly associated with PI3K, cell cycle-apoptosis, and MAPK signaling pathways. In conclusion, MS13 may induce antiproliferation and apoptosis activity in squamous cell carcinoma and adenocarcinoma of NSCLC cells by modulating DEGs associated with PI3K-AKT, cell cycle-apoptosis, and MAPK pathways. Therefore, our present findings could provide an insight into the anticancer activity of MS13 and merits further investigation as a potential anticancer agent for NSCLC cancer therapy.


Assuntos
Alcadienos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/patologia , Curcumina/análogos & derivados , Neoplasias Pulmonares/patologia , Antineoplásicos/química , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Ciclo Celular , Proliferação de Células/efeitos dos fármacos , Curcumina/química , Curcumina/farmacologia , Humanos , Neoplasias Pulmonares/metabolismo , Transdução de Sinais , Células Tumorais Cultivadas
4.
Phytochemistry ; 189: 112823, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34098255

RESUMO

The hydrocarbons of eight lichen species isolated in Japan were analyzed, and diverse mono-, di-, and tri-unsaturated alkenes were detected. The positions of the double bonds of C17 alkadienes (heptadecadiene) and C17-C20 alkenes were determined by mass spectrometry of their dimethyl disulfide adducts. We found that the six lichens containing green algal photobionts were distinguished by the presence of 1,8-heptadecadiene, 6,9-heptadecadiene, and 8- and 7-heptadecenes. On the other hand, 1-octadecene, 4-octadecene, and 5-nonadecene were the major alkene components of the two lichens with cyanobacterial photobionts. These alkadienes and alkenes were present in large quantities in the lichen samples. In particular, 1,8-heptadecadiene accounted for more than 90% of the total alkenes in all four lichens containing it. Our results provide new insights into the origin of C17 alkadienes and C17-C20 alkenes in environmental and geological samples, and these alkenes can potentially be applied as lichen biomarkers.


Assuntos
Alcadienos , Clorófitas , Líquens , Alcenos , Japão
5.
Chemistry ; 27(52): 13107-13116, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34185926

RESUMO

The use of allenes and 1,3-dienes as chiral allylmetal pronucleophiles in intermolecular catalytic enantioselective reductive additions to aldehydes, ketones, imines, carbon dioxide and other C=X electrophiles is exhaustively catalogued together with redox-neutral hydrogen auto-transfer processes. Coverage is limited to processes that result in both C-H and C-C bond formation. The use of alkynes as latent allylmetal pronucleophiles and multicomponent C=X allylations involving allenes and dienes is not covered. As illustrated in this review, the ability of allenes and 1,3-dienes to serve as tractable non-metallic pronucleophiles has evoked many useful transformations that have no counterpart in traditional allylmetal chemistry.


Assuntos
Alcadienos , Alcinos , Catálise , Estereoisomerismo
6.
J Org Chem ; 86(13): 8891-8899, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34125539

RESUMO

Radical-mediated trifunctionalizations of allenes are virtually unknown, in contrast to well-studied radical difunctionalizations of alkenes and alkynes. In this article, we describe a light-promoted reaction that transforms all three allene carbons to new carbon-heteroatom bonds in one pot with no expensive transition-metal catalyst. Formation of an electron donor-acceptor complex between an electron-deficient aryl and K2CO3, followed by photochemical generation of an amidyl radical and cyclization, yields a vinyl radical that can be trapped by TEMPO to ultimately furnish the product. Insights into the impact of the allene substitution pattern, radical source, and donor are presented, along with studies to unravel the mechanism of this unusual transformation.


Assuntos
Alcadienos , Óxidos N-Cíclicos , Ciclização
7.
Angew Chem Int Ed Engl ; 60(36): 19660-19664, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34145705

RESUMO

We report the first enantioselective addition of pyrazoles to 1,3-dienes. Secondary and tertiary allylic pyrazoles can be generated with excellent regioselectivity. Mechanistic studies support a pathway distinct from previous hydroaminations: a Pd0 -catalyzed ligand-to-ligand hydrogen transfer (LLHT). This hydroamination tolerates a range of functional groups and advances the field of diene hydrofunctionalization.


Assuntos
Alcadienos/química , Pirazóis/química , Catálise , Ligantes , Estrutura Molecular , Paládio/química , Estereoisomerismo
8.
Int J Mol Sci ; 22(9)2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33947016

RESUMO

The CYP74 clan cytochromes (P450) are key enzymes of oxidative metabolism of polyunsaturated fatty acids in plants, some Proteobacteria, brown and green algae, and Metazoa. The CYP74 enzymes, including the allene oxide synthases (AOSs), hydroperoxide lyases, divinyl ether synthases, and epoxyalcohol synthases (EASs) transform the fatty acid hydroperoxides to bioactive oxylipins. A novel CYP74 clan enzyme CYP440A18 of the Asian (Belcher's) lancelet (Branchiostoma belcheri, Chordata) was biochemically characterized in the present work. The recombinant CYP440A18 enzyme was active towards all substrates used: linoleate and α-linolenate 9- and 13-hydroperoxides, as well as with eicosatetraenoate and eicosapentaenoate 15-hydroperoxides. The enzyme specifically converted α-linolenate 13-hydroperoxide (13-HPOT) to the oxiranyl carbinol (9Z,11R,12R,13S,15Z)-11-hydroxy-12,13-epoxy-9,15-octadecadienoic acid (EAS product), α-ketol, 12-oxo-13-hydroxy-9,15-octadecadienoic acid (AOS product), and cis-12-oxo-10,15-phytodienoic acid (AOS product) at a ratio of around 35:5:1. Other hydroperoxides were converted by this enzyme to the analogous products. In contrast to other substrates, the 13-HPOT and 15-HPEPE yielded higher proportions of α-ketols, as well as the small amounts of cyclopentenones, cis-12-oxo-10,15-phytodienoic acid and its higher homologue, dihomo-cis-12-oxo-3,6,10,15-phytotetraenoic acid, respectively. Thus, the CYP440A18 enzyme exhibited dual EAS/AOS activity. The obtained results allowed us to ascribe a name "B. belcheri EAS/AOS" (BbEAS/AOS) to this enzyme. BbEAS/AOS is a first CYP74 clan enzyme of Chordata species possessing AOS activity.


Assuntos
Sistema Enzimático do Citocromo P-450/isolamento & purificação , Anfioxos/enzimologia , Alcadienos/metabolismo , Sequência de Aminoácidos , Animais , Sequência Conservada , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Peróxido de Hidrogênio/metabolismo , Cinética , Anfioxos/genética , Oxilipinas/metabolismo , Filogenia , Proteínas Recombinantes/metabolismo , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Especificidade da Espécie , Especificidade por Substrato
9.
Molecules ; 26(5)2021 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-33673650

RESUMO

A new application of vacuum-ultraviolet circular dichroism (VUVCD), which enables the measurement of CD spectra in the vacuum-ultraviolet region (140-200 nm), for the assignment of the absolute configurations of bromoallenes is described. Bromoallene moieties are found in natural products obtained from many marine organisms. To date, the absolute configuration of bromoallenes has been assigned almost exclusively with Lowe's rule, which is based on specific rotation. However, exceptions to Lowe's rule have been reported arising from the presence of other substituents with large specific rotations. For the unambiguous assignment of the absolute configuration of the bromoallene moiety with its characteristic absorption wavelength at 180-190 nm due to the π-π* transition, VUVCD was applied to four pairs of bromoallene diastereomers prepared by modifying the synthetic scheme of omaezallene. The VUVCD spectra clearly showed positive or negative Cotton effects around 180-190 nm according to the configuration of the bromoallene employed, revealing the potential of VUVCD for determining absolute stereochemistry.


Assuntos
Alcadienos/química , Produtos Biológicos/química , Bromo/química , Dicroísmo Circular/métodos , Alcinos/química , Ésteres/química , Estrutura Molecular , Propanóis/química , Estereoisomerismo , Raios Ultravioleta , Vácuo
10.
J Org Chem ; 86(5): 4121-4130, 2021 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-33617248

RESUMO

Computational studies of chiral phosphoric acid (CPA)-catalyzed dynamic kinetic asymmetric hydroamination (DyKAH) of racemic allenes show that the reaction proceeds through a catalytic asymmetric model involving a highly reactive π-allylic carbocationic intermediate, generated from a racemic allene through an intermolecular proton transfer mediated by CPA, which also results in a high E/Z selectivity. Moreover, the distortion-interaction, atom in molecule, and electrostatic interaction analyses and space-filling models are employed on the basis of the DyKAH catalyzed by (S)-A5 (reaction 1) or (R)-A2 (reaction 2) to explain the high enantioselectivity and the controlling effects of SPINOL scaffolds on the signs of enantioselectivity. Our calculations indicate that the enantioselectivity of reactions 1 and 2 can be mainly ascribed to the favorable noncovalent interactions within the stronger chiral electrostatic environment created by the phosphoric acid in the preferential transition states. Finally, the effect of (S/R)-SPINOL-based CPAs on the signs of enantioselectivity can be explained by the different combination modes of substrates into the chiral binding pocket of the catalyst controlled by the chirality of SPINOL backbones. Overall, the new insights into the reaction rationalize the outcome and these key factors that affect the product enantioselectivity are important to guide the DyKAHs.


Assuntos
Fosfatos , Alcadienos , Catálise , Ácidos Fosfóricos , Estereoisomerismo
11.
Molecules ; 26(4)2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33578668

RESUMO

The site- and regio-selectivity of thermal, uncatalysed 1,3-dipolar cycloadditions between arylazides and mono- or tetra-substituted allenes with different electronic features have been investigated by both conceptual (reactivity indices) and computational (M08-HX, ωB97X-D, and B3LYP) DFT approaches. Both approaches show that these cycloadditions follow a nonpolar one-step mechanism. The experimental site- and regio-selectivity of arylazides towards methoxycarbonyl- and sulfonyl-allenes as well as tetramethyl- and tetrafluoro-allenes was calculated by DFT transition state calculations, achieving semiquantitative agreement to both previous and novel experimental findings. From the mechanistic standpoint, 1H-NMR evidence of a methylene-1,2,3-triazoline intermediate reinforces the reliability of the computational scheme.


Assuntos
Alcadienos/química , Azidas/química , Reação de Cicloadição/métodos , Ciclopentanos/química , Teoria da Densidade Funcional , Teoria Quântica , Triazóis/química , Estrutura Molecular , Estereoisomerismo
12.
Sensors (Basel) ; 21(2)2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33445619

RESUMO

An electronic biosensor for odors was assembled by immobilizing the silk moth Bombyx mori pheromone binding protein (BmorPBP1) on a reduced graphene oxide surface of a field-effect transistor. At physiological pH, the sensor detects the B. mori pheromones, bombykol and bombykal, with good affinity and specificity. Among the other odorants tested, only eugenol elicited a strong signal, while terpenoids and other odorants (linalool, geraniol, isoamyl acetate, and 2-isobutyl-3-methoxypyrazine) produced only very weak responses. Parallel binding assays were performed with the same protein and the same ligands, using the common fluorescence approach adopted for similar proteins. The results are in good agreement with the sensor's responses: bombykol and bombykal, together with eugenol, proved to be strong ligands, while the other compounds showed only poor affinity. When tested at pH 4, the protein failed to bind bombykol both in solution and when immobilized on the sensor. This result further indicates that the BmorPBP1 retains its full activity when immobilized on a surface, including the conformational change observed in acidic conditions. The good agreement between fluorescence assays and sensor responses suggests that ligand-binding assays in solution can be used to screen mutants of a binding protein when selecting the best form to be immobilized on a biosensor.


Assuntos
Técnicas Biossensoriais/instrumentação , Proteínas Imobilizadas/metabolismo , Proteínas de Insetos/química , Proteínas de Insetos/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/química , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Odorantes/análise , Alcadienos/análise , Técnicas Biossensoriais/métodos , Eugenol/análise , Álcoois Graxos/análise , Fluorescência , Grafite/química , Concentração de Íons de Hidrogênio , Proteínas Imobilizadas/química , Feromônios/análise , Feromônios/metabolismo , Soluções/química
13.
Bioorg Med Chem ; 32: 115999, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33444848

RESUMO

A series of novel penta-1,4-diene-3-one derivatives containing quinazoline and oxime ether moieties were designed and synthesized. Their anticancer activities were evaluated by MTT assay, the results showed that most compounds exhibited extremely inhibitory effects against hepatoma SMMC-7721 cells. In particular, compounds Q2 and Q8 displayed the more potent inhibitory activity with IC50 values of 0.64 and 0.63 µM, which were better than that of gemcitabine (1.40 µM). Further mechanism studies indicated that compounds Q2, Q8, Q13 and Q19 could control the migration of SMMC-7721 cells effectively, and inhibit the proliferation of cancer cells by inhibiting the DNA replication. Western-blot results showed that compounds Q2 and Q8 induced irreversible apoptosis of SMMC-7721 cells by regulating the expression level of apoptose-related proteins. Those studies demonstrated that the penta-1,4-diene-3-one derivatives containing quinazoline and oxime ether fragments merited further research as potential anticancer agents.


Assuntos
Alcadienos/farmacologia , Antineoplásicos/farmacologia , Desenho de Fármacos , Oximas/farmacologia , Quinazolinas/farmacologia , Alcadienos/síntese química , Alcadienos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Oximas/química , Quinazolinas/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
14.
Mini Rev Med Chem ; 21(9): 1058-1070, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33272171

RESUMO

Medicinal chemists have continuously shown interest in new curcuminoid derivatives, diarylpentadienones, owing to their enhanced stability feature and easy preparation using a one-pot synthesis. Thus far, methods such as Claisen-Schmidt condensation and Julia- Kocienski olefination have been utilised for the synthesis of these compounds. Diarylpentadienones possess a high potential as a chemical source for designing and developing new and effective drugs for the treatment of diseases, including inflammation, cancer, and malaria. In brief, this review article focuses on the broad pharmacological applications and the summary of the structure-activity relationship of molecules, which can be employed to further explore the structure of diarylpentadienone. The current methodological developments towards the synthesis of diarylpentadienones are also discussed.


Assuntos
Alcadienos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Antimaláricos/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Alcadienos/síntese química , Alcadienos/química , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Antimaláricos/síntese química , Antimaláricos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Humanos , Inflamação/tratamento farmacológico , Malária/tratamento farmacológico , Estrutura Molecular
15.
Bioorg Chem ; 104: 104277, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32971414

RESUMO

A series of aminated- (1-9) and sulfonamide-containing diarylpentadienones (10-18) were synthesized, structurally characterized, and evaluated for their in vitro anti-diabetic potential on α-glucosidase and DPP-4 enzymes. It was found that all the new molecules were non-associated PAINS compounds. The sulfonamide-containing series (compounds 10-18) selectively inhibited α-glucosidase over DPP-4, in which compound 18 demonstrated the highest activity with an IC50 value of 5.69 ± 0.5 µM through a competitive inhibition mechanism. Structure-activity relationship (SAR) studies concluded that the introduction of the trifluoromethylbenzene sulfonamide moiety was essential for the suppression of α-glucosidase. The most active compound 18, was then further tested for in vivo toxicities using the zebrafish animal model, with no toxic effects detected in the normal embryonic development, blood vessel formation, and apoptosis of zebrafish. Docking simulation studies were also carried out to better understand the binding interactions of compound 18 towards the homology modeled α -glucosidase and the human lysosomal α -glucosidase enzymes. The overall results suggest that the new sulfonamide-containing diarylpentadienones, compound 18, could be a promising candidate in the search for a new α-glucosidase inhibitor, and can serve as a basis for further studies involving hit-to-lead optimization, in vivo efficacy and safety assessment in an animal model and mechanism of action for the treatment of T2DM patients.


Assuntos
Alcadienos/farmacologia , Desenvolvimento de Medicamentos , Inibidores de Glicosídeo Hidrolases/farmacologia , Simulação de Acoplamento Molecular , alfa-Glucosidases/metabolismo , Alcadienos/síntese química , Alcadienos/química , Animais , Relação Dose-Resposta a Droga , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/química , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia , Peixe-Zebra/embriologia
16.
J Am Chem Soc ; 142(38): 16486-16492, 2020 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-32869987

RESUMO

Two complementary regiodivergent [(P,N)Ni]-catalyzed hydroalkylations of branched dienes are reported. When amides are employed as unstabilized C(sp3) nucleophiles, a highly regioselective 1,4-addition process is favored. The addition products are obtained in high yield and with excellent stereocontrol of the internal olefin. With use of a chiral ligand and imides as carbon nucleophiles, a 3,4-addition protocol was developed, enabling construction of two contiguous tertiary stereocenters in a single step with moderate to high levels of diastereocontrol and excellent enantiocontrol. Both methods operate under mild reaction conditions, display a broad scope, and show excellent functional group tolerance. The synthetic potential of the 3,4-hydroalkylation reaction was established via a series of postcatalytic modifications.


Assuntos
Alcadienos/química , Amidas/química , Níquel/química , Alquilação , Catálise , Estrutura Molecular , Estereoisomerismo
17.
Nature ; 586(7828): 242-247, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32846425

RESUMO

Strained cyclic organic molecules, such as arynes, cyclic alkynes and cyclic allenes, have intrigued chemists for more than a century with their unusual structures and high chemical reactivity1. The considerable ring strain (30-50 kilocalories per mole)2,3 that characterizes these transient intermediates imparts high reactivity in many reactions, including cycloadditions and nucleophilic trappings, often generating structurally complex products4. Although strategies to control absolute stereochemistry in these reactions have been reported using stoichiometric chiral reagents5,6, catalytic asymmetric variants to generate enantioenriched products have remained difficult to achieve. Here we report the interception of racemic cyclic allene intermediates in a catalytic asymmetric reaction and provide evidence for two distinct mechanisms that control absolute stereochemistry in such transformations: kinetic differentiation of allene enantiomers and desymmetrization of intermediate π-allylnickel complexes. Computational studies implicate a catalytic mechanism involving initial kinetic differentiation of the cyclic allene enantiomers through stereoselective olefin insertion, loss of the resultant stereochemical information, and subsequent introduction of absolute stereochemistry through desymmetrization of an intermediate π-allylnickel complex. These results reveal reactivity that is available to cyclic allenes beyond the traditional cycloadditions and nucleophilic trappings previously reported, thus expanding the types of product accessible from this class of intermediates. Additionally, our computational studies suggest two potential strategies for stereocontrol in reactions of cyclic allenes. Combined, these results lay the foundation for the development of catalytic asymmetric reactions involving these classically avoided strained intermediates.


Assuntos
Alcadienos/química , Catálise , Níquel/química , Ciclização
18.
Bioconjug Chem ; 31(9): 2201-2210, 2020 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-32786505

RESUMO

The tetrazine/trans-cyclooctene (TCO) inverse electron-demand Diels-Alder (IEDDA) reaction is the fastest bioorthogonal "click" ligation process reported to date. In this context, TCO reagents have found widespread applications; however, their availability and structural diversity is still somewhat limited due to challenges connected with their synthesis and structural modification. To address this issue, we developed a novel strategy for the conjugation of TCO derivatives to a biomolecule, which allows for the creation of greater structural diversity from a single precursor molecule, i.e., trans,trans-1,5-cyclooctadiene [(E,E)-COD] 1, whose preparation requires standard laboratory equipment and readily available reagents. This two-step strategy relies on the use of new bifunctional TCO linkers (5a-11a) for IEDDA reactions, which can be synthesized via 1,3-dipolar cycloaddition of (E,E)-COD 1 with different azido spacers (5-11) carrying an electrophilic function (NHS-ester, N-succinimidyl carbonate, p-nitrophenyl-carbonate, maleimide) in the ω-position. Following bioconjugation of these electrophilic linkers to the nucleophilic residue (cysteine or lysine) of a protein (step 1), the resulting TCO-decorated constructs can be subjected to a IEDDA reaction with tetrazines functionalized with fluorescent or near-infrared (NIR) tags (step 2). We successfully used this strategy to label bovine serum albumin with the TCO linker 8a and subsequently reacted it in a cell lysate with the fluorescein-isothiocyanate (FITC)-derived tetrazine 12. The same strategy was then used to label the bacterial wall of Gram-positive Staphylococcus aureus, showing the potential of these linkers for live-cell imaging. Finally, we determined the impact of structural differences of the linkers upon the stability of the bioorthogonal constructs. The compounds for stability studies were prepared by conjugation of TCO linkers 6a, 8a, and 10a to mAbs, such as Rituximab and Obinutuzumab, and subsequent labeling with a reactive Cy3-functionalized tetrazine.


Assuntos
Alcadienos/química , Corantes Fluorescentes/química , Alcadienos/síntese química , Animais , Bovinos , Química Click , Reação de Cicloadição , Ciclo-Octanos/síntese química , Ciclo-Octanos/química , Corantes Fluorescentes/síntese química , Soroalbumina Bovina/química , Staphylococcus aureus/citologia , Staphylococcus aureus/isolamento & purificação
19.
Future Med Chem ; 12(16): 1505-1519, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32772720

RESUMO

Aim: To synthesize novel antiproliferative agents. Results & methodology: A variety of 1,4-pentadien-3-one derivatives bearing quinoxaline scaffolds was designed and synthesized and their antiproliferative activities were evaluated. Notably, compounds N3 and N4 exhibited markedly greater antiproliferative activities against SMMC-7721 cells in vitro compared with the well-known antitumor drug gemcitabine. The mechanistic investigation showed that compounds N3 and N4 induced SMMC-7721 cell apoptosis by regulating the expression levels of apoptosis-related proteins. In addition, the molecular docking model further revealed that compound N3 could be a potential peroxisome proliferator-activated receptor inhibitor. Conclusion: These compounds might serve as bioactive fragments and lead compounds for developing more potent apoptosis inducers.


Assuntos
Alcadienos/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Descoberta de Drogas , Quinoxalinas/farmacologia , Alcadienos/síntese química , Alcadienos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Quinoxalinas/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
20.
J Am Chem Soc ; 142(29): 12865-12877, 2020 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-32578428

RESUMO

Additions of acids to 1,3-dienes are conventionally understood as involving discrete intermediates that undergo an ordinary competition between subsequent pathways to form the observed products. The combined experimental, computational, and dynamic trajectory study here suggests that this view is incorrect, and that solvation dynamics plays a critical role in the mechanism. While implicit solvent models were inadequate, QM/QM' trajectories in explicit solvent provide an accurate prediction of the experimental selectivity in the addition of HCl to 1,3-pentadiene. Trajectories initiated from a protonation saddle point on the potential of mean force surface are predominantly unproductive due to a gating effect of solvation that allows diene protonation only when the incipient ion pair is neither too solvent-stabilized nor too little. Protonation then leads to relatively unsolvated ion pairs, and a majority of these collapse rapidly to the 1,2-product, without barrier and without achieving equilibrium solvation as intermediates. The remainder decay slowly, at a rate consistent with equilibrium solvation as true intermediates, affording a mixture of addition products. Overall, an accurate description of the nature and pathway selectivity of the ion pair intermediates in carbocation reactions must allow for species lacking equilibrium solvation. Potential reinterpretations of a series of historically notable observations in carbocation reactions are discussed.


Assuntos
Alcadienos/química , Ácido Clorídrico/química , Termodinâmica , Concentração de Íons de Hidrogênio , Estrutura Molecular , Teoria Quântica , Solventes/química
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