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1.
Molecules ; 26(4)2021 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-33673007

RESUMO

Malaria remains a significant cause of morbidity and mortality in Sub-Saharan Africa and South Asia. While clinical antimalarials are efficacious when administered according to local guidelines, resistance to every class of antimalarials is a persistent problem. There is a constant need for new antimalarial therapeutics that complement parasite control strategies to combat malaria, especially in the tropics. In this work, nopol-based quinoline derivatives were investigated for their inhibitory activity against Plasmodium falciparum, one of the parasites that cause malaria. The nopyl-quinolin-8-yl amides (2-4) were moderately active against the asexual blood stage of chloroquine-sensitive strain Pf3D7 but inactive against chloroquine-resistant strains PfK1 and PfNF54. The nopyl-quinolin-4-yl amides and nopyl-quinolin-4-yl-acetates analogs were generally less active on all three strains. Interesting, the presence of a chloro substituent at C7 of the quinoline ring of amide 8 resulted in sub-micromolar EC50 in the PfK1 strain. However, 8 was more than two orders of magnitude less active against Pf3D7 and PfNF54. Overall, the nopyl-quinolin-8-yl amides appear to share similar antimalarial profile (asexual blood-stage) with previously reported 8-aminoquinolines like primaquine. Future work will focus on investigating the moderately active and selective nopyl-quinolin-8-yl amides on the gametocyte or liver stages of Plasmodium falciparum and Plasmodium vivax.


Assuntos
Antimaláricos/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Plasmodium/efeitos dos fármacos , Quinolinas/farmacologia , Antimaláricos/síntese química , Antimaláricos/química , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Células Hep G2 , Humanos , Quinolinas/síntese química , Quinolinas/química
2.
Ecotoxicol Environ Saf ; 202: 110915, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32800250

RESUMO

Benzobicyclon is a systemic herbicide that was officially registered in China in 2018. The environmental behaviors of benzobicyclon hydrolysate (BH), the main metabolite and active product of benzobicyclon, remain poorly understood in paddy fields. Here, agricultural soil samples were collected from paddy fields in Jiangxi (Ferralsols), Shandong (Alisols), Hebei (Luvisols), Heilongjiang (Phaeozems), Zhejiang (Anthrosols), Sichuan (Gleysols), Hainan (Plinthosols), and Hubei (Lixisols) across China. The equilibrium oscillation method was used to study the adsorption-desorption behaviors of BH in the eight soils. The relationships between BH adsorption and soil physicochemical properties, environmental factors (temperature and initial solution pH), and other external conditions (addition of humic acid, biochar, and metal ions) were quantified. The adsorption-desorption parameters of BH in all soils were well fitted by the Freundlich model. The adsorption constant of BH varied between 0.066 and 4.728. The BH adsorption capacity decreased in the following order: Phaeozems > Alisols > Ferralsols > Lixisols > Plinthosols > Anthrosols > Luvisols > Gleysols. The Freundlich adsorption and desorption constants of BH were linearly positively correlated with soil clay content (R2 = 0.711 and 0.709; P = 0.009 and 0.009, respectively), organic carbon content (R2 = 0.684 and 0.672; P = 0.011 and 0.013, respectively), and organic matter content (R2 = 0.698 and 0.683; P = 0.010 and 0.011, respectively); however, their linear relationships with soil cation exchange capacity were not significant (R2 = 0.192 and 0.192; P = 0.278 and 0.278, respectively). The adsorption and desorption constants of BH had negative, albeit not significant, correlations with soil pH (R2 = 0.104 and 0.100; P = 0.437 and 0.445, respectively). The adsorption of BH by soil occurred spontaneously and was mainly based on physical adsorption. Either low or high temperature reduced the ability of the soil to adsorb BH. The addition of humic acid to the soil increased BH adsorption, while the addition of biochar increased the solution pH, resulting in decreased BH adsorption. Cation type and ionic strength also had strong effects on BH adsorption. With the exception of Phaeozems, BH exhibited intermediate or high mobility in the agricultural soils and thus poses risks to surface water and groundwater.


Assuntos
Compostos Bicíclicos com Pontes/química , Herbicidas/química , Poluentes do Solo/química , Sulfonas/química , Adsorção , Agricultura , China , Argila , Água Subterrânea , Herbicidas/análise , Solo/química , Poluentes do Solo/análise
3.
J Chromatogr A ; 1625: 461243, 2020 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-32709315

RESUMO

The long identified toxic gas, hydrogen sulfide (H2S), which has also been confirmed as the third gaseous signaling molecule following NO and CO, plays important roles in various physiological and pathological process. The current most established quantification method for H2S is HPLC method coupled with fluorescence detection after derivatization with a costly fluorescent reagent, Monobromobimane (MBB). However, The MBB method is characterized by strict reaction condition, long reaction time, tedious operation, and inconsistent reported results. In this study, based on the thiolysis reaction of 7-nitro-2, 1, 3-benzoxadiazole (NBD) ether, the commonly used chromatographic modifier 4-chloro-7-nitro-2,1,3- benzoxadiazole (NBDCl) and four probes (NBDOMe, NBDOEt, NBDOTFE and NBDOCMR) synthesized from NBDCl were tested as alternatives for fast quantification of H2S by LC-MS/MS. The reaction product between NBD ethers/NBDCl and H2S showed special pink color visible to the naked eye and was easy to synthesize and separate in lab; it also showed good retention on common chromatographic columns and high instrument response; therefore it is a good determinand. After establishment of LC-MS/MS methods for all the related compounds, the reaction conditions were optimized for all the probes with H2S. Then the stability, selectivity, reaction rate, sensitivity and quantitative linear relationship between the reaction product and H2S concentration were studied for each probe. Finally, NBDOEt was selected for LC-MS/MS detection of H2S. In comparision with the MBB method, the established NBDOEt method showed matched sensitivity and linearity, better selectivity, and higher repeatability; and had the advantages of easy operation, simple reaction condition, and cheap raw materials. The method was successfully validated and applied to determination of Na2S content in Na2S∙9H2O bulk drug and injection. In conclusion, NBDOEt is a promising option for quantification of H2S in abiotic matrix.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Éter/química , Sulfeto de Hidrogênio/análise , Espectrometria de Massas em Tandem/métodos , Compostos Bicíclicos com Pontes/química , Sulfeto de Hidrogênio/química , Concentração de Íons de Hidrogênio , Oxidiazóis/química , Reprodutibilidade dos Testes
4.
Org Biomol Chem ; 18(13): 2410-2415, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32195526

RESUMO

Xylarilongipins A (1) and B (2), two diterpenes each with an unusual cage-like bicyclo[2.2.2]octane moiety, along with their biosynthetic precursor hymatoxin L (3), were isolated from the culture broth of the fungicolous fungus Xylaria longipes HFG1018 inhabiting in the medicinal fungus Fomitopsis betulinus. The structures and absolute configurations of the three compounds were established by extensive spectroscopic analysis and single-crystal X-ray diffraction analysis. Xylarilongipin A (1) displayed moderate inhibitory activity against the cell proliferation of concanavalin A-induced T lymphocytes and lipopolysaccharide-induced B lymphocytes with IC50 values of 13.6 and 22.4 µM, respectively. Additionally, the biosynthetic pathways for compounds 1-3 are discussed. This work not only corroborates the structure of the 9,16-cyclo-(18-nor-)isopimarane skeleton by single-crystal X-ray diffraction analysis for the first time, but also provides new insights into the biosynthetic origin of the unusual diterpene skeletons.


Assuntos
Compostos Bicíclicos com Pontes/farmacologia , Diterpenos/farmacologia , Imunossupressores/farmacologia , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/toxicidade , Linhagem Celular Tumoral , Diterpenos/química , Diterpenos/toxicidade , Humanos , Imunossupressores/química , Imunossupressores/toxicidade , Xylariales/química
5.
J Med Chem ; 63(6): 2833-2853, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32026697

RESUMO

A series of chemical optimizations guided by in vitro affinity at the α4ß2 receptor in combination with selectivity against the α3ß4 receptor, pharmacokinetic evaluation, and in vivo efficacy in a forced swim test resulted in identification of 3-(6-chloropyridine-3-yloxymethyl)-2-azabicyclo[3.1.0]hexane hydrochloride (9h, SUVN-911) as a clinical candidate. Compound 9h is a potent α4ß2 receptor ligand with a Ki value of 1.5 nM. It showed >10 µM binding affinity toward the ganglionic α3ß4 receptor apart from showing selectivity over 70 other targets. It is orally bioavailable and showed good brain penetration in rats. Marked antidepressant activity and dose-dependent receptor occupancy in rats support its potential therapeutic utility in the treatment of depression. It does not affect the locomotor activity at doses several folds higher than its efficacy dose. It is devoid of cardiovascular and gastrointestinal side effects. Successful long-term safety studies in animals and phase-1 evaluation in healthy humans for safety, tolerability, and pharmacokinetics paved the way for its further development.


Assuntos
Antidepressivos/farmacologia , Antagonistas Nicotínicos/farmacologia , Piridinas/farmacologia , Receptores Nicotínicos/metabolismo , Administração Oral , Animais , Antidepressivos/administração & dosagem , Antidepressivos/química , Compostos Bicíclicos com Pontes/administração & dosagem , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/farmacologia , Depressão/tratamento farmacológico , Halogenação , Humanos , Masculino , Antagonistas Nicotínicos/administração & dosagem , Antagonistas Nicotínicos/química , Piridinas/administração & dosagem , Piridinas/química , Ratos , Ratos Wistar
6.
Macromol Rapid Commun ; 41(1): e1900510, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31750985

RESUMO

Alternatives for strain-promoted azide-alkyne cycloaddition (SPAAC) chemistries are needed because of the employment of expensive and not easily scalable precursors such as bicyclo[6.1.0]non-4-yne (BCN). Inverse electron demand Diels Alder (iEDDA)-based click chemistries, using dienophiles and tetrazines, offer a more bioorthogonal and faster toolbox, especially in the biomedical field. Here, the straightforward synthesis of dendritic polyglycerin dienophiles (dPG-dienophiles) and dPG-methyl-tetrazine (dPG-metTet) as macromonomers for a fast, stable, and scalable nanogel formation by inverse nanoprecipitation is reported. Nanogel size-influencing parameters are screened such as macromonomer concentration and water-to-acetone ratio are screened. dPG-norbonene and dPG-cyclopropene show fast and stable nanogel formation in the size range of 40-200 nm and are thus used for the coprecipitation of the model protein myoglobin. High encapsulation efficiencies of more than 70% at a 5 wt% feed ratio are obtained in both cases, showing the suitability of the mild gelation chemistry for the encapsulation of small proteins.


Assuntos
Química Click , Nanogéis/química , Compostos Bicíclicos com Pontes/química , Reação de Cicloadição , Compostos Heterocíclicos/química , Mioglobina/química , Tamanho da Partícula
7.
Chemistry ; 26(13): 2808-2812, 2020 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-31823414

RESUMO

Bicyclo[1.1.0]butanes (BCBs) are highly strained carbocycles that have emerged as versatile synthetic tools, particularly for the construction of functionalized small molecules. This work reports two efficient pathways for the rapid preparation of over 20 structurally diverse BCB ketones, encompassing simple alkyl and aryl derivatives, as well as unprecedented amino acid, dipeptide, bioisostere, and bifunctional linchpin reagents currently inaccessible using literature methods. Analogues are readily forged in two steps and in high yields from simple carboxylic acids or through unsymmetrical ketone synthesis beginning with a convenient carbonyl dication equivalent. The utility of this novel toolbox of strained electrophiles for the selective modification of proteinogenic nucleophiles is highlighted.


Assuntos
Compostos Bicíclicos com Pontes/química , Butanos/química , Ácidos Carboxílicos/química , Catálise , Estrutura Molecular
8.
Chem Commun (Camb) ; 56(3): 415-418, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31821393

RESUMO

We report a novel 1,2-catechol based radioiodinated precursor for radioiodination of bicyclo[6.1.0]nonyne (BCN) installed biologically active molecules using a strain-promoted oxidation-controlled cyclooctyne-1,2-quinone cycloaddition reaction (SPOCQ) under ambient conditions. Compared to the reported methodologies, the new strategy demonstrates some clear advantages, including high in vitro and in vivo stability, high radiochemical yield, and exceptionally fast reaction kinetics at micro-molar concentration.


Assuntos
Reação de Cicloadição , Quinonas/química , Compostos Radiofarmacêuticos/química , Animais , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Catecóis/química , Coração/diagnóstico por imagem , Radioisótopos do Iodo/química , Marcação por Isótopo , Cinética , Camundongos , Camundongos Endogâmicos ICR , Oxirredução , Compostos Radiofarmacêuticos/síntese química , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único
9.
J Org Chem ; 84(22): 14670-14678, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31603325

RESUMO

Oxidopyrylium ylides are useful intermediates in synthetic organic chemistry because of their capability of forming structurally complex cycloadducts. They can also self-dimerize via [5 + 3] cycloaddition, which is an oft-reported side reaction that can negatively impact [5 + 2] cycloadduct yields and efficiency. In select instances, these dimers can be synthesized and used as the source of oxidopyrylium ylide, although the generality of this process remains unclear. Thus, how the substitution pattern governs both dimerization and cycloaddition reactions is of fundamental interest to probe factors to regulate them. The following manuscript details our findings that maltol-derived oxidopyrylium ylides (i.e., with ortho methyl substitution relative to oxide) can be trapped prior to dimerization more efficiently than the regioisomeric allomaltol-derived ylide (i.e., with a para methyl substitution relative to oxide). Density functional theory studies provide evidence in support of a sterically (kinetically) controlled mechanism, whereby gauche interactions between appendages of the approaching maltol-derived ylides are privileged by higher barriers for dimerization and thus are readily intercepted by dipolarophiles via [5 + 2] cycloadditions.


Assuntos
Compostos Bicíclicos com Pontes/síntese química , Pironas/química , Tropolona/síntese química , Compostos Bicíclicos com Pontes/química , Reação de Cicloadição , Dimerização , Cinética , Estrutura Molecular , Tropolona/química
10.
Yakugaku Zasshi ; 139(10): 1259-1265, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31582609

RESUMO

The first total synthesis of avenaol was achieved using a new robust strategy involving all-cis-substituted cyclopropane formation via an alkylidene cyclopropane. The keys to success for the total synthesis were (i) Rh-catalyzed intramolecular cyclopropanation of an allene; (ii) Ir-catalyzed stereoselective double-bond isomerization to form an all-cis cyclopropane; and (iii) differentiation of two hydroxymethyl groups via regioselective cyclization and oxidation of tetrahydropyran based on the reactivity of cyclopropyl group. This strategy effectively avoids cyclopropane ring opening and undesired formation of a cage structure. Additionally, the proposed structure of avenaol, especially unique all-cis-substituted cyclopropane was confirmed correct by this total synthesis.


Assuntos
Compostos Bicíclicos com Pontes/síntese química , Ciclopropanos/química , Alcadienos/química , Compostos Bicíclicos com Pontes/química , Catálise , Ciclização , Ciclopropanos/síntese química , Conformação Molecular , Fenômenos de Química Orgânica , Oxirredução , Estereoisomerismo
11.
Bioorg Med Chem ; 27(23): 115146, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31648876

RESUMO

In this study, the impact of one or two hydroxy moieties at the benzo[7]annulene scaffold on the GluN2B affinity and cytoprotective activity was analyzed. The key intermediate for the synthesis of OH-substituted benzo[7]annulenamines 11-13 and 17 was the epoxyketone 8. Reductive epoxide opening of 8 resulted with high regioselectivity in the 5-hydroxyketone 9 (Pd(OAc)2, HCO2H, phosphane ligand) or the 6-hydroxyketone 10 (H2, Pd/C), whereas hydrolysis in aqueous dioxane led to the dihydroxyketone 14. Reductive amination of these ketones with primary amines and NaBH(OAc)3 afforded the benzo[7]annulenamines 11-13 and 17. In receptor binding studies 5-OH derivatives 11 and 12 showed higher GluN2B affinity than 6-OH derivatives 13, which in turn were more active than 5,6-di-OH derivative 17a. The same order was found for the cytoprotective activity of the ligands. The tertiary amine 12a with one OH moiety in 5-position represents the most promising GluN2B negative allosteric modulator with a binding affinity of Ki = 49 nM and a cytoprotective activity of IC50 = 580 nM. In the binding pocket 12a shows a crucial H-bond between the benzylic OH moiety and the backbone carbonyl O-atom of Ser132 (GluN1b). It was concluded that a 5-OH moiety is essential for the inhibition of the NMDA receptor associated ion channel, whereas a OH moiety in 6-position is detrimental for binding and inhibition. An OH or CH2OH moiety at 2-position results in binding at the ifenprodil binding site, but very weak ion channel inhibition.


Assuntos
Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/farmacologia , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Compostos Bicíclicos com Pontes/síntese química , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Ligantes , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Receptores de N-Metil-D-Aspartato/química , Relação Estrutura-Atividade
12.
Angew Chem Int Ed Engl ; 58(44): 15876-15882, 2019 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-31476269

RESUMO

Inverse electron-demand Diels-Alder cycloadditions (iEDDAC) between tetrazines and strained alkenes/alkynes have emerged as essential tools for studying and manipulating biomolecules. A light-triggered version of iEDDAC (photo-iEDDAC) is presented that confers spatio-temporal control to bioorthogonal labeling in vitro and in cellulo. A cyclopropenone-caged dibenzoannulated bicyclo[6.1.0]nonyne probe (photo-DMBO) was designed that is unreactive towards tetrazines before light-activation, but engages in iEDDAC after irradiation at 365 nm. Aminoacyl tRNA synthetase/tRNA pairs were discovered for efficient site-specific incorporation of tetrazine-containing amino acids into proteins in living cells. In situ light activation of photo-DMBO conjugates allows labeling of tetrazine-modified proteins in living E. coli. This allows proteins in living cells to be modified in a spatio-temporally controlled manner and may be extended to photo-induced and site-specific protein labeling in animals.


Assuntos
Compostos Bicíclicos com Pontes/química , Ciclopropanos/química , Proteínas de Escherichia coli/química , Corantes Fluorescentes/química , Compostos Heterocíclicos com 1 Anel/química , Luz , Compostos Bicíclicos com Pontes/síntese química , Reação de Cicloadição , Corantes Fluorescentes/síntese química , Estrutura Molecular , Processos Fotoquímicos
13.
Pharmacol Res Perspect ; 7(5): e00520, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31523433

RESUMO

MGS0274 besylate is an ester-based lipophilic prodrug of a metabotropic glutamate (mGlu) 2 and mGlu3 receptor agonist MGS0008 and being developed for the treatment of schizophrenia. We investigated the disposition of these compounds in rats and monkeys and in vitro metabolism in humans to evaluate whether MGS0274 besylate could be useful as a prodrug in humans. After the oral administration of MGS0274 besylate to monkeys (2.89 mg/kg), MGS0008 was immediately found in plasma, reached a maximum concentration at 4 hours postdose, and decreased with a terminal half-life of 16.7 hours; MGS0274 was barely detectable. The oral bioavailability as MGS0008 was 83.7%, which was approximately 20-fold greater than that after oral dosing of MGS0008 (3.8%). In rats, MGS0008 penetrated the cerebrospinal fluid and was eliminated slower than from plasma. The in vitro metabolism study indicated that MGS0274 was rapidly hydrolyzed to MGS0008, which was not further metabolized. After the intravenous administration of MGS0008 to rats and monkeys, almost all the dose was excreted unchanged in urine. These results suggested that MGS0274 was, as expected, presystemically hydrolyzed to MGS0008 after gastrointestinal absorption and that MGS0008 was distributed throughout the body without further metabolism and ultimately excreted in urine in the animals. Furthermore, the hydrolytic activity against MGS0274 in the human liver S9 fraction was comparable to that in monkeys, suggesting the possibility of the rapid presystemic hydrolysis of MGS0274 to MGS0008 in humans, as it is in monkeys. Consequently, MGS0274 besylate is expected to function as a preferable prodrug in humans.


Assuntos
Compostos Bicíclicos com Pontes/sangue , Ácidos Dicarboxílicos/administração & dosagem , Ácidos Dicarboxílicos/farmacocinética , Administração Intravenosa , Administração Oral , Animais , Disponibilidade Biológica , Compostos Bicíclicos com Pontes/química , Ácidos Dicarboxílicos/sangue , Ácidos Dicarboxílicos/química , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Haplorrinos , Humanos , Masculino , Estrutura Molecular , Pró-Fármacos/administração & dosagem , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Ratos
14.
J Transl Med ; 17(1): 274, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31429778

RESUMO

BACKGROUND: Neointimal hyperplasia and its related arterial stiffness are the crucial pathophysiological features in atherosclerosis and in-stent restenosis. Cluster of differentiation 147 (CD147), a member of the immunoglobulin super family that induces the expression of matrix metalloproteinase-9 (MMP-9) by dimerization, may play important roles in neointimal hyperplasia and may therefore be an effective target for the treatment of this condition. Here, we investigated whether a novel CD147 inhibitor SP-8356 ((1S,5R)-4-(3,4-dihydroxy-5-methoxystyryl)-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-one) reduces neointimal hyperplasia and arterial stiffness in a rat model of partial carotid artery ligation. METHODS: Neointimal hyperplasia was induced in Sprague-Dawley rats by partial ligation of the right carotid artery combined with a high fat diet and vitamin D injection. Rats were subdivided into vehicle, SP-8356 (50 mg/kg), and rosuvastatin (10 mg/kg) groups. The drugs were administrated via intraperitoneal injections for 4 weeks. The elasticity of blood vessels was assessed by measuring pulse wave velocity using Doppler ultrasonography before sacrifice. Histomolecular analysis was carried out on harvested carotid arteries. RESULTS: SP-8356 significantly reduced MMP activity by inhibiting CD147 dimerization. SP-8356 reduced neointimal hyperplasia and prevented the deterioration of vascular elasticity. SP-8356 had a greater inhibitory effect on neointimal hyperplasia than did rosuvastatin. Furthermore, rosuvastatin did not improve vascular elasticity. SP-8356 increased the expression of smooth muscle myosin heavy chain (SM-MHC), but decreased the expression of collagen type III and MMP-9 in the neointimal region. In contrast to SP-8356, rosuvastatin did not alter the expression of SM-MHC or MMP-9. CONCLUSIONS: The ability of SP-8356 to reduce neointimal hyperplasia and improve arterial stiffness in affected carotid artery suggests that SP-8356 could be a promising therapeutic drug for vascular remodeling disorders involving neointimal hyperplasia and arterial stiffness.


Assuntos
Basigina/antagonistas & inibidores , Monoterpenos Bicíclicos/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Artérias Carótidas/patologia , Artérias Carótidas/fisiopatologia , Neointima/patologia , Rigidez Vascular/efeitos dos fármacos , Animais , Basigina/metabolismo , Monoterpenos Bicíclicos/química , Compostos Bicíclicos com Pontes/química , Linhagem Celular , Células Cultivadas , Colágeno Tipo III/metabolismo , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Descoberta de Drogas , Hiperplasia , Ligadura , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Músculo Liso Vascular/metabolismo , Fenótipo , Ratos Sprague-Dawley
16.
J Med Chem ; 62(15): 6972-6984, 2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31283227

RESUMO

4-(Pyrimidin-4-yl)morpholines are privileged pharmacophores for PI3K and PIKKs inhibition by virtue of the morpholine oxygen, both forming the key hydrogen bonding interaction and conveying selectivity over the broader kinome. Key to the morpholine utility as a kinase hinge binder is its ability to adopt a coplanar conformation with an adjacent aromatic core favored by the morpholine nitrogen nonbonding pair of electrons interacting with the electron deficient pyrimidine π-system. Few selective morpholine replacements have been identified to date. Herein we describe the discovery of a potent non-nitrogen containing morpholine isostere with the ability to mimic this conformation and its application in a potent selective dual inhibitor of mTORC1 and mTORC2 (29b).


Assuntos
Compostos Bicíclicos com Pontes/química , Cicloeptanos/química , Morfolinas/química , Fosfatidilinositol 3-Quinases , Inibidores de Fosfoinositídeo-3 Quinase/química , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Serina-Treonina Quinases TOR/antagonistas & inibidores , Compostos Bicíclicos com Pontes/farmacologia , Cicloeptanos/farmacologia , Descoberta de Drogas/métodos , Humanos , Morfolinas/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/metabolismo
17.
Bioorg Med Chem ; 27(17): 3879-3888, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31324566

RESUMO

The modulation of VDR signaling is important in regulating tumor-related signal transduction and protecting from microorganismal infection. In this study we discovered by luciferase reporter assay that several fused bicyclic derivatives of 1H-pyrrolo[1,2-c]imidazol-1-one with the assistance of calcitriol result in up to three-fold increases of VDR promoter activity. Preliminary SAR results from 20 compounds disclose that ideal VDR signaling regulators of these compounds are built up by the optimal combination of multiple factors. Western blot analysis indicates that compounds of ZD-3, ZD-4 and ZD-5 not only significantly upregulate p62 and LC3-II but also elevate the ratio of LC3-II/LC3-I, which possibly leads to activated autophagy. All of five compounds also significantly downregulate p65 and upregulate p-p65 and ZD-3 is the most active one to NF-κB signaling, suggesting a possible induction of apoptosis through the regulation of NF-κB signal transduction mediated by VDR signaling. Compounds of ZD-3, ZD-4 and ZD-5 significantly counteract the interference by VDR shRNA, in which ZD-3 gets the highest compensation of VDR expression and the highest ratio of LC3-II/LC3-I, indicating that ZD-3 very likely activates VDR-mediated autophagy. Taken together, these 1H-pyrrolo[1,2-c]imidazol-1-one derivatives can modulate VDR signaling, possibly resulting in the regulation of some signal pathways to induce autophagy and apoptosis.


Assuntos
Compostos Bicíclicos com Pontes/farmacologia , Descoberta de Drogas , Imidazóis/farmacologia , Receptores de Calcitriol/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Relação Dose-Resposta a Droga , Células HeLa , Humanos , Imidazóis/síntese química , Imidazóis/química , Estrutura Molecular , RNA Interferente Pequeno/farmacologia , Receptores de Calcitriol/metabolismo , Relação Estrutura-Atividade
18.
Science ; 365(6451): 393-396, 2019 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-31346065

RESUMO

The genetic variation of rice cultivars provides a resource for further varietal improvement through breeding. Some rice varieties are sensitive to benzobicyclon (BBC), a ß-triketone herbicide that inhibits 4-hydroxyphenylpyruvate dioxygenase (HPPD). Here we identify a rice gene, HIS1 (HPPD INHIBITOR SENSITIVE 1), that confers resistance to BBC and other ß-triketone herbicides. We show that HIS1 encodes an Fe(II)/2-oxoglutarate-dependent oxygenase that detoxifies ß-triketone herbicides by catalyzing their hydroxylation. Genealogy analysis revealed that BBC-sensitive rice variants inherited a dysfunctional his1 allele from an indica rice variety. Forced expression of HIS1 in Arabidopsis conferred resistance not only to BBC but also to four additional ß-triketone herbicides. HIS1 may prove useful for breeding herbicide-resistant crops.


Assuntos
Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/farmacologia , Genes de Plantas , Resistência a Herbicidas/genética , Oryza/efeitos dos fármacos , Oryza/genética , Oxigenases/genética , Sulfonas/química , Sulfonas/farmacologia , 4-Hidroxifenilpiruvato Dioxigenase/antagonistas & inibidores , Cetonas/química
19.
Bioorg Chem ; 89: 103020, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31185392

RESUMO

Despite recent advancements in its control, malaria is still a deadly parasitic disease killing millions of people each year. Progresses in combating the infection have been made by using the so-called artemisinin combination therapies (ACTs). Natural and synthetic peroxides are an important class of antimalarials. Here we describe a new series of peroxides synthesized through a new elaboration of the scaffold of bicyclic-fused/bridged synthetic endoperoxides previously developed by us. These peroxides are produced by a straightforward synthetic protocol and are characterized by submicromolar potency when tested against both chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum strains. To investigate their mode of action, the biomimetic reaction of the representative compound 6w with Fe(II) was studied by EPR and the reaction products were characterized by NMR. Rationalization of the observed structure-activity relationship studies was performed by molecular docking. Taken together, our data robustly support the hypothesized mode of activation of peroxides 6a-cc and led to the definition of the key structural requirements responsible for the antiplasmodial potency. These data will pave the way in future to the rational design of novel optimized antimalarials suitable for in vivo investigation.


Assuntos
Antimaláricos/farmacologia , Materiais Biomiméticos/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Compostos Férricos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Antimaláricos/síntese química , Antimaláricos/química , Materiais Biomiméticos/síntese química , Materiais Biomiméticos/química , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Relação Dose-Resposta a Droga , Compostos Férricos/síntese química , Compostos Férricos/química , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade
20.
Chemistry ; 25(45): 10698-10709, 2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31149749

RESUMO

Two structurally constrained chelators based on a fused bicyclic scaffold, 4-amino-4-methylperhydro-pyrido[1,2-a][1,4]diazepin-N,N',N'-triacetic acids [(4R*,10aS*)-PIDAZTA (L1) and (4R*,10aR*)-PIDAZTA (L2)], were designed for the preparation of GaIII -based radiopharmaceuticals. The stereochemistry of the ligand scaffold has a deep impact on the properties of the complexes, with unexpected [Ga(L2)OH] species being superior in terms of both thermodynamic stability and inertness. This peculiar behavior was rationalized on the basis of molecular modeling and appears to be related to a better fit in size of GaIII into the cavity of L2. Fast and efficient formation of the GaIII chelates at room temperature was observed at pH values between 7 and 8, which enables 68 Ga radiolabeling under truly physiological conditions (pH 7.4).


Assuntos
Compostos Bicíclicos com Pontes/química , Quelantes/química , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Complexos de Coordenação/metabolismo , Cristalografia por Raios X , Teoria da Densidade Funcional , Radioisótopos de Gálio/química , Meia-Vida , Humanos , Concentração de Íons de Hidrogênio , Cinética , Conformação Molecular , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/metabolismo , Transferrina/química
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