Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 706
Filtrar
1.
J Enzyme Inhib Med Chem ; 35(1): 549-554, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31967484

RESUMO

A small series of 2,4-dioxothiazolidinyl acetic acids was prepared from thiourea, chloroacetic acid, aromatic aldehydes, and ethyl-2-bromoacetate. They were assayed for the inhibition of four physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isoforms of human (h) origin, the cytosolic hCA I and II, and the transmembrane hCA IX and XII, involved among others in tumorigenesis (hCA IX and XII) and glaucoma (hCA II and XII). The two cytosolic isoforms were not inhibited by these carboxylates, which were also rather ineffective as hCA IX inhibitors. On the other hand, they showed submicromolar hCA XII inhibition, with KIs in the range of 0.30-0.93 µM, making them highly CA XII-selective inhibitors.


Assuntos
Acetatos/farmacologia , Anidrase Carbônica IX/antagonistas & inibidores , Inibidores da Anidrase Carbônica/classificação , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Tiazóis/farmacologia , Acetatos/síntese química , Acetatos/química , Antígenos de Neoplasias/metabolismo , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química
2.
Chem Commun (Camb) ; 55(82): 12348-12351, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31559401

RESUMO

A multimeric MRI contrast agent based on the closo-borane motif is reported. Twelve copies of a modified AAZTA chelate with an alkyne end group are appended on an azide-functionalized closo-borane motif using Cu(i) catalyzed click chemistry. The presence of two water molecules on the Gd-bound AAZTA chelate results in high relaxivity for the closomer in vitro/in vivo.


Assuntos
Acetatos/química , Azepinas/química , Boranos/química , Quelantes/química , Meios de Contraste/química , Complexos de Coordenação/química , Imagem por Ressonância Magnética , Acetatos/síntese química , Azepinas/síntese química , Boranos/síntese química , Quelantes/síntese química , Meios de Contraste/síntese química , Complexos de Coordenação/síntese química , Estrutura Molecular
3.
Eur J Med Chem ; 179: 608-622, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31279294

RESUMO

Based on an old phenoxyacetic acid scaffold, CPU014 (compound 14) has been identified as a superior agonist by comprehensive exploration of structure-activity relationship. In vitro toxicity study suggested that CPU014 has lower risk of hepatotoxicity than TAK-875. During acute toxicity study (5-500 mg/kg), a favorable therapeutic window of CPU014 was observed by evaluation of plasma profiles and liver slices. Moreover, CPU014 promotes insulin secretion in a glucose-dependent manner, while no GLP-1 secretion has been enhanced. Other than good pharmacokinetic properties, CPU014 significantly improved glucose tolerance both in normal and diabetic models without the risk of hypoglycemia. These subversive findings provided a safer candidate CPU014, which is currently in preclinical study to assess its potential for the treatment of diabetes.


Assuntos
Acetatos/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Desenho de Drogas , Hipoglicemiantes/farmacologia , Receptores Acoplados a Proteínas-G/agonistas , Acetatos/síntese química , Acetatos/química , Animais , Diabetes Mellitus Tipo 2/metabolismo , Relação Dose-Resposta a Droga , Teste de Tolerância a Glucose , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas-G/metabolismo , Relação Estrutura-Atividade
4.
Chem Commun (Camb) ; 55(61): 8975-8978, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31290492
5.
Amino Acids ; 51(7): 991-998, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31079215

RESUMO

DMDP acetic acid [N-carboxymethyl-2,5-dideoxy-2,5-imino-D-mannitol] 5 from Stevia rebaudiana is the first isolated natural amino acid derived from iminosugars bearing an N-alkyl acid side chain; it is clear from GCMS studies that such derivatives with acetic and propionic acids are common in a broad range of plants including mulberry, Baphia, and English bluebells, but that they are very difficult to purify. Reaction of unprotected pyrrolidine iminosugars with aqueous glyoxal gives the corresponding N-acetic acids in very high yield; Michael addition of both pyrrolidine and piperidine iminosugars and that of polyhydroxylated prolines to tert-butyl acrylate give the corresponding N-propionic acids in which the amino group of ß-alanine is incorporated into the heterocyclic ring. These easy syntheses allow the identification of this new class of amino acid in plant extracts and provide pure samples for biological evaluation. DMDP N-acetic and propionic acids are potent α-galactosidase inhibitors in contrast to potent ß-galactosidase inhibition by DMDP.


Assuntos
Acetatos/síntese química , Aminoácidos/química , Glicosídeo Hidrolases/antagonistas & inibidores , Imino Açúcares/isolamento & purificação , Propionatos/síntese química , Pirrolidinas/síntese química , Stevia/química , Aminoácidos/síntese química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Cromatografia Gasosa-Espectrometria de Massas , Glicina/química , Glicosídeos/metabolismo , Hidroxiprolina/química , Imino Açúcares/química , Piperidinas/síntese química , alfa-Galactosidase/antagonistas & inibidores , beta-Alanina/química , beta-Galactosidase/antagonistas & inibidores
6.
Pest Manag Sci ; 75(12): 3160-3166, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30941863

RESUMO

BACKGROUND: Strobilurin fungicides are some of the most potent and successful agrochemicals. However, continued use of traditional strobilurins has led to the emergence of fungicide-resistant biotypes. Thus, a supply of new strobilurin fungicides is highly valuable. In this study, a series of novel methoxyacrylate analogs containing a cyano-substituted hydrazine moiety as the side chain was synthesized and evaluated for their anti-plant pathogenic activities. RESULTS: Compounds 2-04, 2-05, 2-07 and 2-14 exhibited a relatively broad range of fungicidal activity. Compounds 2-04, 2-13 and 2-14 exhibited good fungicidal activity against Sclerotinia sclerotiorum with median effective concentrations (EC50 ) of 3.84, 3.50 and 3.80 µg mL-1 , respectively. Most of these compounds showed excellent inhibition of spore germination in Magnaporthe grisea at 25 µg mL-1 . Moreover, in an in vivo test, compounds 2-02, 2-04, 2-07 and 2-13 exhibited potent fungicidal activities against the tested plant diseases at 400 µg mL-1 . Notably, compound 2-07 showed comparable or better activity than the commercially positive controls, azoxystrobin and procloraz, against powdery mildew of cucumber and rice blast fungus in the field trails at the same application dosages. CONCLUSON: This study indicated that methoxyacrylate analogs containing a cyano-substituted hydrazone side chain can serve as potential fungicidal candidates for crop protection. © 2019 Society of Chemical Industry.


Assuntos
Acetatos , Ascomicetos/efeitos dos fármacos , Fungicidas Industriais , Magnaporthe/efeitos dos fármacos , Controle de Pragas , Acetatos/síntese química , Fungicidas Industriais/síntese química , Doenças das Plantas/prevenção & controle
7.
Nat Chem ; 11(4): 342-350, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30903037

RESUMO

The architecture and bioactivity of natural products frequently serve as embarkation points for the exploration of biologically relevant chemical space. Total synthesis followed by derivative synthesis has historically enabled a deeper understanding of structure-activity relationships. However, synthetic strategies towards a natural product are not always guided by hypotheses regarding the structural features required for bioactivity. Here, we report an approach to natural product total synthesis that we term 'pharmacophore-directed retrosynthesis'. A hypothesized, pharmacophore of a natural product is selected as an early synthetic target and this dictates the retrosynthetic analysis. In an ideal application, sequential increases in the structural complexity of this minimal structure enable development of a structure-activity relationship profile throughout the course of the total synthesis effort. This approach enables the identification of simpler congeners retaining bioactivity at a much earlier stage of a synthetic effort, as demonstrated here for the spongiane diterpenoid, gracilin A, leading to simplified derivatives with potent neuroprotective and immunosuppressive activity.


Assuntos
Acetatos/química , Diterpenos/química , Furanos/química , Imunossupressores/química , Fármacos Neuroprotetores/química , Acetatos/síntese química , Acetatos/farmacologia , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular/efeitos dos fármacos , Cristalografia por Raios X , Reação de Cicloadição , Diterpenos/síntese química , Diterpenos/farmacologia , Desenho de Drogas , Furanos/síntese química , Furanos/farmacologia , Humanos , Imunossupressores/síntese química , Imunossupressores/farmacologia , Membranas Mitocondriais/metabolismo , Conformação Molecular , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade
8.
Bioorg Med Chem Lett ; 29(6): 826-831, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30704813

RESUMO

DNA methylation is an epigenetic modification that is performed by DNA methyltransferases (DNMTs) and that leads to the transfer of a methyl group from S-adenosylmethionine (SAM) to the C5 position of cytosine. This transformation results in hypermethylation and silencing of genes such as tumor suppressor genes. Aberrant DNA methylation has been associated with the development of many diseases, including cancer. Inhibition of DNMTs promotes the demethylation and reactivation of epigenetically silenced genes. NSC 106084 and 14778 have been reported to inhibit DNMTs in the micromolar range. We report herein the synthesis of NSC 106084 and 14778 and the evaluation of their DNMT inhibitory activity. Our results indicate that while commercial NSC 14778 is moderately active against DNMT1, 3A/3L and 3B/3L, resynthesized NSC 14778 is inactive under our assay conditions. Resynthesized 106084 was also found to be inactive.


Assuntos
Acetatos/química , Compostos Benzidrílicos/química , Benzofenonas/química , DNA (Citosina-5-)-Metiltransferases/antagonistas & inibidores , Inibidores Enzimáticos/química , Salicilatos/química , Acetatos/síntese química , Compostos Benzidrílicos/síntese química , Benzofenonas/síntese química , Ensaios Enzimáticos , Inibidores Enzimáticos/síntese química , Salicilatos/síntese química
9.
J Biomol Struct Dyn ; 37(3): 623-640, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29375009

RESUMO

Our study focus on the biological importance of synthesized 5ß-dihydrocortisol (Dhc) and 5ß-dihydrocortisol acetate (DhcA) molecules, the cytotoxic study was performed on breast cancer cell line (MCF-7) normal human embryonic kidney cell line (HEK293), the IC50 values for MCF-7 cells were 28 and 25 µM, respectively, whereas no toxicity in terms of cell viability was observed with HEK293 cell line. Further experiment proved that Dhc and DhcA induced 35.6 and 37.7% early apoptotic cells and 2.5, 2.9% late apoptotic cells, respectively, morphological observation of cell death through TUNEL assay revealed that Dhc and DhcA induced apoptosis in MCF-7 cells. The complexes of HSA-Dhc and HSA-DhcA were observed as static quenching, and the binding constants (K) was 4.7 ± .03 × 104 M-1 and 3.9 ± .05 × 104 M-1, and their binding free energies were found to be -6.4 and -6.16 kcal/mol, respectively. The displacement studies confirmed that lidocaine 1.4 ± .05 × 104 M-1 replaced Dhc, and phenylbutazone 1.5 ± .05 × 104 M-1 replaced by DhcA, which explains domain I and domain II are the binding sites for Dhc and DhcA. Further, FT-IR, synchronous spectroscopy, and CD results revealed that the secondary structure of HSA was altered in the presence of Dhc and DhcA. Furthermore, the atomic force microscopy and transmission electron microscopy showed that the dimensions like height and molecular size of the HSA-Dhc and HSA-DhcA complex were larger compared to HSA alone. Detailed analysis through molecular dynamics simulations also supported greater stability of HSA-Dhc and HSA-DhcA complexes, and root-mean-square-fluctuation interpreted the binding site of Dhc as domain IB and domain IIA for DhcA. This information is valuable for further development of steroid derivative with improved pharmacological significance as novel anti-cancer drugs.


Assuntos
Acetatos/química , Antineoplásicos/farmacologia , Hidrocortisona/análogos & derivados , Albumina Sérica Humana/metabolismo , Acetatos/síntese química , Acetatos/farmacologia , Sítios de Ligação , Morte Celular/efeitos dos fármacos , Dicroísmo Circular , Células HEK293 , Humanos , Hidrocortisona/síntese química , Hidrocortisona/química , Hidrocortisona/farmacologia , Células MCF-7 , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Secundária de Proteína , Albumina Sérica Humana/química , Espectrometria de Fluorescência , Espectroscopia de Infravermelho com Transformada de Fourier , Análise Espectral , Termodinâmica
10.
Georgian Med News ; (280-281): 173-178, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30204120

RESUMO

Today we know that NO· and ONOO- are clue pathophysiological factors for progression some ischemic diseases of the central nervous system. So investigation of the antioxidants which will be able to decrease NO· and ONOO- toxicity seems to be very of current interest. The six esters and three amides of 2-(3,4-dihydro-3-oxo-2H-[1,2,4]triazino[4,3-c]quinazolin-4-yl)acetic acid were synthesized for this study, and we showed evidence of antioxidant activity of these new original derivatives. We studied the effect of 2-(3,4-dihydro-3-oxo-2H-[1,2,4]triazino[4,3-c]quinazolin-4-yl)acetic acid derivatives on superoxide dismutase activity under the condition of excessive NO· and ONOO- production. NO· induction was performed by the action of light on sodium nitroprusside Na2[Fe(NO)(CN)5]×2H2O in vitro. Also, the investigation of the substances was carried out in the brain supernatant obtained from the white Wistar rats in vivo. For nitrosative stress modeling dinitrozolic complex of Fe2+ and cysteine were utilized. Our data showed that 2-(3,4-dihydro-3-oxo-2H-[1,2,4]triazino[4,3-c]quinazolin-4-yl)acetic acid is not active compound while its esters and amides have antioxidant activity. Compound benzyl ester of this acid revealed the most effective antioxidant activity.


Assuntos
Acetatos/farmacologia , Antioxidantes/farmacologia , Estresse Nitrosativo/efeitos dos fármacos , Quinazolinas/farmacologia , Triazinas/farmacologia , Acetatos/síntese química , Amidas/síntese química , Amidas/farmacologia , Animais , Antioxidantes/síntese química , Encéfalo/metabolismo , Ésteres/síntese química , Ésteres/farmacologia , Masculino , Óxido Nítrico/biossíntese , Ácido Peroxinitroso/biossíntese , Quinazolinas/síntese química , Ratos Wistar , Relação Estrutura-Atividade , Superóxido Dismutase/metabolismo , Triazinas/síntese química , Tirosina/análogos & derivados , Tirosina/metabolismo
11.
Bioorg Med Chem ; 26(15): 4382-4389, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-30054191

RESUMO

In this study, we designed and synthesized several novel "Y"-shaped biaryl PPARδ agonists. Structure-activity relationship (SAR) studies demonstrated that compound 3a was the most active agonist with an EC50 of 2.6 nM. We also synthesized and evaluated enantiospecific R and S isomers of compound 3a to confirm that R isomer (EC50 = 0.7 nM) shows much more potent activity than S isomer (EC50 = 6.1 nM). Molecular docking studies between the PPAR ligand binding domain and enantiospecific R and S isomers of compound 3a were performed. In vitro absorption, distribution, metabolism, excretion, and toxicity (ADMET) and in vivo PK profiles show that compound 3a possesses superior drug-like properties including good bioavailability. Our overall results clearly demonstrate that this orally administrable PPARδ agonist 3a is a viable drug candidate for the treatment of various PPARδ-related disorders.


Assuntos
Acetatos/química , Compostos de Bifenilo/síntese química , PPAR delta/agonistas , Acetatos/síntese química , Acetatos/farmacocinética , Administração Oral , Animais , Sítios de Ligação , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Cristalografia por Raios X , Desenho de Drogas , Meia-Vida , Humanos , Concentração Inibidora 50 , Camundongos , Microssomos/metabolismo , Simulação de Acoplamento Molecular , PPAR delta/metabolismo , Estrutura Terciária de Proteína , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/metabolismo
12.
Pak J Pharm Sci ; 31(4): 1393-1397, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30033425

RESUMO

2-(3-hydroxy-1-adamantyl)-2-oxoacetic acid (IV), a key intermediate of saxagliptin for type 2 diabetes mellitus (T2DM), was prepared from 1-adamantanecarboxylic acid(I) via oxidation by potassium permanganate(KMnO4) to afford 3-hydroxy-1-adamantanecarboxylic acid (II), which was treated with a one-pot method to give 1-acetyl-3-hydroxyadamantane (III) followed by oxidation. Some key steps were optimized and the overall yield was about 51%.


Assuntos
Acetatos/síntese química , Adamantano/análogos & derivados , Adamantano/síntese química , Técnicas de Química Sintética/métodos , Dipeptídeos/química , Hipoglicemiantes/síntese química , Acetatos/química , Acetatos/farmacologia , Adamantano/química , Adamantano/farmacologia , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Estrutura Molecular , Permanganato de Potássio/química
13.
J Invest Dermatol ; 138(12): 2635-2643, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29908149

RESUMO

Overexpression of hexokinase 2, and its binding to VDAC1 on the outer mitochondrial membrane of cancer cells, is key to their metabolic reprogramming to aerobic glycolysis, which enables them to proliferate. We describe Comp-1, an allosteric small molecule that selectively detaches hexokinase 2 from the mitochondria. Detachment of hexokinase 2 reduces glycolysis and triggers apoptosis in cancer cells, without affecting hexokinase 1-expressing normal cells. The anti-cancer activity of Comp-1 was demonstrated in the UVB-damaged skin model in SKH-1 mice. Topical treatment with Comp-1 led to 70% reduction in lesion number and area. This in vivo efficacy was obtained without local skin reactions or other safety findings. Mechanism-related pharmacodynamic markers, including hexokinase 2 and cleaved caspase 3 levels, are affected by Comp-1 treatment in vivo. Good Laboratory Practice toxicology studies in minipigs for 28 days and 13 weeks established no systemic toxicities and minimal dermal reaction for once-daily application of up to 20% and 15% ointment strengths, respectively. Thus, Comp-1 may address a significant unmet medical need for a non-irritating efficacious topical actinic keratosis treatment.


Assuntos
Acetatos/uso terapêutico , Antineoplásicos/uso terapêutico , Ciclopentanos/uso terapêutico , Ceratose Actínica/tratamento farmacológico , Neoplasias de Células Escamosas/tratamento farmacológico , Oxilipinas/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Pele/patologia , Raios Ultravioleta/efeitos adversos , Acetatos/síntese química , Acetatos/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Apoptose , Linhagem Celular , Ciclopentanos/síntese química , Ciclopentanos/farmacologia , Feminino , Glicólise , Hexoquinase/metabolismo , Humanos , Camundongos , Camundongos Mutantes , Mitocôndrias/metabolismo , Modelos Animais , Oxilipinas/síntese química , Oxilipinas/farmacologia , Pele/efeitos dos fármacos , Suínos , Porco Miniatura , Canal de Ânion 1 Dependente de Voltagem/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Eur J Med Chem ; 151: 686-704, 2018 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-29660689

RESUMO

Morita-Baylis-Hillman acetates and α-bromonitroalkenes have been employed in cascade reactions with lawsone and 2-aminonaphthoquinone for the one-pot synthesis of heterocycle fused quinonoid compounds. The reactions reported here utilized the 1,3-binucleophilic potential of hydroxy- and aminonaphthoquinones and the 1,2/1,3-bielectrophilic potential of bromonitroalkenes and Morita-Baylis-Hillman acetates for the synthesis of pyrrole and furan fused naphthoquinones. The synthesized compounds were evaluated against HCT-116 (human colon carcinoma cells), PC3 (human prostate cancer cells), HL-60 (human promyelocytic leukemia cells), SF295 (human glioblastoma cells) and NCI-H460 (human lung cancer cells) and exhibited antitumor activity with IC50 values as low as < 2 µM. Selected compounds were also evaluated against OVCAR-8 (ovary), MX-1 (breast) and JURKAT (leukemia) cell lines. The cytotoxic potential of the quinones evaluated was also assayed using non-tumor cells, exemplified by peripheral blood mononuclear (PBMC) and L929 cells.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Pirróis/química , Pirróis/farmacologia , Quinonas/química , Quinonas/farmacologia , Acetatos/síntese química , Acetatos/química , Alcenos/síntese química , Alcenos/química , Aminação , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Técnicas de Química Sintética , Furanos/síntese química , Furanos/química , Furanos/farmacologia , Halogenação , Humanos , Modelos Moleculares , Naftoquinonas/síntese química , Naftoquinonas/química , Neoplasias/tratamento farmacológico , Pirróis/síntese química , Quinonas/síntese química , Relação Estrutura-Atividade
15.
Bioorg Med Chem ; 26(9): 2287-2290, 2018 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-29580850

RESUMO

The binding stoichiometry, binding constants, and inclusion mode of some water-soluble negatively charged cyclodextrin derivatives, i.e. heptakis-[6-deoxy-6-(3-sulfanylpropanoic acid)]-ß-cyclodextrin(H1), heptakis-[6-deoxy-6-(2-sulfanylacetic acid)]-ß-cyclodextrin(H2), mono-[6-deoxy-6-(3-sulfanylpropanoic acid)]-ß-cyclodextrin (H3) and mono-[6-deoxy-6-(2-sulfanylacetic acid)]-ß-cyclodextrin (H4), with three anticancer drugs, i.e. irinotecan hydrochloride; topotecan hydrochloride; doxorubicin hydrochloride, were investigated by means of 1H NMR, UV-Vis spectroscopy, mass spectra and 2D NMR. Polyanionic cyclodextrins H1-H2 showed the significantly high binding abilities of up to 2.6 × 104-2.0 × 105 M-1 towards the selected anticancer drugs, which were nearly 50-1000 times higher than the corresponding Ks values of native ß-cyclodextrin. In addition, these polyanionic cyclodextrins also showed the pH-controlled release behaviors. That is, the anticancer drugs could be efficiently encapsulated in the cyclodextrin cavity at a pH value similar to that of serum but sufficiently released at an endosomal pH value of a cancer cell, which would make these cyclodextrin derivatives the potential carriers for anticancer drugs.


Assuntos
Acetatos/química , Antineoplásicos/química , Ciclodextrinas/química , Portadores de Fármacos/química , Propionatos/química , Acetatos/síntese química , Ciclodextrinas/síntese química , Preparações de Ação Retardada/síntese química , Preparações de Ação Retardada/química , Doxorrubicina/química , Portadores de Fármacos/síntese química , Liberação Controlada de Fármacos , Concentração de Íons de Hidrogênio , Irinotecano/química , Propionatos/síntese química , Topotecan/química
16.
Bioconjug Chem ; 29(4): 1428-1437, 2018 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-29470084

RESUMO

Molecular imaging requires the specific accumulation of contrast agents at the target. To exploit the superb resolution of MRI for applications in molecular imaging, gadolinium chelates, as the MRI contrast agents (CA), have to be conjugated to a specific vector able to recognize the epitope of interest. Several Gd(III)-chelates can be chemically linked to the same binding vector in order to deliver multiple copies of the CA (multimers) in a single targeting event thus increasing the sensitivity of the molecular probe. Herein three novel bifunctional agents, carrying one functional group for the bioconjugation to targeting vectors and four Gd(III)-AAZTA chelate functions for MRI contrast enhancement (AAZTA = 6-amino-6-methylperhydro-1,4-diazepinetetraacetic acid), are reported. The relaxivity in the tetrameric derivatives is 16.4 ± 0.2 mMGd-1 s-1 at 21.5 MHz and 25 °C, being 2.4-fold higher than that of parent, monomeric Gd(III)-AAZTA. These compounds can be used as versatile building blocks to insert preformed, high relaxivity, and high density Gd-centers to biological targeting vectors. As an example, we describe the use of these bifunctional Gd(III)-chelates to label a fibrin-targeting peptide.


Assuntos
Acetatos/síntese química , Azepinas/síntese química , Quelantes/síntese química , Meios de Contraste/síntese química , Gadolínio/química , Compostos Organometálicos/síntese química , Acetatos/química , Acetatos/metabolismo , Azepinas/química , Azepinas/metabolismo , Quelantes/química , Quelantes/metabolismo , Meios de Contraste/química , Meios de Contraste/metabolismo , Dimerização , Fibrina/metabolismo , Gadolínio/metabolismo , Humanos , Imagem por Ressonância Magnética , Compostos Organometálicos/química , Compostos Organometálicos/metabolismo , Ligação Proteica
17.
Eur J Med Chem ; 145: 649-660, 2018 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-29353720

RESUMO

The emergence and global spread of metallo-ß-lactamase (MBL) mediated resistance to almost all ß-lactam antibacterials poses a serious threat to public health. Since no clinically useful MBL inhibitors have been reported, there is an urgent need to develop new potent broad-spectrum MBL inhibitors effective against antibacterial resistance. Herein, we synthesized a set of 2-substituted ((S)-3-mercapto-2-methylpropanamido) acetic acid derivatives, some of which displayed potent inhibition with high ligand efficiency to the clinically relevant MBL subtypes, Verona Integron-encoded MBL (VIM)-2 and New Delhi MBL (NDM)-1. Kinetic studies revealed that the inhibitors are not strong zinc chelators in solution, and they bind reversibly to VIM-2 but dissociate very slowly. Crystallographic analyses revealed that they inhibit VIM-2 via chelating the active site zinc ions and interacting with catalytically important residues. Further cell- and zebrafish-based assays revealed that the inhibitors slightly increase susceptibility of E. coli cells expressing VIM-2 to meropenem, and they have no apparent toxicity to the viability of HEK293T cells and the zebrafish embryogenesis.


Assuntos
Acetatos/farmacologia , Inibidores de beta-Lactamases/farmacologia , beta-Lactamases/metabolismo , Acetatos/síntese química , Acetatos/química , Animais , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Cinética , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Peixe-Zebra , Inibidores de beta-Lactamases/síntese química , Inibidores de beta-Lactamases/química
18.
ChemSusChem ; 11(4): 726-734, 2018 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-29372624

RESUMO

It is of great significance to convert platform molecules and their derivatives into high value-added alcohols, which have multitudinous applications. This study concerns systematic conversion of 2-methyltetrahydrofuran (MTHF), which is obtained from furfural, into 1-pentanol acetate (PA) and 1,4-pentanediol acetate (PDA). Reaction parameters, such as the Lewis acid species, reaction temperature, and hydrogen pressure, were investigated in detail. 1 H NMR spectroscopy and reaction dynamics study were also conducted to help clarify the reaction mechanism. Results suggested that cleavage of the primary alcohol acetate was less facile than that of the secondary alcohol acetate, with the main product being PA. A PA yield of 91.8 % (150 °C, 3 MPa H2 , 30 min) was achieved by using Pd/C and Sc(OTf)3 as a cocatalytic system and an 82 % yield of PDA was achieved (150 °C, 30 min) by using Sc(OTf)3 catalyst. Simultaneously, the efficient conversion of acetic esters into alcohols by simple saponification was carried out and led to a good yield.


Assuntos
Acetatos/síntese química , Álcoois/síntese química , Furanos/química , Catálise , Mesilatos , Paládio , Pentanóis/síntese química , Pressão , Escândio , Temperatura Ambiente
19.
Chem Biol Drug Des ; 91(3): 781-788, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29130625

RESUMO

The biological behavior of 68 Ga-based radiopharmaceuticals can be significantly affected by the chelators' attributes (size, charge, lipophilicity). Thus, this study aimed at examining the influence of three different chelators, DOTAGA, NODAGA, and HBED-CC on the distribution pattern of 68 Ga-labeled NGR peptides targeting CD13 receptors. 68 Ga-DOTAGA-c(NGR), 68 Ga-NODAGA-c(NGR), and 68 Ga-HBED-CC-c(NGR) were observed to be hydrophilic with respective log p values being -3.5 ± 0.2, -3.3 ± 0.08, and -2.8 ± 0.14. The three radiotracers exhibited nearly similar uptake in human fibrosarcoma HT-1080 tumor cells with 86%, 63%, and 33% reduction during blocking studies with unlabeled cNGR peptide for 68 Ga-DOTAGA-c(NGR), 68 Ga-NODAGA-c(NGR), and 68 Ga-HBED-CC-c(NGR), respectively, indicating higher receptor specificity of the first two radiotracers. The neutral radiotracer 68 Ga-NODAGA-c(NGR) demonstrated better target-to-non-target ratios during in vivo studies compared to its negatively charged counterparts, 68 Ga-DOTAGA-c(NGR) and 68 Ga-HBED-CC-c(NGR). The three radiotracers had similar HT-1080 tumor uptake and being hydrophilic exhibited renal excretion with minimal uptake in non-target organs. Significant reduction (p < .005) in HT-1080 tumor uptake of the radiotracers was observed during blocking studies. It may be inferred from these studies that the three radiotracers are promising probes for in vivo imaging of CD13 receptor expressing cancer sites; however, 68 Ga-NODAGA-c(NGR) is a better candidate.


Assuntos
Acetatos , Quelantes , Sistemas de Liberação de Medicamentos/métodos , Etilenodiaminas , Radioisótopos de Gálio , Compostos Heterocíclicos com 1 Anel , Imagem Molecular/métodos , Neoplasias , Oligopeptídeos , Compostos Radiofarmacêuticos , Acetatos/síntese química , Acetatos/química , Acetatos/farmacologia , Linhagem Celular Tumoral , Quelantes/síntese química , Quelantes/química , Quelantes/farmacologia , Etilenodiaminas/síntese química , Etilenodiaminas/química , Etilenodiaminas/farmacologia , Radioisótopos de Gálio/química , Radioisótopos de Gálio/farmacologia , Compostos Heterocíclicos com 1 Anel/síntese química , Compostos Heterocíclicos com 1 Anel/química , Compostos Heterocíclicos com 1 Anel/farmacologia , Humanos , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Oligopeptídeos/síntese química , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacologia
20.
J Am Chem Soc ; 139(42): 15022-15032, 2017 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-29022341

RESUMO

The Rh(I)-catalyzed allenic Pauson-Khand reaction (APKR) is an efficient, redox-neutral method of synthesizing α-acyloxy cyclopentenones. An enantioselective APKR could provide access to chiral, nonracemic α-acyloxy and α-hydroxy cyclopentenones and their corresponding redox derivatives, such as thapsigargin, a cytotoxic natural product with potent antitumor activity. Rapid scrambling of axial chirality of allenyl acetates in the presence of Rh(I) catalysts enables the conversion of racemic allene to enantiopure cyclopentenone product in a dynamic kinetic asymmetric transformation (DyKAT). A combined experimental and computational approach was taken to develop an effective catalytic system to achieve the asymmetric transformation. The optimization of the denticity, and steric and electronic properties of the ancillary ligand (initially (S)-MonoPhos, 58:42 er), afforded a hemilabile bidentate (S)-MonoPhos-alkene-Rh(I) catalyst that provided α-acyloxy cyclopentenone product in up to 14:86 er. Enantioselectivity of the Rh(I)-(S)-MonoPhos-alkene catalyst was rationalized using ligand-substrate steric interactions and distortion energies in the computed transition states. This asymmetric APKR of allenyl acetates is a rare example of a Type I DyKAT reaction of an allene, the first example of DyKAT in a cyclocarbonylation reaction, and the first catalyst-controlled enantioselective APKR.


Assuntos
Acetatos/química , Ciclopentanos/síntese química , Acetatos/síntese química , Alcenos/química , Catálise , Ciclopentanos/química , Cinética , Ligantes , Reprodutibilidade dos Testes , Rodaminas/química , Estereoisomerismo , Tapsigargina/síntese química , Tapsigargina/química
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA