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1.
Anal Chem ; 91(18): 11803-11811, 2019 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-31426630

RESUMO

Kinases are widely distributed in nature and are implicated in many human diseases. Thus, an understanding of their activity and regulation is of fundamental importance. Several kinases are known to be inhibited by ADP. However, thorough investigation of this phenomenon is hampered by the lack of a simple and effective assay for studying this inhibition. We now present a quick, general approach for measuring the effects of reaction products on kinase activity. The method, based on isothermal titration calorimetry, is the first universal, reporter-free, continuous assay for probing kinase inhibition or activation by ADP. In applications to an aminoglycoside phosphotransferase [APH(3')-IIIa] and pantothenate kinases from Escherichia coli (EcPanK) and Pseudomonas aeruginosa (PaPanK), we found ADP to be an efficient inhibitor of all three kinases, with inhibition constant (Ki) values similar to or lower than the Michaelis-Menten constant (Km) values of ATP. Interestingly, ADP was an activator at low concentrations and an inhibitor at high concentrations for EcPanK. This unusual effect was quantitatively modeled and attributed to cooperative interactions between the two subunits of the dimeric enzyme. Importantly, our results suggest that, at typical bacterial intracellular concentrations of ATP and ADP (approximately 1.5 mM and 180 µM, respectively), all three kinases are partially inhibited by ADP, allowing enzyme activity to rapidly respond to changes in the levels of both metabolites.


Assuntos
Difosfato de Adenosina/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Difosfato de Adenosina/química , Trifosfato de Adenosina/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Calorimetria/métodos , Ativação Enzimática , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Canamicina/química , Canamicina/metabolismo , Cinética , Fosfotransferases (Aceptor do Grupo Álcool)/química , Pseudomonas aeruginosa/enzimologia , Reprodutibilidade dos Testes
2.
Chembiochem ; 19(19): 2107-2113, 2018 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-30059603

RESUMO

Aminoglycosides are a group of broad-spectrum antibiotics that have been used in the clinic for almost a century. The rapid spread of bacterial genes coding for aminoglycoside-modifying enzymes has, however, dramatically decreased the utility of aminoglycosides. We have previously reported several aminoglycoside potentiators that work by inhibiting aminoglycoside N-6'-acetyltransferase, one of the most common determinants of aminoglycoside resistance. Among these, prodrugs that combine the structure of an aminoglycoside with that of pantothenate into one molecule are especially promising. We report here a series of cellular studies to investigate the activity and mechanism of action of these prodrugs further. Our results reveal a new aminoglycoside resistance inhibitor, as well as the possibility that these prodrugs are transformed into more than one inhibitor in bacteria. We also report that the onset of the potentiators is rapid. Their low cell cytotoxicity, good stability, and potentiation of various aminoglycosides, against both Gram-positive and Gram-negative bacteria, make them interesting compounds for the development of new drugs.


Assuntos
Acetiltransferases/efeitos dos fármacos , Antibacterianos , Farmacorresistência Bacteriana/efeitos dos fármacos , Enterococcus faecium/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Pró-Fármacos , Aminoglicosídeos/metabolismo , Antibacterianos/química , Antibacterianos/farmacologia , Células HeLa , Humanos , Pró-Fármacos/química , Pró-Fármacos/farmacologia
3.
Bioorg Med Chem ; 26(22): 5896-5902, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30429095

RESUMO

Pantothenate kinase (PanK) catalyzes the transformation of pantothenate to 4'-phosphopantothenate, the first committed step in coenzyme A biosynthesis. While numerous pantothenate antimetabolites and PanK inhibitors have been reported for bacterial type I and type II PanKs, only a few weak inhibitors are known for bacterial type III PanK enzymes. Here, a series of pantothenate analogues were synthesized using convenient synthetic methodology. The compounds were exploited as small organic probes to compare the ligand preferences of the three different types of bacterial PanK. Overall, several new inhibitors and substrates were identified for each type of PanK.


Assuntos
Antibacterianos/farmacologia , Bacillus anthracis/efeitos dos fármacos , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Bacillus anthracis/enzimologia , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ligantes , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade
4.
Beilstein J Org Chem ; 12: 963-8, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27340487

RESUMO

Pantothenamides are known for their in vitro antimicrobial activity. Our group has previously reported a new stereoselective route to access derivatives modified at the geminal dimethyl moiety. This route however fails in the addition of large substituents. Here we report a new synthetic route that exploits the known allyl derivative, allowing for the installation of larger groups via cross-metathesis. The method was applied in the synthesis of a new pantothenamide with improved stability in human blood.

5.
Medicine (Baltimore) ; 103(15): e37722, 2024 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-38608101

RESUMO

RATIONALE: Due to the lack of specificity symptoms and site of onset of castleman disease (CD), it is difficult to diagnose and poses unique challenges for both patients and clinicians, leading to confusion in diagnosis and delays in treatment. To enhance understanding, we present 3 cases of CD treated at our hospital, including a single-center, multicenter, and mixed-type CD. PATIENT CONCERNS: Case 1: A 53-year-old female patient was admitted with a chief complaint of "abdominal pain and fever for 10 days." Marked enlargement of inguinal lymph nodes on both sides was observed. Case 2: A 58-year-old female patient was admitted with the main complaint of "discovering a left lower abdominal mass during a routine checkup for the past 10 days." Upon deep palpation, a palpable mass of approximately 5.0 * 3.0 cm was identified in the left lower abdomen. Case 3: A 40-year-old male patient was admitted with the main complaint of "progressive right upper abdominal and lumbar back pain for over 6 months." Computed tomography examination revealed multiple nodular soft tissue masses between the abdominal aorta and inferior vena cava, with the largest measuring 5.0 * 4.0 cm. DIAGNOSES: Based on the immunohistochemical results, the diagnoses for the 3 patients are as follows: Case 1: Multicentric Castleman's Disease (Mixed Type). Case 2: Pelvic Retroperitoneal Castleman Disease (Hyaline Vascular Type). Case 3: Castleman Disease Multicentric Type. INTERVENTION: Case 1: cyclophosphamide 0.6-1 g + vincristine 2 mg + methylprednisolone 50 mg/5 days. Cyclophosphamide 1 g + prednisone 30-50 mg/5 days. This alternating chemotherapy cycle is repeated every 6 months. Case 2: Laparoscopic pelvic mass excision surgery. Case 3: Surgical excision of the mass. OUTCOMES: Case 1: After a 43-month follow-up, the patient's general symptoms have improved compared to before, but regular chemotherapy is still necessary at present. Case 2: The patient did not take any medication postoperatively, and there has been no evidence of metastasis or recurrence during the 18-month follow-up. Case 3: The patient did not take any medication, and there has been no evidence of metastasis or recurrence during the 21-month follow-up. LESSONS SUBSECTIONS: The lack of specific signs on imaging studies and nonspecific blood tests increases the difficulty of diagnosis. However, tissue biopsy remains a feasible option. Therefore, we recommend conducting thorough examinations for suspected CD patients to reduce misdiagnosis and determine the CD type for effective targeted treatment.


Assuntos
Hiperplasia do Linfonodo Gigante , Feminino , Masculino , Humanos , Pessoa de Meia-Idade , Adulto , Hiperplasia do Linfonodo Gigante/diagnóstico , Dor Abdominal/etiologia , Aorta Abdominal , Biópsia , Ciclofosfamida , Estudos Multicêntricos como Assunto
6.
J Med Chem ; 64(8): 4478-4497, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33792339

RESUMO

Malaria-causing Plasmodium parasites are developing resistance to antimalarial drugs, providing the impetus for new antiplasmodials. Although pantothenamides show potent antiplasmodial activity, hydrolysis by pantetheinases/vanins present in blood rapidly inactivates them. We herein report the facile synthesis and biological activity of a small library of pantothenamide analogues in which the labile amide group is replaced with a heteroaromatic ring. Several of these analogues display nanomolar antiplasmodial activity against Plasmodium falciparum and/or Plasmodium knowlesi, and are stable in the presence of pantetheinase. Both a known triazole and a novel isoxazole derivative were further characterized and found to possess high selectivity indices, medium or high Caco-2 permeability, and medium or low microsomal clearance in vitro. Although they fail to suppress Plasmodium berghei proliferation in vivo, the pharmacokinetic and contact time data presented provide a benchmark for the compound profile likely required to achieve antiplasmodial activity in mice and should facilitate lead optimization.


Assuntos
Antimaláricos/química , Isoxazóis/química , Ácido Pantotênico/análogos & derivados , Tiadiazóis/química , Triazóis/química , Animais , Antimaláricos/metabolismo , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Células CACO-2 , Proliferação de Células/efeitos dos fármacos , Estabilidade de Medicamentos , Eritrócitos/citologia , Eritrócitos/parasitologia , Feminino , Meia-Vida , Humanos , Malária Falciparum/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Ácido Pantotênico/química , Ácido Pantotênico/metabolismo , Ácido Pantotênico/farmacologia , Ácido Pantotênico/uso terapêutico , Plasmodium falciparum/efeitos dos fármacos , Plasmodium knowlesi/efeitos dos fármacos , Relação Estrutura-Atividade
9.
ChemMedChem ; 13(24): 2677-2683, 2018 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-30370998

RESUMO

Pantothenamides are potent growth inhibitors of the malaria parasite Plasmodium falciparum. Their clinical use is, however, hindered due to the ubiquitous presence of pantetheinases in human serum, which rapidly degrade pantothenamides into pantothenate and the corresponding amine. We previously reported that replacement of the labile amide bond with a triazole ring not only imparts stability toward pantetheinases, but also improves activity against P. falciparum. A small library of new triazole derivatives was synthesized, and their use in establishing structure-activity relationships relevant to antiplasmodial activity of this family of compounds is discussed herein. Overall it was observed that 1,4-substitution on the triazole ring and use of an unbranched, one-carbon linker between the pantoyl group and the triazole are optimal for inhibition of intraerythrocytic P. falciparum growth. Our results imply that the triazole ring may mimic the amide bond with an orientation different from what was previously suggested for this amide bioisostere.


Assuntos
Amidas/síntese química , Antimaláricos/síntese química , Ácido Pantotênico/análogos & derivados , Ácido Pantotênico/síntese química , Plasmodium falciparum/efeitos dos fármacos , Triazóis/síntese química , Amidas/farmacologia , Antimaláricos/farmacologia , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Ácido Pantotênico/farmacologia , Relação Estrutura-Atividade , Triazóis/farmacologia
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