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1.
Org Biomol Chem ; 18(5): 920-930, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-31922164

RESUMO

By choosing pyridostatin (PDS) with high thermal stabilization towards mixed-type G-quadruplexes as the monomer in dimers, three novel polyether-tethered PDS dimers (1a-c) were first synthesized and their interaction with human telomere G-quadruplex dimers (G2T1) was studied. Through the regulation of the linker length in PDS dimers, the dimer with a medium-length polyether linker (1b) showed higher binding selectivity and thermal stabilization (ΔTm = 29.5 °C) towards antiparallel G2T1 over G-quadruplex monomers (G1). Furthermore, the dimer with the longest-length polyether linker (1c) showed higher binding selectivity and thermal stabilization towards mixed-type G2T1 over mixed-type G1, c-kit 1, c-kit 2, c-myc and ds DNA. This work provides new insights into the development of G2T1 binders, especially mixed-type G2T1 binders, which could be promoted by a polymer formed with a mixed-type G-quadruplex binder. In addition, dimer 1c exhibited stronger telomerase inhibition than dimers 1a and 1b.


Assuntos
Aminoquinolinas/química , Dimerização , Quadruplex G , Ácidos Picolínicos/química , Telômero/metabolismo , Aminoquinolinas/síntese química , Calorimetria , Dicroísmo Circular , Inibidores Enzimáticos/farmacologia , Humanos , Cinética , Ácidos Picolínicos/síntese química , Telomerase/antagonistas & inibidores , Termodinâmica
2.
Eur J Med Chem ; 168: 315-329, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30826508

RESUMO

Two series of picolinamide derivatives bearing (thio)urea and dithiocarbamate moieties were designed and synthesized as VEGFR-2 kinase inhibitors. All the new compounds were screened for their cytotoxic activity against A549 cancer cell line and VEGFR-2 inhibitory activity. Compounds 7h, 9a and 9l showed potent inhibitory activity against VEGFR-2 kinase with IC50 values of 87, 27 and 94 nM, respectively in comparison to sorafenib (IC50 = 180 nM) as a reference. Compounds 7h, 9a and 9l were further screened for their antitumor activity against specific resistant human cancer cell lines from different origins (Panc-1, OVCAR-3, HT29 and 786-O cell lines) where compound 7h showed significant cell death in most of them. Multi-kinase inhibition assays were performed for the most potent VEGFR-2 inhibitors where compound 7h showed enhanced potency towards EGFR, HER-2, c-MET and MER kinases. Cell cycle analysis of A549 cells treated with 9a showed cell cycle arrest at G2/M phase and pro-apoptotic activity as indicated by annexin V-FITC staining.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Simulação de Acoplamento Molecular , Ácidos Picolínicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Ácidos Picolínicos/síntese química , Ácidos Picolínicos/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
3.
Bioorg Chem ; 86: 513-537, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30782571

RESUMO

Cancer is the second most important cause of death worldwide. There is always a demand for new anticancer drugs and continuously a wide variety of natural and synthetic compounds were developed by the researchers. Nowadays, a large number of drugs in clinical practice were found to have a high incidence of side effect and multidrug conflict. The development of novel less toxic, low cost and very energetic N-methylpicolinamide-bearing hybrids is a hot research topic in the community of medicinal chemistry. Herein we highlight the current advances in the synthesis of picolinamide-containing heterocyclic compounds as potent anticancer agents. In addition, briefly explore their structure-activity relationship studies for the inspiration of the innovation and development of more potent and effective drugs against various death-causing cancer diseases.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Ácidos Picolínicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Sítios de Ligação/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Micro-Ondas , Estrutura Molecular , Ácidos Picolínicos/síntese química , Ácidos Picolínicos/química , Relação Estrutura-Atividade
4.
Mol Pharm ; 16(3): 978-986, 2019 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-30648870

RESUMO

Development of an effective and potent RNA delivery system remains a challenge for the clinical application of RNA therapeutics. Herein, we describe the development of an RNA delivery platform derived from self-assembled bicontinuous cubic lyotropic liquid crystalline phases, functionalized with zinc coordinated lipids. These metallo-cubosomes were prepared from a series of novel lipidic zinc(II)-bis(dipicolylamine) (Zn2BDPA)) complexes admixed with glycerol monooleate (GMO). The zinc metallo-cubosomes showed the high affinity to siRNA through interaction between Zn2BDPA and the phosphate groups of RNA molecules. Using a combination of dynamic light scattering (DLS), small-angle X-ray scattering (SAXS), and cryogenic transmission electron microscopy (cryo-TEM), we demonstrated that a variety of Zn2BDPA lipid derivatives can be loaded into GMO cubosomes and the introduction of Zn2BDPA lipids effected an internal cubic phase transition of the resulting metallo-cubosomes. The findings of this study lay the foundations for the development of a new class of noncationic lipid-based encapsulation systems, metallo-cubosomes for RNA therapeutic delivery.


Assuntos
Sistemas de Liberação de Medicamentos , Glicerídeos/química , Nanopartículas/química , Compostos Organometálicos/química , Ácidos Picolínicos/química , RNA Interferente Pequeno/química , Células A549 , Animais , Células CHO , Sobrevivência Celular/efeitos dos fármacos , Cricetulus , Difusão Dinâmica da Luz , Inativação Gênica , Humanos , Microscopia Eletrônica de Transmissão , Compostos Organometálicos/síntese química , Transição de Fase , Ácidos Picolínicos/síntese química , Ligação Proteica , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/uso terapêutico , Espalhamento a Baixo Ângulo , Difração de Raios X
5.
Bioorg Med Chem ; 27(3): 483-491, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30611634

RESUMO

Metabotropic glutamate receptor 2 (mGluR2) has been suggested as a therapeutic target for treating schizophrenia-like symptoms arising from increased glutamate transmission in the human forebrain. However, no reliable positron emission tomography (PET) radiotracer allowing for in vivo visualization of mGluR2 in the human brain is currently available. In this study, we synthesized 4-(2-fluoro-4-[11C]methoxyphenyl)-5-((2-methylpyridin-4-yl)methoxy)picolinamide ([11C]1) and evaluated its potential as a PET tracer for imaging mGluR2 in the rodent brain. Compound 1, a negative allosteric modulator (NAM) of mGluR2, showed high in vitro binding affinity (IC50: 26 nM) for mGluR2 overexpressed in human cells. [11C]1 was synthesized by O-[11C]methylation of the phenol precursor 2 with [11C]methyl iodide. After the reaction, HPLC purification and formulation, [11C]1 of 7.4 ±â€¯2.8 GBq (n = 8) was obtained from [11C]carbon dioxide of 22.5 ±â€¯4.8 GBq (n = 8) with >99% radiochemical purity and 70 ±â€¯32 GBq/µmol (n = 8) molar activity at the end of synthesis. In vitro autoradiography for rat brains showed that [11C]1 binding was heterogeneously distributed in the cerebral cortex, striatum, hippocampus, and cerebellum. This pattern is consistent with the regional distribution pattern of mGluR2 in the rodent brain. The radioactivity was significantly reduced by self- or MNI-137 (a mGluR2 NAM) blocking. Small-animal PET studies indicated a low in vivo specific binding of [11C]1 in the rat brain. The brain uptake was increased in a P-glycoprotein and breast cancer resistant protein double knockout mouse, when compared to a wild-type mouse. While [11C]1 presented limited potential as an in vivo PET tracer for mGluR2, we suggested that it can be used as a lead compound for developing new radiotracers with improved in vivo brain properties.


Assuntos
Encéfalo/diagnóstico por imagem , Ácidos Picolínicos/química , Tomografia por Emissão de Pósitrons , Receptores de Glutamato Metabotrópico/análise , Animais , Encéfalo/metabolismo , Radioisótopos de Carbono , Relação Dose-Resposta a Droga , Humanos , Masculino , Camundongos , Camundongos Endogâmicos , Camundongos Knockout , Estrutura Molecular , Ácidos Picolínicos/síntese química , Ácidos Picolínicos/farmacocinética , Traçadores Radioativos , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Distribuição Tecidual
6.
Bioorg Med Chem Lett ; 29(1): 47-50, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30446311

RESUMO

This letter describes the further chemical optimization of VU0424238 (auglurant), an mGlu5 NAM clinical candidate that failed in non-human primate (NHP) 28 day toxicology due to accumulation of a species-specific aldehyde oxidase (AO) metabolite of the pyrimidine head group. Here, we excised the pyrimidine moiety, identified the minimum pharmacophore, and then developed a new series of saturated ether head groups that ablated any AO contribution to metabolism. Putative back-up compounds in this novel series provided increased sp3 character, uniform CYP450-mediated metabolism across species, good functional potency and high CNS penetration. Key to the optimization was a combination of matrix and iterative libraries that allowed rapid surveillance of multiple domains of the allosteric ligand.


Assuntos
Descoberta de Drogas , Ácidos Picolínicos/farmacologia , Receptor de Glutamato Metabotrópico 5/antagonistas & inibidores , Regulação Alostérica/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Humanos , Ligantes , Estrutura Molecular , Ácidos Picolínicos/síntese química , Ácidos Picolínicos/química , Ratos , Receptor de Glutamato Metabotrópico 5/metabolismo , Relação Estrutura-Atividade
7.
J Am Chem Soc ; 140(49): 17071-17078, 2018 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-30485079

RESUMO

Insoluble BaSO4 scale is a costly and time-consuming problem in the petroleum industry. Clearance of BaSO4-impeded pipelines requires chelating agents that can efficiently bind Ba2+, the largest nonradioactive +2 metal ion. Due to the poor affinity of currently available chelating agents for Ba2+, however, the dissolution of BaSO4 remains inefficient, requiring very basic solutions of ligands. In this study, we investigated three diaza-18-crown-6 macrocycles bearing different pendent arms for the chelation of Ba2+ and assessed their potential for dissolving BaSO4 scale. Remarkably, the bis-picolinate ligand macropa exhibits the highest affinity reported to date for Ba2+ at pH 7.4 (log K' = 10.74), forming a complex of significant kinetic stability with this large metal ion. Furthermore, the BaSO4 dissolution properties of macropa dramatically surpass those of the state-of-the-art ligands DTPA and DOTA. Using macropa, complete dissolution of a molar equivalent of BaSO4 is reached within 30 min at room temperature in pH 8 buffer, conditions under which DTPA and DOTA only achieve 40% dissolution of BaSO4. When further applied for the dissolution of natural barite, macropa also outperforms DTPA, showing that this ligand is potentially valuable for industrial processes. Collectively, this work demonstrates that macropa is a highly effective chelator for Ba2+ that can be applied for the remediation of BaSO4 scale.


Assuntos
Sulfato de Bário/química , Quelantes/química , Éteres de Coroa/química , Ácidos Picolínicos/química , Bário/química , Quelantes/síntese química , Complexos de Coordenação/síntese química , Éteres de Coroa/síntese química , Ligantes , Ácidos Picolínicos/síntese química , Solubilidade/efeitos dos fármacos
9.
Org Biomol Chem ; 16(23): 4261-4271, 2018 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-29701218

RESUMO

In view of the excellent copper(ii) and 64-copper(ii) complexation of a TE1PA ligand, a monopicolinate cyclam, in both aqueous medium and in vivo, we looked for a way to make it bifunctional, while maintaining its chelating properties. Overcoming the already known drawback of grafting via its carboxyl group, which is essential to the overall properties of the ligand, a TE1PA bifunctional derivative bearing an additional isothiocyanate coupling function on a carbon atom of the macrocyclic ring was synthesized. This led to an architecture that is comparable to that of other commercially available bifunctional copper(ii) chelators such as p-SCN-Bn-DOTA already used in clinical trials for 64Cu-immuno-PET imaging. The C-functionalization of TE1PA on one carbon atom in the ß-N position of the cyclam backbone was successfully achieved by adapting our patented methodology to the huge challenge, allowing the regiospecific mono-N-functionalization of the unsymmetrical ligand. The obtained ligand p-SCN-Bn-TE1PA was coupled to a 9E7.4 murine antibody (mAb), an IgG2a anti CD-138 for multiple myeloma (MM) targeting. The conjugation efficiency was assessed by looking at the 64Cu radiolabeling and the radiopharmaceutical 64Cu-9E7.4-p-SCN-Bn-TE1PA immunoreactivity, and in particular by comparing with 9E7.4-p-SCN-Bn-NOTA and 9E7.4-p-SCN-Bn-DOTA obtained from commercial and presumably highly efficient chelators NOTA and DOTA, respectively. The results are quite clear, showing that p-SCN-Bn-TE1PA has a coupling rate 5 times higher and an immunoreactivity 1.5 to 2 times greater than those of its two competitors. p-SCN-Bn-TE1PA also outperforms TE1PA conjugated via its carboxylic function on the same antibody. The first 64Cu-immuno-PET preclinical study in a syngeneic model of MM was performed, confirming the good in vivo properties of 64Cu-9E7.4-p-SCN-Bn-TE1PA for PET imaging, considering the high clearance even after 24 h and the particularly important tumor-to-liver ratio that was increasing at 48 h.


Assuntos
Quelantes/farmacologia , Complexos de Coordenação/farmacologia , Imunoconjugados/farmacologia , Mieloma Múltiplo/diagnóstico por imagem , Ácidos Picolínicos/farmacologia , Compostos Radiofarmacêuticos/farmacologia , Animais , Anticorpos Monoclonais/imunologia , Linhagem Celular Tumoral , Quelantes/síntese química , Complexos de Coordenação/síntese química , Radioisótopos de Cobre , Imunoconjugados/imunologia , Camundongos , Mieloma Múltiplo/imunologia , Ácidos Picolínicos/síntese química , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/síntese química , Sindecana-1/imunologia
10.
Bioorg Med Chem Lett ; 28(4): 606-611, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29395980

RESUMO

In previous study, a series of benzamides was identified as potent antipsychotic agents. As a continuation of the program to discover novel antipsychotics, herein we reported the evaluation of a series of pyridinecarboxamide derivatives. The most promising compound 7h not only held good activities on dopamine D2, serotonin 5-HT1A and 5-HT2A receptors, but also exhibited low potency for α1A, H1 and 5-HT2C receptors, indicating a low propensity of side effects like orthostatic hypotension and weight gain. Furthermore, 7h exhibited more potent antipsychotic-like effect than aripiprazole in behavioral studies. The preliminary results were promising enough for further research around this scaffold.


Assuntos
Antipsicóticos/farmacologia , Ácidos Picolínicos/farmacologia , Animais , Antipsicóticos/síntese química , Antipsicóticos/química , Antipsicóticos/metabolismo , Aripiprazol/farmacologia , Antagonistas dos Receptores de Dopamina D2/síntese química , Antagonistas dos Receptores de Dopamina D2/química , Antagonistas dos Receptores de Dopamina D2/metabolismo , Antagonistas dos Receptores de Dopamina D2/farmacologia , Humanos , Masculino , Camundongos Endogâmicos ICR , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Ácidos Picolínicos/síntese química , Ácidos Picolínicos/química , Ácidos Picolínicos/metabolismo , Risperidona/farmacologia , Antagonistas do Receptor 5-HT1 de Serotonina/síntese química , Antagonistas do Receptor 5-HT1 de Serotonina/química , Antagonistas do Receptor 5-HT1 de Serotonina/metabolismo , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia , Antagonistas do Receptor 5-HT2 de Serotonina/síntese química , Antagonistas do Receptor 5-HT2 de Serotonina/química , Antagonistas do Receptor 5-HT2 de Serotonina/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Relação Estrutura-Atividade
11.
J Enzyme Inhib Med Chem ; 33(1): 110-114, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29166796

RESUMO

A series of benzamide and picolinamide derivatives containing dimethylamine side chain (4a-4c and 7a-7i) were synthesised and evaluated for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity in vitro. Structure-activity relationship investigation revealed that the substituted position of dimethylamine side chain markedly influenced the inhibitory activity and selectivity against AChE and BChE. In addition, it seemed that the bioactivity of picolinamide amide derivatives was stronger than that of benzamide derivatives. Among them, compound 7a revealed the most potent AChE inhibitory activity (IC50: 2.49 ± 0.19 µM) and the highest selectivity against AChE over BChE (Ratio: 99.40). Enzyme kinetic study indicated that compound 7a show a mixed-type inhibition against AChE. The molecular docking study revealed that this compound can bind with both the catalytic site and the peripheral site of AChE.


Assuntos
Benzamidas/farmacologia , Inibidores da Colinesterase/farmacologia , Dimetilaminas/farmacologia , Ácidos Picolínicos/farmacologia , Acetilcolinesterase/metabolismo , Amidas/síntese química , Amidas/química , Amidas/farmacologia , Animais , Benzamidas/síntese química , Benzamidas/química , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Dimetilaminas/química , Relação Dose-Resposta a Droga , Enguias , Humanos , Modelos Moleculares , Estrutura Molecular , Ácidos Picolínicos/síntese química , Ácidos Picolínicos/química , Relação Estrutura-Atividade
12.
Bioorg Med Chem ; 26(1): 245-256, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29203143

RESUMO

Four series of N-methylpicolinamide moiety and thienopyrimidine moiety bearing pyridazinone were designed and synthesized and evaluated for the IC50 values against three cancer cell lines (A549, HepG2 and MCF-7) and some selected compounds were further evaluated for the activity against c-Met, Flt-3, VEGFR-2, c-Kit and EGFR kinases. Three compounds (35, 39 and 43) showed more active than positive control Foretinib against A549, HepG2 and MCF-7 cell lines. The most promising compound 43 showed superior activity against A549, HepG2 and MCF-7, with the IC50 values of 0.58 ±â€¯0.15 µM, 0.47 ±â€¯0.06 µM and 0.74 ±â€¯0.12 µM, which were 3.73-5.39-fold more activity than Foretinib, respectively. The experiments of enzyme-based showed that 43 restrain the c-Met selectively, with the IC50 values of 16 nM, which showed equal activity to Foretinib (14 nM) and better than the compound 5 (90 nM). Moreover, AO and Annexin V/PI staining and docking studies were carried out.


Assuntos
Antineoplásicos/farmacologia , Ácidos Picolínicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Pirimidinas/farmacologia , Amidas/síntese química , Amidas/química , Amidas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Ácidos Picolínicos/síntese química , Ácidos Picolínicos/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-met/metabolismo , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade
13.
Molecules ; 22(12)2017 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-29186917

RESUMO

l-Dopa, the metabolic precursor of dopamine, is the treatment of choice for the symptomatic relief of the advanced stages of Parkinson's disease. The oral bioavailability of l-dopa, however, is only about 10% to 30%, and less than 1% of the oral dose is estimated to reach the brain unchanged. l-Dopa's physicochemical properties are responsible for its poor bioavailability, short half-life and the wide range of inter- and intrapatient variations of plasma levels. An l-dopa-lazabemide prodrug is proposed to overcome the problems associated with l-dopa absorption. Lazabemide is a monoamine oxidase (MAO)-B inhibitor, a class of compounds that slows the depletion of dopamine stores in Parkinson's disease and elevates dopamine levels produced by exogenously administered l-dopa. l-Dopa was linked at the carboxylate with the primary aminyl functional group of lazabemide via an amide, a strategy which is anticipated to protect l-dopa against peripheral decarboxylation and possibly also enhance the membrane permeability of the prodrug. Selected physicochemical and biochemical properties of the prodrug were determined and included lipophilicity (logD), solubility, passive diffusion permeability, pKa, chemical and metabolic stability as well as cytotoxicity. Although oral and i.p. treatment of mice with the prodrug did not result in enhanced striatal dopamine levels, 3,4-dihydroxyphenylacetic acid (DOPAC) levels were significantly depressed compared to saline, l-dopa and carbidopa/l-dopa treatment. Based on the results, further preclinical evaluation of the l-dopa-lazabemide prodrug should be undertaken with the aim of discovering prodrugs that may be advanced to the clinical stages of development.


Assuntos
Levodopa/química , Inibidores da Monoaminoxidase/química , Doença de Parkinson/tratamento farmacológico , Ácidos Picolínicos/química , Pró-Fármacos/química , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Disponibilidade Biológica , Carbidopa/química , Carbidopa/farmacologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Dopamina/metabolismo , Combinação de Medicamentos , Células HeLa , Humanos , Levodopa/síntese química , Levodopa/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/farmacologia , Permeabilidade , Ácidos Picolínicos/síntese química , Ácidos Picolínicos/farmacologia , Pró-Fármacos/síntese química , Pró-Fármacos/farmacologia , Solubilidade , Relação Estrutura-Atividade
14.
Inorg Chem ; 56(20): 12457-12468, 2017 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-28972748

RESUMO

Ternary oxidovanadium(IV) complexes of curcumin (Hcur), dipicolylamine (dpa) base, and its derivatives having pendant noniodinated and di-iodinated boron-dipyrromethene (BODIPY) moiety (L1 and L2, respectively), namely, [VO(dpa)(cur)]ClO4 (1), [VO(L1)(cur)]ClO4 (2), and [VO(L2)(cur)]ClO4 (3) and their chloride salts (1a-3a) were prepared, characterized, and studied for anticancer activity. The chloride salts were used for biological studies due to their aqueous solubility. Complex 1 was structurally characterized by single-crystal X-ray crystallography. The complex has a VO2+ moiety bound to dpa ligand showing N,N,N-coordination in a facial mode, and curcumin is bound in its mono-anionic enolic form. The V-O(cur) distances are 1.950(18) and 1.977(16) Å, while the V-N bond lengths are 2.090(2), 2.130(2), and 2.290(2) Å. The bond trans to V═O is long due to trans effect. The complexes are stable in a solution phase over a long period of time of 48 h without showing any apparent degradation of the curcumin ligand. The diiodo-BODIPY ligand (L2) or Hcur alone showed limited solution stability in dark. The emissive BODIPY (L1) containing complex 2a showed preferential mitochondrial localization in MCF-7 cells in cellular imaging experiments. The cytotoxicity of the complexes was studied by MTT assay. The BODIPY complex 3a showed excellent photodynamic therapy effect in visible light (400-700 nm) giving IC50 values of 2-6 µM in HeLa and MCF-7 cancer cells, while being less toxic in dark (∼100 µM). The cell death was apoptotic in nature involving reactive oxygen species (ROS). Mechanistic data from pUC19 DNA photocleavage studies revealed photogenerated ROS as primarily 1O2 from the BODIPY moiety and ·OH radicals from the curcumin ligand.


Assuntos
Antineoplásicos/farmacologia , Compostos de Boro/farmacologia , Complexos de Coordenação/farmacologia , Curcumina/análogos & derivados , Curcumina/farmacologia , Mitocôndrias/metabolismo , Fármacos Fotossensibilizantes/farmacologia , Vanádio/química , Aminas/síntese química , Aminas/química , Aminas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/efeitos da radiação , Apoptose/efeitos dos fármacos , Compostos de Boro/síntese química , Compostos de Boro/química , Compostos de Boro/efeitos da radiação , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/efeitos da radiação , Curcumina/síntese química , Curcumina/efeitos da radiação , Clivagem do DNA , Estabilidade de Medicamentos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Ligantes , Luz , Mitocôndrias/genética , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/efeitos da radiação , Ácidos Picolínicos/síntese química , Ácidos Picolínicos/química , Ácidos Picolínicos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Oxigênio Singlete/química
15.
Bioconjug Chem ; 28(7): 1878-1892, 2017 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-28581724

RESUMO

A series of zinc(II) dipicolylamine (ZnDPA)-based drug conjugates have been synthesized to probe the potential of phosphatidylserine (PS) as a new antigen for small molecule drug conjugate (SMDC) development. Using in vitro cytotoxicity and plasma stability studies, PS-binding assay, in vivo pharmacokinetic studies, and maximum tolerated dose profiles, we provided a roadmap and the key parameters required for the development of the ZnDPA based drug conjugate. In particular, conjugate 24 induced tumor regression in the COLO 205 xenograft model and exhibited a more potent antitumor effect with a 70% reduction of cytotoxic payload compared to that of the marketed irinotecan when dosed at the same regimen. In addition to the validation of PS as an effective pharmacodelivery target for SMDC, our work also provided the foundation that, if applicable, a variety of therapeutic agents could be conjugated in the same manner to treat other PS-associated diseases.


Assuntos
Antineoplásicos/farmacocinética , Imunoconjugados/uso terapêutico , Terapia de Alvo Molecular/métodos , Compostos Organometálicos/imunologia , Fosfatidilserinas/imunologia , Ácidos Picolínicos/imunologia , Animais , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Humanos , Imunoconjugados/química , Imunoconjugados/farmacocinética , Compostos Organometálicos/síntese química , Compostos Organometálicos/farmacologia , Fosfatidilserinas/metabolismo , Ácidos Picolínicos/síntese química , Ácidos Picolínicos/farmacologia , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
16.
J Med Chem ; 60(12): 5072-5085, 2017 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-28530802

RESUMO

Preclinical evidence in support of the potential utility of mGlu5 NAMs for the treatment of a variety of psychiatric and neurodegenerative disorders is extensive, and multiple such molecules have entered clinical trials. Despite some promising results from clinical studies, no small molecule mGlu5 NAM has yet to reach market. Here we present the discovery and evaluation of N-(5-fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (27, VU0424238), a compound selected for clinical evaluation. Compound 27 is more than 900-fold selective for mGlu5 versus the other mGlu receptors, and binding studies established a Ki value of 4.4 nM at a known allosteric binding site. Compound 27 had a clearance of 19.3 and 15.5 mL/min/kg in rats and cynomolgus monkeys, respectively. Imaging studies using a known mGlu5 PET ligand demonstrated 50% receptor occupancy at an oral dose of 0.8 mg/kg in rats and an intravenous dose of 0.06 mg/kg in baboons.


Assuntos
Aminopiridinas/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Ácidos Picolínicos/farmacologia , Receptor de Glutamato Metabotrópico 5/metabolismo , Relação Estrutura-Atividade , Regulação Alostérica , Aminopiridinas/síntese química , Animais , Técnicas de Química Sintética , Células HEK293 , Ensaios de Triagem em Larga Escala/métodos , Humanos , Macaca fascicularis , Masculino , Camundongos Endogâmicos , Ácidos Picolínicos/síntese química , Ratos Sprague-Dawley , Receptor de Glutamato Metabotrópico 5/agonistas , Distribuição Tecidual
17.
ChemMedChem ; 12(11): 845-849, 2017 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-28482143

RESUMO

VIM-2 is one of the most common carbapenem-hydrolyzing metallo ß-lactamases (MBL) found in many drug-resistant Gram-negative bacterial strains. Currently, there is a lack of effective lead compounds with optimal therapeutic potential within our drug development pipeline. Here we report the discovery of 1-hydroxypyridine-2(1H)-thione-6-carboxylic acid (3) as a first-in-class metallo ß-lactamase inhibitor (MBLi) with a potent inhibition Ki of 13 nm against VIM-2 that corresponds to a remarkable 0.99 ligand efficiency. We further established that 3 can restore the antibiotic activity of amoxicillin against VIM-2-producing E. coli in a whole cell assay with an EC50 of 110 nm. The potential mode of binding of 3 from molecular modeling provided structural insights that could corroborate the observed changes in the biochemical activities. Finally, 3 possesses a low cytotoxicity (CC50 ) of 97 µm with a corresponding therapeutic index of 880, making it a promising lead candidate for further optimization in combination antibacterial therapy.


Assuntos
Ácidos Picolínicos/síntese química , Ácidos Picolínicos/farmacologia , Tionas/síntese química , Tionas/farmacologia , Inibidores de beta-Lactamases/química , Inibidores de beta-Lactamases/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Células HEK293 , Humanos , Concentração Inibidora 50 , Testes de Sensibilidade Microbiana , Modelos Moleculares , Ácidos Picolínicos/toxicidade , Pseudomonas aeruginosa/efeitos dos fármacos , Tionas/toxicidade , Inibidores de beta-Lactamases/toxicidade , beta-Lactamases/metabolismo
18.
BMC Med Imaging ; 17(1): 27, 2017 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-28431519

RESUMO

BACKGROUND: Phosphatidylserine (PS)-targeting positron emission tomography (PET) imaging with labeled small-molecule tracer is a crucial non-invasive molecule imaging method of apoptosis. In this study, semi-automatic radiosynthesis and biodistribution of N-(2-18F-fluoropropionyl)-bis(zinc(II)-dipicolylamine) (18F-FP-DPAZn2), as a potential small-molecule tracer for PET imaging of cell death in Alzheimer's disease (AD) model, were performed. METHODS: 18F-FP-DPAZn2 was synthesized on the modified PET-MF-2V-IT-I synthesizer. Biodistribution was determined in normal mice and PET images of AD model were obtained on a micro PET-CT scanner. RESULTS: With the modified synthesizer, the total decay-corrected radiochemical yield of 18F-FP-DPAZn2 was 35 ± 6% (n = 5) from 18F- within 105 ± 10 min. Biodistribution results showed that kidney has the highest uptake of 18F-FP-DPAZn2. The uptake of radioactivity in brain kept at a relatively low level during the whole observed time. In vivo 18F-FP-DPAZn2 PET images demonstrated more accumulation of radioactivity in the brain of AD model mice than that in the brain of normal mice. CONCLUSIONS: The semi-automatic synthetic method provides a slightly higher radiochemical yield and shorter whole synthesis time of 18F-FP-DPAZn2 than the manual operation method. This improved method can give enough radioactivity and high radiochemical purity of 18F-FP-DPAZn2 for in vivo PET imaging. The results show that 18F-FP-DPAZn2 seems to be a potential cell death tracer for AD imaging.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Radioisótopos de Flúor/farmacocinética , Marcação por Isótopo/métodos , Compostos Organometálicos/síntese química , Compostos Organometálicos/farmacocinética , Ácidos Picolínicos/síntese química , Ácidos Picolínicos/farmacocinética , Animais , Encéfalo/diagnóstico por imagem , Composição de Medicamentos/métodos , Radioisótopos de Flúor/química , Taxa de Depuração Metabólica , Camundongos , Imagem Molecular/métodos , Especificidade de Órgãos , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Robótica/métodos , Distribuição Tecidual
19.
Med Chem ; 13(2): 176-185, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27855595

RESUMO

BACKGROUND: Sorafenib is an important VEGFR2/KDR inhibitor which is widely used for the treatment of cancer. OBJECTIVE: In this paper, two series of sorafenib analogues N-(3-fluoro-4-(pyridin-4-yloxy)phenyl)-4- phenylpicolinamides(13a-k) and N-(3-fluoro-4-(pyridin-4-yloxy)phenyl)-5-phenylpicolinamides (14a-k) were designed and synthesized. METHODS: Their structures were confirmed by various analytical methods, such as 1 H and 13 C NMR, m.p., MS, HRMS. All of them were evaluated for IC50 values against three cancer cell lines (A549, PC-3 and MCF-7). RESULTS: Eleven of the synthesized compounds showed moderate to excellent cytotoxicity activity against different cancer cells, whose potency from single-digit µM to nanomolar range. And five of them were equal to more potent than sorafenib against one or more cell lines. The most promising compound 14c showed excellent antitumor activities against PC-3 and MCF-7 cell lines with IC50 values of 2.62±1.07 µM and 1.14±0.92 µM, which were 1.15 to 2.75-fold more active than sorafenib (3.03±1.01 µM, 3.14±1.65 µM), respectively. CONCLUSION: Structure-activity relationships (SARs) and docking studies indicated that the replacement of diarylurea of sorafenib with phenylpicolinamide moiety benefited to the activity. The position of aryl group and the substituents of aryl group had a great influence on antitumor activity and selectivity. The aryl groups with the substitute of alkyl groups (-CH3), halogen atoms (-F,Cl) were favorable to the cytotoxicity. However, this series of compounds showed moderate activity against VEGFR2/KDR kinase. Mechanism of target compounds was not quite clear and further study will be carried out to identify the possible target.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Simulação de Acoplamento Molecular , Niacinamida/análogos & derivados , Compostos de Fenilureia/química , Ácidos Picolínicos/síntese química , Ácidos Picolínicos/farmacologia , Amidas/síntese química , Amidas/química , Amidas/metabolismo , Amidas/farmacologia , Antineoplásicos/química , Antineoplásicos/metabolismo , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Niacinamida/química , Ácidos Picolínicos/química , Ácidos Picolínicos/metabolismo , Conformação Proteica , Sorafenibe , Relação Estrutura-Atividade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
20.
J Med Chem ; 60(2): 722-748, 2017 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-27982588

RESUMO

Autotaxin (ATX) is a secreted enzyme responsible for the hydrolysis of lysophosphatidylcholine (LPC) to the bioactive lysophosphatidic acid (LPA) and choline. The ATX-LPA signaling pathway is implicated in cell survival, migration, and proliferation; thus, the inhibition of ATX is a recognized therapeutic target for a number of diseases including fibrotic diseases, cancer, and inflammation, among others. Many of the developed synthetic inhibitors for ATX have resembled the lipid chemotype of the native ligand; however, a small number of inhibitors have been described that deviate from this common scaffold. Herein, we report the structure-activity relationships (SAR) of a previously reported small molecule ATX inhibitor. We show through enzyme kinetics studies that analogues of this chemotype are noncompetitive inhibitors, and by using a crystal structure with ATX we confirm the discrete binding mode.


Assuntos
Indóis/química , Inibidores de Fosfodiesterase/química , Diester Fosfórico Hidrolases/química , Ácidos Picolínicos/química , Sítios de Ligação , Cristalografia por Raios X , Indóis/síntese química , Cinética , Modelos Químicos , Simulação de Acoplamento Molecular , Inibidores de Fosfodiesterase/síntese química , Ácidos Picolínicos/síntese química , Relação Estrutura-Atividade
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