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2.
ACS Omega ; 7(20): 17083-17097, 2022 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-35647450

RESUMO

The anaplastic lymphoma kinase (ALK) is abnormally expressed and hyperactivated in a number of tumors and represents an ideal therapeutic target. Despite excellent clinical responses to ALK inhibition, drug resistance still represents an issue and novel compounds that overcome drug-resistant mutants are needed. We designed, synthesized, and evaluated a large series of azacarbazole inhibitors. Several lead compounds endowed with submicromolar potency were identified. Compound 149 showed selective inhibition of native and mutant drug-refractory ALK kinase in vitro as well as in a Ba/F3 model and in human ALK+ lymphoma cells. The three-dimensional (3D) structure of a 149:ALK-KD cocrystal is reported, showing extensive interaction through the hinge region and the catalytic lysine 1150.

3.
Eur J Med Chem ; 238: 114488, 2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35665691

RESUMO

The Anaplastic Lymphoma Kinase (ALK) is a therapeutic target for personalized medicine in selected cancers. Despite excellent clinical responses to ALK inhibitors, most patients develop drug resistance and relapse. New compounds with alternative binding modes are needed to overcome resistant mutants. Here we describe a medicinal chemistry effort to the design and development of novel ALK inhibitors based on a 4,6-substituted α-carboline scaffold. Active compounds were able to inhibit the gatekeeper L1196M mutant, in several cases better than the wild-type enzyme. Compound 43 showed potent non-ATP-competitive inhibition of wild-type and mutant ALK, including G1202R, in biochemical and cellular assays, as well as in xenograft mouse models.


Assuntos
Carbolinas , Receptores Proteína Tirosina Quinases , Quinase do Linfoma Anaplásico , Animais , Carbolinas/farmacologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Humanos , Camundongos , Mutação , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia
4.
J Org Chem ; 86(24): 17955-17964, 2021 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-34846894

RESUMO

We report a computational investigation of two reaction cascades occurring following the Claisen rearrangements of aryl propargyl ethers to the alternate ortho positions in unsymmetrical reactants. Our computations explain how substituents influence reactivity and regioselectivity. Rearrangement to the substituted ortho carbon leads to a tricyclo[3.2.1.0]octane core, while rearrangement to an unsubstituted ortho carbon leads to a benzopyran. Density functional theory with ωB97X-D indicates that these reactions involve rate-determining Claisen rearrangements followed by subsequent reaction cascades of the Claisen rearrangement products depending on the presence or absence of a substituent at the ortho carbon.

5.
ACS Med Chem Lett ; 11(5): 686-690, 2020 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-32435371

RESUMO

A synthetic sphingolipid related to a ring-constrained hydroxymethyl pyrrolidine analog of FTY720 that was known to starve cancer cells to death was chemically modified to include a series of alkoxy-tethered 3,6-substituted 1,2-pyridazines. These derivatives exhibited excellent antiproliferative activity against eight human cancer cell lines from four different cancer types. A 2.5- to 9-fold reduction in IC50 in these cell lines was observed relative to the lead compound, which lacked the appended heterocycle.

6.
Bioorg Med Chem Lett ; 29(18): 2681-2685, 2019 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-31383588

RESUMO

Inspired by the cytotoxicity of perphenazine toward cancer cells and its ability to activate the serine/threonine protein phosphatase 2A (PP2A), we prepared series of ether-carbon linked analogs of a constrained synthetic sphingolipid analog 3, known for its cytotoxicity, nutrient transporter down-regulation and vacuolation properties, incorporating the tricyclic neuroleptics phenoxazine and phenothiazine to represent hybrid structures with possible synergistic cytotoxic activity. While the original activity of the lead compound 3 was diminished by fusion with the phenoxazine or phenothiazine tethered moieties, the corresponding 3-pyridyltetryl ether analog 10 showed cytotoxicity and nutrient transporter down-regulation similar to the lead compound 3, although it separated these PP2A-dependent phenotypes from that of vacuolation.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Oxazinas/farmacologia , Fenotiazinas/farmacologia , Proteína Fosfatase 2/antagonistas & inibidores , Esfingolipídeos/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Camundongos , Estrutura Molecular , Oxazinas/química , Fenotiazinas/química , Proteína Fosfatase 2/metabolismo , Esfingolipídeos/química , Relação Estrutura-Atividade
7.
Eur J Med Chem ; 159: 217-242, 2018 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-30292898

RESUMO

A series of compounds containing pyrrolidine and pyrrolizidine cores with appended hydrophobic substituents were prepared as constrained analogs of FTY720 and phytosphingosine. The effect of these compounds on the viability of cancer cells, on downregulation of the nutrient transport systems, and on their ability to cause vacuolation was studied. An attempt to inhibit HDACs with some phosphate esters of our analogs was thwarted by our failure to reproduce the reported inhibitory action of FTY720-phosphate.


Assuntos
Antineoplásicos/farmacologia , Epigênese Genética/efeitos dos fármacos , Cloridrato de Fingolimode/farmacologia , Esfingosina/análogos & derivados , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Cloridrato de Fingolimode/análogos & derivados , Cloridrato de Fingolimode/química , Camundongos , Estrutura Molecular , Esfingosina/síntese química , Esfingosina/química , Esfingosina/farmacologia , Relação Estrutura-Atividade
8.
Org Lett ; 20(14): 4277-4280, 2018 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-29975546

RESUMO

A highly stereocontrolled total synthesis of (-)-yaequinolone J1 and (+)-yaequinolone J2 was accomplished using an Evans auxiliary to establish a syn-diol unit in an acyclic appendage to a preformed benzopyran core bearing a homoprenyl group. The first total synthesis of a complex member of this family of 3,4-dioxygenated 3,4-dihydro 4-aryl quinolin-2-(1 H)-ones also allowed the assignment of absolute stereochemistry, thereby suggesting the same for several members of this family of biogenetically related alkaloids hitherto reported with relative configurations of stereogenic carbons for some and absolute assignments relying on empirical data for others.

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