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1.
Chem Biol Interact ; 330: 109236, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32866467

RESUMO

A series of novel pyrrolopyrimidine urea derivatives were synthesized and evaluated for their anticancer activity against colon cancer cell lines. Compounds showed the remarkable cytotoxic activity on HCT-116 wt cell line. The most potent compound 4c (IC50 = 0.14 µM) induced apoptosis in HCT-116 wt and HCT-116 p53-/- cell lines. Otherwise, treatment of HCT-116 BAX-/-BAK-/- cells with compound 4c didn't lead to activation of apoptosis, suggesting that compound 4c induces apoptotic cell death by activating BAX/BAK-dependent pathway. Moreover, while the compound 4c increase the activation of caspase-3 and caspase-9 levels in HCT-116 wt and HCT-116 p53-/- cells, caspase-3 or caspase-9 activation was not observed in HCT-116 BAX-/-BAK-/- cells. In addition, compound 4c induced mitochondrial apoptosis in cells grown as oncospheroids, which better mimic the in vivo milieu of tumors. 4c treatment also activated JNK along with inhibition of prosurvival kinases such as Akt and ERK 1/2 in HCT-116 wt and HCT-116 p53 -/- cells as well as in HCT-116 BAX-/-BAK-/- cells. Notably, our results indicated that compound 4c induced mitochondrial apoptosis through activation p53-independent apoptotic signaling pathways.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Pirimidinas/farmacologia , Pirróis/farmacologia , Proteína Supressora de Tumor p53/fisiologia , Caspase 3/genética , Caspase 9/genética , Linhagem Celular Tumoral , Neoplasias do Colo/patologia , Técnicas de Inativação de Genes , Células HCT116 , Humanos , Mitocôndrias/metabolismo , Pirimidinas/síntese química , Pirimidinas/química , Pirróis/síntese química , Pirróis/química , Proteína Supressora de Tumor p53/genética , Proteína Killer-Antagonista Homóloga a bcl-2/genética , Proteína X Associada a bcl-2/genética
2.
Chemistry ; 26(24): 5441-5448, 2020 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-32271495

RESUMO

N6 -(2-Deoxy-α,ß-d-erythropentofuranosyl)-2,6-diamino-4-hydroxy-5-formamidopyrimidine (Fapy⋅dG) is a major DNA lesion produced from 2'-deoxyguanosine under oxidizing conditions. Fapy⋅dG is produced from a common intermediate that leads to 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-OxodGuo), and in greater quantities in cells. The impact of Fapy⋅dG on DNA structure and function is much less well understood than that of 8-OxodGuo. This is largely due to the significantly greater difficulty in synthesizing oligonucleotides containing Fapy⋅dG than 8-OxodGuo. We describe a synthetic approach for preparing oligonucleotides containing Fapy⋅dG that will facilitate intensive studies of this lesion in DNA. A variety of oligonucleotides as long as 30 nucleotides are synthesized. We anticipate that the chemistry described herein will provide an impetus for a wide range of studies involving Fapy⋅dG.


Assuntos
8-Hidroxi-2'-Desoxiguanosina/síntese química , DNA/química , Desoxiguanosina/química , Formamidas/síntese química , Furanos/síntese química , Oligonucleotídeos/síntese química , Pirimidinas/síntese química , 8-Hidroxi-2'-Desoxiguanosina/química , Formamidas/química , Furanos/química , Oligonucleotídeos/química , Oxirredução , Estresse Oxidativo , Pirimidinas/química
3.
Eur J Med Chem ; 193: 112239, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32200202

RESUMO

CDK4/6 has been identified as an attractive therapeutic target for treatment of cancer. For unmet clinical needs, a novel class of imidazo [1',2':1,6]pyrido [2,3-d]pyrimidin derivatives, which had distinctive triheteroaryl structure, had been discovered as CDK4/6 inhibitors. The compounds 10b and 10c, displayed the low nanomolar range activities on CDK4/6, desirable antiproliferative activities, excellent metabolic properties, and acceptable pharmacokinetic characters. In Colo-205 and U87MG xenograft models, compounds 10b and 10c also showed significant tumor growth inhibitions with controllable toxicities. All data confirmed that imidazo [1',2':1,6]pyrido [2,3-d]pyrimidin derivatives 10b and 10c could be promising drug candidates for cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/síntese química , Pirimidinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Distribuição Tecidual
4.
J Med Chem ; 63(6): 3327-3347, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32129996

RESUMO

Cyclin-dependent kinases (CDKs) are promising therapeutic targets for cancer therapy. Herein, we describe our efforts toward the discovery of a series of 5-chloro-N4-phenyl-N2-(pyridin-2-yl)pyrimidine-2,4-diamine derivatives as dual CDK6 and 9 inhibitors. Intensive structural modifications lead to the identification of compound 66 as the most active dual CDK6/9 inhibitor with balancing potency against these two targets and good selectivity over CDK2. Further biological studies revealed that compound 66 was directly bound to CDK6/9, resulting in suppression of their downstream signaling pathway and inhibition of cell proliferation by blocking cell cycle progression and inducing cellular apoptosis. More importantly, compound 66 significantly inhibited tumor growth in a xenograft mouse model with no obvious toxicity, indicating the promising therapeutic potential of CDK6/9 dual inhibitors for cancer treatment. Therefore, the above results are of great importance in the development of dual CDK6/9 inhibitors for cancer therapy.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Pirimidinas/uso terapêutico , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Domínio Catalítico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/química , Quinase 6 Dependente de Ciclina/metabolismo , Quinase 9 Dependente de Ciclina/antagonistas & inibidores , Quinase 9 Dependente de Ciclina/química , Quinase 9 Dependente de Ciclina/metabolismo , Humanos , Masculino , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Piridinas/administração & dosagem , Piridinas/síntese química , Piridinas/metabolismo , Pirimidinas/administração & dosagem , Pirimidinas/síntese química , Pirimidinas/metabolismo , Ratos Sprague-Dawley , Relação Estrutura-Atividade
5.
J Med Chem ; 63(6): 3298-3316, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32125159

RESUMO

Cruzain, an essential cysteine protease of the parasitic protozoan, Trypanosoma cruzi, is an important drug target for Chagas disease. We describe here a new series of reversible but time-dependent inhibitors of cruzain, composed of a dipeptide scaffold appended to vinyl heterocycles meant to provide replacements for the irreversible reactive "warheads" of vinyl sulfone inactivators of cruzain. Peptidomimetic vinyl heterocyclic inhibitors (PVHIs) containing Cbz-Phe-Phe/homoPhe scaffolds with vinyl-2-pyrimidine, vinyl-2-pyridine, and vinyl-2-(N-methyl)-pyridine groups conferred reversible, time-dependent inhibition of cruzain (Ki* = 0.1-0.4 µM). These cruzain inhibitors exhibited moderate to excellent selectivity versus human cathepsins B, L, and S and showed no apparent toxicity to human cells but were effective in cell cultures of Trypanosoma brucei brucei (EC50 = 1-15 µM) and eliminated T. cruzi in infected murine cardiomyoblasts (EC50 = 5-8 µM). PVHIs represent a new class of cruzain inhibitors that could progress to viable candidate compounds to treat Chagas disease and human sleeping sickness.


Assuntos
Inibidores de Cisteína Proteinase/farmacologia , Peptidomiméticos/farmacologia , Proteínas de Protozoários/antagonistas & inibidores , Tripanossomicidas/farmacologia , Compostos de Vinila/farmacologia , Animais , Cisteína Endopeptidases/metabolismo , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/metabolismo , Desenho de Fármacos , Ensaios Enzimáticos , Humanos , Cinética , Camundongos , Simulação de Acoplamento Molecular , Mioblastos Cardíacos/efeitos dos fármacos , Peptidomiméticos/síntese química , Peptidomiméticos/metabolismo , Ligação Proteica , Proteínas de Protozoários/metabolismo , Piridinas/síntese química , Piridinas/metabolismo , Piridinas/farmacologia , Pirimidinas/síntese química , Pirimidinas/metabolismo , Pirimidinas/farmacologia , Tripanossomicidas/síntese química , Tripanossomicidas/metabolismo , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma cruzi/efeitos dos fármacos , Compostos de Vinila/síntese química , Compostos de Vinila/metabolismo
6.
J Med Chem ; 63(7): 3678-3700, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32153186

RESUMO

Bromodomain-containing protein 4 (BRD4) and histone deacetylases (HDAC) are both attractive epigenetic targets in cancer and other chronic diseases. Based on the integrated fragment-based drug design, synthesis, and in vitro and in vivo evaluations, a series of novel thieno[2,3-d]pyrimidine-based hydroxamic acid derivatives are discovered as selective BRD4-HDAC dual inhibitors. Compound 17c is the most potent inhibitor for BRD4 and HDAC with IC50 values at nanomolar levels, as well as the expression level of c-Myc, and increases the acetylation of histone H3. Moreover, 17c presents inhibitory effects on the proliferation of colorectal carcinoma (CRC) cells via inducing autophagic cell death. It also has a good pharmacokinetic profile in rats and oral bioavailability of 40.5%. In the HCT-116 xenograft in vivo models, 17c displays potent inhibitory efficiency on tumor growth by inducing autophagic cell death and suppressing IL6-JAK-STAT signaling pathways. Our results suggest that the BRD4-HDAC dual inhibition might be an attractive therapeutic strategy for CRC.


Assuntos
Antineoplásicos/uso terapêutico , Autofagia/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Inibidores de Histona Desacetilases/uso terapêutico , Ácidos Hidroxâmicos/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/metabolismo , Histona Desacetilases/metabolismo , Humanos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/metabolismo , Masculino , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/metabolismo , Pirimidinas/uso terapêutico , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/metabolismo , Tiofenos/uso terapêutico , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-Zebra
7.
J Med Chem ; 63(6): 3188-3204, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32134652

RESUMO

Autotaxin (ATX, also known as ENPP2) is a predominant lysophosphatidic acid (LPA)-producing enzyme in the body, and LPA regulates various physiological functions, such as angiogenesis and wound healing, as well as pathological functions, including proliferation, metastasis, and fibrosis, via specific LPA receptors. Therefore, the ATX-LPA axis is a promising therapeutic target for dozens of diseases, including cancers, pulmonary and liver fibroses, and neuropathic pain. Previous structural studies revealed that the catalytic domain of ATX has a hydrophobic pocket and a hydrophobic channel; these serve to recognize the substrate, lysophosphatidylcholine (LPC), and deliver generated LPA to LPA receptors on the plasma membrane. Most reported ATX inhibitors bind to either the hydrophobic pocket or the hydrophobic channel. Herein, we present a unique ATX inhibitor that binds mainly to the hydrophobic pocket and also partly to the hydrophobic channel, inhibiting ATX activity with high potency and selectivity in vitro and in vivo. Notably, our inhibitor can rescue the cardia bifida (two hearts) phenotype in ATX-overexpressing zebrafish embryos.


Assuntos
Imidazóis/uso terapêutico , Inibidores de Fosfodiesterase/uso terapêutico , Diester Fosfórico Hidrolases/metabolismo , Pirimidinas/uso terapêutico , Animais , Domínio Catalítico , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Cristalografia por Raios X , Cardiopatias/prevenção & controle , Humanos , Interações Hidrofóbicas e Hidrofílicas , Imidazóis/síntese química , Imidazóis/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Estrutura Molecular , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/metabolismo , Ligação Proteica , Pirimidinas/síntese química , Pirimidinas/metabolismo , Relação Estrutura-Atividade , Peixe-Zebra
8.
Eur J Med Chem ; 194: 112220, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32222676

RESUMO

P21-activated kinase 1 (PAK1) is associated with cell proliferation, survival and migration. Deregulation of PAK1 activity is involved in various human diseases, including cancer, inflammation, and neurological disorders. Using a high-throughput virtual screening, we identified the 1H-pyrazolo [3,4-d]pyrimidine scaffold as a promising lead for targeting PAK1. We designed and synthesized a focused library through a structure-based strategy. A novel potent PAK1 inhibitor, ZMF-10, was discovered, which presented an IC50 value of 174 nM with a good selectivity. In addition, ZMF-10 could inhibit PAK1-ERK signaling to suppress MDA-MB-231 cells proliferation with an IC50 value of 3.48 µM for 48 h. Subsequently, ZMF-10 was documented to induce cell apoptosis. Interestingly, according to the RNASeq-based analyses, we substantiated that ZMF-10 induced significant ER-Stress, suppressed migration via FOXO3 activation, JNK1/2, ERK1/2 and AKT signaling inhibition. Together, these results demonstrate that ZMF-10 is a novel PAK1 inhibitor triggering apoptosis, ER stress and anti-migration effect in MDA-MB-231 cells, which may provide a candidate lead for the development of novel potent inhibitors of PAK1.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Desenho de Fármacos , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Quinases Ativadas por p21/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Quinases Ativadas por p21/metabolismo
9.
Eur J Med Chem ; 191: 112148, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32097841

RESUMO

As non-receptor tyrosine kinases, Janus kinases (JAKs) have become an attractive target for the treatment of autoimmune diseases and cancers. JAKs play a pivotal role in innate immunity, inflammation, and hematopoiesis by mediating the signaling of numerous cytokines, growth factors, and interferons (IFNs). Selective inhibitors of a variety of JAK members are expected to inhibit pro-inflammatory cytokine-mediated inflammation and immune responses, while preventing targeting other subtypes of JAKs. In this work, poorly selective compounds based on 4- or 6-phenyl-pyrimidine derivatives have been improved to highly potent and selective compounds by designing a covalent binding tether, which attaches to the unique cysteine (Cys909) residue in JAK3. Compound 12 exhibited potent JAK3 inhibitory activity (IC50 = 1.7 nM) with an excellent selectivity profile when compared to the other JAK isoforms (>588-fold). In a cellular assay, compound 12 strongly inhibited JAK3-dependent signaling and T cell proliferation. Moreover, in vivo data revealed that compound 12 significantly suppressed oxazolone (OXZ)-induced delayed hypersensitivity responses in Balb/c mice. Compound 12 also displayed decent pharmacokinetic properties and was suitable for in vivo use. Taken together, these results indicated that compound 12 may be a promising tool compound as a selective JAK3 inhibitor for treating autoimmune diseases.


Assuntos
Desenho de Fármacos , Janus Quinase 3/antagonistas & inibidores , Pirimidinas/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Feminino , Janus Quinase 3/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade
10.
Molecules ; 25(4)2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-32075253

RESUMO

In this study cytotoxicity of organotin(IV) compounds with 1,2,4-triazolo[1,5-a]pyrimidines, Me3Sn(5tpO) (1), n-Bu3Sn(5tpO) (2), Me3Sn(mtpO) (3), n-Bu3Sn(mtpO) (4), n-Bu3Sn(HtpO2) (5), Ph3Sn(HtpO2) (6) where 5HtpO = 4,5-dihydro-5-oxo-[1,2,4]triazolo-[1,5-a]pyrimidine, HmtpO = 4,7-dihydro-5-methyl-7-oxo-[1,2,4]triazolo-[1,5-a]pyrimidine, and H2tpO2 = 4,5,6,7-tetrahydro-5,7- dioxo-[1,2,4]triazolo-[1,5-a]-pyrimidine, was assessed on three different human tumor cell lines: HCT-116 (colorectal carcinoma), HepG2 (hepatocarcinoma) and MCF-7 (breast cancer). While 1 and 3 were inactive, compounds 2, 4, 5 and 6 inhibited the growth of the three tumor cell lines with IC50 values in the submicromolar range and showed high selectivity indexes towards the tumor cells (SI > 90). The mechanism of cell death triggered by the organotin(IV) derivatives, investigated on HCT-116 cells, was apoptotic, as evident from the externalization of phosphatidylserine to the cell surface, and occurred via the intrinsic pathway with fall of mitochondrial inner membrane potential and production of reactive oxygen species. While compound 6 arrested the cell progression in the G2/M cell cycle phase and increased p53 and p21 levels, compounds 2, 4 and 5 blocked cell duplication in the G1 phase without affecting the expression of either of the two tumor suppressor proteins. Compounds 1 and 2 were also investigated using single crystal X-ray diffraction and found to be, in both cases, coordination polymers forming 1 D chains based on metal-ligand interactions. Interestingly, for n-Bu3Sn(5tpO)(2) H-bonding interactions between 5tpO- ligands belonging to adjacent chains were also detected that resemble the "base-pairing" assembly and could be responsible for the higher biological activity compared to compound 1. In addition, they are the first example of bidentate N(3), O coordination for the 5HtpO ligand on two adjacent metal atoms.


Assuntos
Apoptose/efeitos dos fármacos , Citotoxinas/farmacologia , Regulação Neoplásica da Expressão Gênica , Compostos Orgânicos de Estanho/farmacologia , Pirimidinas/farmacologia , Triazóis/farmacologia , Apoptose/genética , Sobrevivência Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Citotoxinas/síntese química , Desenho de Fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/genética , Células HCT116 , Células Hep G2 , Humanos , Concentração Inibidora 50 , Células MCF-7 , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Membranas Mitocondriais/efeitos dos fármacos , Compostos Orgânicos de Estanho/síntese química , Pirimidinas/síntese química , Espécies Reativas de Oxigênio/agonistas , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Triazóis/síntese química , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
11.
Molecules ; 25(3)2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32041285

RESUMO

Despite the substantial interest in C-glycosyl heterocycles as mimetics of biologically active native glycans, the appearance of C-glycopyranosyl derivatives of six-membered heterocycles, both in synthetic and biological contexts, is rather scarce. As part of our ongoing research program aimed at preparing hitherto barely known 2-C-glycopyranosyl pyrimidines, the goal of the present study was to synthesize new 5-mono- and multiply substituted derivatives of this compound class. Thus, 2-C-(ß-D-glucopyranosyl)-5,6-disubstituted-pyrimidin-4(3H)-ones and 4-amino-2-C-(ß-D-glucopyranosyl)-5,6-disubstituted-pyrimidines were prepared by base-mediated cyclocondensations of O-perbenzylated and O-unprotected C-(ß-D-glucopyranosyl) formamidine hydrochlorides with methylenemalonic acid derivatives. The 2-C-(ß-D-glucopyranosyl)-5-substituted-pyrimidines were obtained from the same amidine precursors upon treatment with vinamidinium salts. The deprotected derivatives of these pyrimidines were tested as inhibitors of some glycoenzymes. None of them showed inhibitory activity towards glycogen phosphorylase and α- and ß-glucosidase enzymes, but some members of the sets exhibited moderate inhibition against bovine liver ß-galactosidase.


Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Glicogênio Fosforilase/antagonistas & inibidores , Pirimidinas/síntese química , Pirimidinas/farmacologia , Animais , Bovinos , alfa-Glucosidases/metabolismo , beta-Galactosidase/metabolismo
12.
Org Lett ; 22(4): 1547-1551, 2020 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-32009412

RESUMO

Regioselective C-H arylations of thieno[2,3-d]pyrimidine are accomplished under palladium catalysis. Thieno[2,3-d]pyrimidines react with aryl iodides at the C6-position and with aryl boronic acids at the C5-position, showing excellent regioselectivity. Mechanistic investigations indicate that the regioselectivity is controlled by the nature of the palladium catalyst: the cationic palladium favorably arylates the C5-position. The utility of this direct arylation has been highlighted in the streamlined synthesis of kinase inhibitors and their derivatives.


Assuntos
Inibidores de Proteínas Quinases/síntese química , Pirimidinas/síntese química , Catálise , Estrutura Molecular , Paládio/química , Inibidores de Proteínas Quinases/química , Pirimidinas/química , Estereoisomerismo
13.
Eur J Med Chem ; 188: 112021, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31901743

RESUMO

A series of novel sulfonamide derivatives bearing pyrrole and pyrrolopyrimidine scaffolds were synthesized and screened as carbonic anhydrase inhibitors. The inhibition activity of the synthesized compounds was evaluated against the cytosolic human carbonic anhydrase isoforms I and II and the transmembranal isoforms IX and XII. Several candidates showed potent inhibitory activity against IX and XII isoforms. Furthermore, ex vivo screening of cytotoxic selectivity and activity of the most potent derivatives were carried out against normal cells (WI38) and cervical cancer cell line (HeLa) under normal and hypoxic conditions using acetazolamide as reference drug. Compound 11b potency was nearly three folds higher in hypoxic than normoxic condition whereas that of compound 11f was nearly four folds higher in hypoxic vs. normoxic HeLa cells. All the screened derivatives exhibited less potency on normal cells (WI38). Molecular docking was carried out to discover the possible binding mode of compounds within the active site of isoform CA IX.


Assuntos
Antineoplásicos/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Sulfonamidas/farmacologia , Antígenos de Neoplasias/química , Antígenos de Neoplasias/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Anidrase Carbônica IX/química , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/toxicidade , Domínio Catalítico , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Simulação de Acoplamento Molecular , Pirimidinas/síntese química , Pirimidinas/toxicidade , Pirróis/síntese química , Pirróis/toxicidade , Sulfonamidas/síntese química , Sulfonamidas/toxicidade
14.
J Med Chem ; 63(4): 1624-1641, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-31935084

RESUMO

SRC is a major regulator of many signaling pathways and contributes to cancer development. However, development of a selective SRC inhibitor has been challenging, and FDA-approved SRC inhibitors, dasatinib and bosutinib, are multitargeted kinase inhibitors. Here, we describe our efforts to develop a selective SRC covalent inhibitor by targeting cysteine 277 on the P-loop of SRC. Using a promiscuous covalent kinase inhibitor (CKI) SM1-71 as a starting point, we developed covalent inhibitor 15a, which discriminates SRC from other covalent targets of SM1-71 including TAK1 and FGFR1. As an irreversible covalent inhibitor, compound 15a exhibited sustained inhibition of SRC signaling both in vitro and in vivo. Moreover, 15a exhibited potent antiproliferative effects in nonsmall cell lung cancer cell lines harboring SRC activation, thus providing evidence that this approach may be promising for further drug development efforts.


Assuntos
Anilidas/farmacologia , Cisteína/química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Quinases da Família src/antagonistas & inibidores , Domínio AAA , Sequência de Aminoácidos , Anilidas/síntese química , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Pirimidinas/síntese química , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Quinases da Família src/química
15.
Molecules ; 25(2)2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31936309

RESUMO

A series of novel 7-substituted-5-(1H-indol-3-yl)tetrazolo[1,5-a]pyrimidine-6-carbonitrile was synthesized via a one-pot, three-multicomponent reaction of appropriate aldehydes, 1H-tetrazole-5-amine and 3-cyanoacetyl indole in catalytic triethylamine. The cytotoxic activity of the new synthesized tetrazolopyrimidine-6-carbonitrile compounds was investigated against HCT-116, MCF-7, MDA-MB-231, A549 human cancer cell lines and one human healthy normal cell line (RPE-1) using the MTT cytotoxicity assay. Compounds 4h, 4b, 4c, 4i and 4a showed potent anticancer activities against human colon cancer. Additionally, all the compounds showed potent anticancer activities on human lung cancer.


Assuntos
Nitrilos/farmacologia , Pirimidinas/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Alcaloides Indólicos/química , Alcaloides Indólicos/farmacologia , Concentração Inibidora 50 , Nitrilos/síntese química , Nitrilos/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade
16.
Eur J Med Chem ; 189: 112061, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31951960

RESUMO

Epidermal growth factor receptor (EGFR), a member of the HER family, is closely related to the development of multiple cancers. Herein, we report the discovery of small molecule EGFR degraders based on the proteolysis targeting chimera (PROTAC) strategy. In the present study, 13 EGFR degraders containing pyrido[3,4-d] pyrimidine moiety were designed and synthesized. Promising PROTACs 2 and 10 induced degradation of EGFR in HCC827 cells with the DC50 values of 45.2 and 34.8 nM, respectively. Cellular protein-controlling machinery ubiquitin proteasome system (UPS) was involved in the degradation process. Furthermore, the degraders 2 and 10 could significantly induce the apoptosis of HCC827 cells and arrest the cells in G1 phase. These findings demonstrated that compounds 2 and 10 could serve as effective EGFRdel19-targeting degraders in HCC827 cells. v.


Assuntos
Antineoplásicos/farmacologia , Proteólise/efeitos dos fármacos , Piridinas/farmacologia , Pirimidinas/farmacologia , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Piridinas/síntese química , Pirimidinas/síntese química
17.
Eur J Med Chem ; 188: 112024, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31923858

RESUMO

A series of 2,7-disubstituted-thieno[3,2-d]pyrimidine derivatives were designed, synthesized and evaluated as novel focal adhesion kinase (FAK) inhibitors. The novel 2,7-disubstituted-thieno[3,2-d]pyrimidine scaffold has been designed as a new kinase inhibitor platform that mimics the bioactive conformation of the well-known diaminopyrimidine motif. Most of the compounds potently suppressed the enzymatic activities of FAK and potently inhibited the proliferation of U-87MG, A-549 and MDA-MB-231 cancer cell lines. Among these derivatives, the optimized compound 26f potently inhibited the enzyme (IC50 = 28.2 nM) and displayed stronger potency than TAE-226 in U-87MG, A-549 and MDA-MB-231 cells, with IC50 values of 0.16, 0.27, and 0.19 µM, respectively. Compound 26f also exhibited relatively less cytotoxicity (IC50 = 3.32 µM) toward a normal human cell line, HK2. According to the flow cytometry results, compound 26f induced the apoptosis of MDA-MB-231 cells in a dose-dependent manner and effectively arrested MDA-MB-231 cells in G0/G1 phase. Further investigations revealed that compound 26f potently suppressed the migration of MDA-MB-231 cells. Collectively, these data support the further development of compound 26f as a lead compound for FAK-targeted anticancer drug discovery.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Quinase 1 de Adesão Focal/antagonistas & inibidores , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Quinase 1 de Adesão Focal/metabolismo , Humanos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade
18.
Arch Pharm (Weinheim) ; 353(3): e1900271, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31989670

RESUMO

In the present study, a novel series of polyfunctionalized imidazopyrimidines 6a-u and 9a-d were efficiently constructed by a domino reaction between 2-imino-6-substituted-2,3-dihydropyrimidin-4(1H)-ones 4a-d or 8a-c and 2-bromoacetophenones 5a-i under mild basic conditions. The synthesized series were screened for their antibacterial activity against Staphylococcus aureus and Bacillus subtilis as Gram-positive (+) bacteria, as well as against Gram-negative (-) bacteria Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Salmonella typhi. Most of the synthesized derivatives of imidazopyrimidines 6 and 9 showed remarkable selectivity against Gram(-) bacteria over the Gram(+) ones. Compounds 6c, 6f, and 6g displayed potent and broad-spectrum antibacterial activity against all tested strains. Compounds 6f and 6g displayed promising inhibitory activity on GryB ATPase from E. coli with IC50 = 1.14 and 0.73 µM, respectively. Simultaneously, some of the synthesized imidazopyrimidines were screened for their antiproliferative activity against 60 cancer cell lines at a concentration of 10 µM. Compound 9d showed potent activity against most of the tested cell lines, with a mean growth inhibition of 37%. The ADME (absorption, distribution, metabolism, and excretion) prediction study demonstrated that the synthesized hits have, in addition to their promising chemotherapeutic activity, acceptable pharmacokinetic properties, and a drug-likeness nature to be further developed.


Assuntos
Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Citotoxinas/farmacologia , Imidazóis/farmacologia , Pirimidinas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Bacillus subtilis , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Citotoxinas/síntese química , Citotoxinas/química , Ensaios de Seleção de Medicamentos Antitumorais , Escherichia coli , Humanos , Imidazóis/síntese química , Imidazóis/química , Klebsiella pneumoniae , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Pseudomonas aeruginosa , Pirimidinas/síntese química , Pirimidinas/química , Salmonella typhi , Staphylococcus aureus , Relação Estrutura-Atividade
19.
J Med Chem ; 63(2): 676-695, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31895575

RESUMO

The transcriptional repressor B-cell lymphoma 6 (BCL6) is frequently misregulated in diffuse large B-cell lymphoma (DLBCL) and has emerged as an attractive drug target for the treatments of lymphoma. In this article, a series of N-phenyl-4-pyrimidinamine derivatives were designed and synthesized as potent BCL6 inhibitors by optimizing hit compound N4-(3-chloro-4-methoxyphenyl)-N2-isobutyl-5-fluoro-2,4-pyrimidinediamine on the basis of the structure-activity relationship. Among them, compound 14j displayed the most potent activities, which significantly blocked the interaction of BCL6 with its corepressors, reactivated BCL6 target genes in a dose-dependent manner, and had better effects compared with the two positive controls. Further studies indicated that a low dose of 14j could effectively inhibit germinal center formation. More importantly, 14j not only showed potent inhibition of DLBCL cell proliferation in vitro but also strongly suppressed the growth of DLBCL in vivo.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-6/antagonistas & inibidores , Pirimidinas/síntese química , Pirimidinas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células , Relação Dose-Resposta a Droga , Repressão Epigenética/efeitos dos fármacos , Centro Germinativo/efeitos dos fármacos , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Simulação de Acoplamento Molecular , Proteínas Proto-Oncogênicas c-bcl-6/genética , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Eur J Med Chem ; 187: 111914, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31806538

RESUMO

Structural optimization of aminopyrimidine-based CXCR4 antagonists is reported. The optimization is guided by molecular docking studies based on available CXCR4-small molecule crystal complex. The optimization identifies a number of compounds with improved receptor binding affinity and functional activity exemplified by compound 23 (inhibition of APC-conjugate clone 12G5 for CXCR4 binding in a cell based assay: IC50 = 8.8 nM; inhibition of CXCL12 induced cytosolic calcium increase: IC50 = 0.02 nM). In addition, compound 23 potently inhibits CXCR4/CXLC12 mediated chemotaxis in a matrigel invasion assay. Furthermore, compound 23 exhibits good physicochemical properties (MW 367, clogP 2.1, PSA 48, pKa 7.2) and in vitro safety profiles (marginal/moderate inhibition of CYP isozymes and hERG). These results represent significant improvement over the initial hit from scaffold hybridization and suggest that compound 23 can be used as a starting point to support lead optimization.


Assuntos
Pirimidinas/farmacologia , Receptores CXCR4/antagonistas & inibidores , Relação Dose-Resposta a Droga , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Receptores CXCR4/metabolismo , Relação Estrutura-Atividade
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