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1.
ChemSusChem ; : e202401025, 2024 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-38984900

RESUMO

The rampant exploitation of fossil fuels has led to the significant energy scarcity and environmental disruption, affecting the sound momentum of development and progress of human civilization. To build a closed-loop anthropogenic carbon cycle, development of biofuels employing sustainable biomass feedstocks stands at the forefront of advancing carbon neutrality, yet its widespread adoption is mainly hampered by the high production costs. Montmorillonite, however, has garnered considerable attention serving as an efficient heterogeneous catalyst of ideal economic feasibility for biofuel production, primarily due to its affordability, accessibility, stability, and excellent plasticity. Up to now, nevertheless, it has merely received finite concerns and interests in production of various biofuels using montmorillonite-based catalysts. There is no timely and comprehensive review that addresses this latest relevant progress. This review fills the gap by providing a systematically review and summary in controllable synthesis, performance enhancement, and applications related to different kinds of biofuels including biodiesel, biohydrogenated diesel, levulinate, γ-valerolactone, 5-ethoxymethylfurfural, gaseous biofuels (CO, H2), and cycloalkane, by using montmorillonite catalysts and its modified forms. Particularly, this review critically depicts the design strategies for montmorillonite, illustrates the relevant reaction mechanisms, and assesses their economic viability, realizing sustainable biofuels production via efficient biomass valorization.

2.
J Med Chem ; 67(5): 3504-3519, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38377311

RESUMO

Photopharmacology is an emerging approach for achieving light-controlled drug activity. Herein, we design and synthesize a novel series of photoswitchable PI3K inhibitors by replacing a sulfonamide moiety with an azo group in a 4-methylquinazoline-based scaffold. Through structure-activity relationship studies, compound 6g is identified to be effectively switched between its trans- and cis-configuration under irradiation with proper wavelengths. Molecular docking studies show the cis-isomer of 6g is favorable to bind to the PI3K target, supporting compound 6g in the PSS365 (cis-isomer enriched) was more potent than that in the PSSdark (trans-isomer dominated) in PI3K enzymatic assay, cell antiproliferative assay, Western blotting analysis on PI3K downstream effectors, cell cycle analysis, colony formation assay, and wound-healing assay. Relative to the cis-isomer, the trans-isomer is more metabolically stable and shows good pharmacokinetic properties in mice. Moreover, compound 6g inhibits tumor growth in nude mice and a zebrafish HGC-27 xenograft model.


Assuntos
Antineoplásicos , Neoplasias , Humanos , Animais , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Simulação de Acoplamento Molecular , Camundongos Nus , Peixe-Zebra/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Relação Estrutura-Atividade , Proliferação de Células , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico
3.
Eur J Med Chem ; 264: 116015, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38048697

RESUMO

Simultaneous inhibition of PI3K and HDAC has shown promise for treating various cancers, leading to discovery and development of their dual inhibitors as novel anticancer agents. Herein, we disclose a new series of PI3K/HDAC dual inhibitors bearing a benzamide moiety as the pharmacophore of HDAC inhibition. Based on systematic structure-activity relationship study, compounds 36 and 51 featuring an alkyl and benzoyl linker respectively were identified with favorable potencies against both PI3K and HDAC. In cellular assays, compounds 36 and 51 showed significantly enhanced antiproliferative activities against various cancer cell lines relative to single-target inhibitors. Furthermore, western blotting analysis shows compounds 36 and 51 suppressed AKT phosphorylation and increased H3 acetylation in MV4-11 cells, while flow cytometry analysis reveals both compounds dose-dependently induced cell cycle arrest and cell apoptosis. Supported by pharmacokinetic studies, compounds 36 and 51 were subjected to the in vivo evaluation in a MV4-11 xenograft model, demonstrating significant and dose-dependent anticancer efficacies. Overall, this work provides a promising approach for the treatment of AML by simultaneously inhibiting PI3K and HDAC with a dual inhibitor.


Assuntos
Antineoplásicos , Leucemia Mieloide Aguda , Humanos , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Inibidores de Histona Desacetilases/química , Linhagem Celular Tumoral , Fosfatidilinositol 3-Quinases/metabolismo , Proliferação de Células , Antineoplásicos/química , Relação Estrutura-Atividade , Leucemia Mieloide Aguda/tratamento farmacológico , Zinco/farmacologia , Apoptose
4.
Bioorg Chem ; 140: 106814, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37657197

RESUMO

Phosphatidylinositol 3-kinase (PI3K) signaling is among the most common alterations in cancer and has become a key target for cancer drug development. Based on a 4-methyl quinazoline scaffold, we designed and synthesized a novel series of bivalent PI3K inhibitors with different linker lengths and types. Bivalent PI3K inhibitor 27 demonstrates improved PI3K potency and antiproliferative cell activity, relative to the corresponding monovalent inhibitor 11. Compound 27 also significantly blocks the PI3K signal pathway, induces cell cycle arrest in G1 phase, and inhibits colony formation and cell migration. Furthermore, compound 27 shows dose-dependent anticancer efficacies in a HGC-27 xenograft mice model. Overall, this work provides a possible strategy to discover novel PI3K inhibitors for the treatment of cancers.


Assuntos
Neoplasias , Fosfatidilinositol 3-Quinases , Humanos , Animais , Camundongos , Neoplasias/tratamento farmacológico , Fosfatidilinositol 3-Quinase , Movimento Celular , Modelos Animais de Doenças , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia
5.
J Med Chem ; 65(24): 16372-16391, 2022 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-36511661

RESUMO

Targeting the colchicine binding site on tubulin is a promising strategy to develop cancer therapeutics. Herein, we describe our systematic structure-activity relationship studies of benzamide derivatives that lead to an identification of a potent and orally active tubulin inhibitor 48, which occupied all three zones of the colchicine binding site in the X-ray co-crystal structure, inhibited tubulin polymerization, promoted mitotic blockade and apoptosis, and exhibited significant antiproliferative activities against various cancer cell lines. Compound 48 demonstrated favorable pharmacokinetic profiles, robust in vivo antitumor efficacies, and acceptable safety profiles. Furthermore, 48 overcame drug resistance in the paclitaxel-resistant A549 xenograft model. Collectively, 48 has been advanced into further preclinical evaluation for the development of next-generation microtubule-targeting drugs.


Assuntos
Antineoplásicos , Moduladores de Tubulina , Humanos , Moduladores de Tubulina/farmacologia , Moduladores de Tubulina/uso terapêutico , Moduladores de Tubulina/química , Colchicina/metabolismo , Tubulina (Proteína)/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/química , Linhagem Celular Tumoral , Sítios de Ligação , Relação Estrutura-Atividade , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais
6.
Org Biomol Chem ; 20(24): 4993-4998, 2022 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-35694953

RESUMO

A synthetic protocol based on Cp*CoIII-catalyzed C-H amidation/annulation of 2-aryl-1H-imidazoles with 1,4,2-dioxazol-5-ones was developed to give imidazo[1,2-c]quinazoline derivatives with broad substrate scope in moderate to good yields. The method has good prospects of application in the synthesis of imidazo[1,2-c]quinazoline drugs.


Assuntos
Imidazóis , Quinazolinas , Catálise , Reação de Cicloadição
7.
Bioorg Med Chem Lett ; 71: 128825, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-35644299

RESUMO

The synergistic anti-tumor effect by simultaneous inhibitions of PI3K and HDAC has been verified to provide the rationality of PI3K/HDAC dual inhibitors for cancer treatment. Notably, the outstanding effect of PI3K/HDAC dual inhibitors against DLBCL has been paid much attention, especially for RR-DLBCL. Our previously reported 4-methylquinazoine scaffold based PI3K/HDAC dual inhibitors could suppress the growth of solid tumors and hematologic malignancies both in vitro and in vivo, validating the potential as new therapeutic agents for cancer. In this research, we further investigated the anti-tumor activity of one of our compounds against DLBCL cell lines and in vivo zebrafish xenograft model as well as the underlying mechanism, hoping to provide a novel therapeutic agent for treating DLBCL.


Assuntos
Inibidores de Histona Desacetilases , Linfoma Difuso de Grandes Células B , Animais , Apoptose , Linhagem Celular Tumoral , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-Zebra
8.
J Med Chem ; 65(11): 8011-8028, 2022 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-35609190

RESUMO

Phosphoinositide 3-kinase δ (PI3Kδ) plays a critical role in B lymphocyte (B-cell) development and activation and has been a validated target for the treatment of B-cell malignancies. Herein, we report a series of thienopyrimidine derivatives as novel potent and selective PI3Kδ inhibitors based on a scaffold hopping design strategy. Among them, compound 6 exhibited nanomolar PI3Kδ potency and a favorable selectivity profile compared to other class I PI3K isoforms. In cellular assays, compound 6 showed antiproliferative activity against a panel of B-cell lymphoma cell lines in a low micromolar range, caused cell cycle arrest, and induced apoptosis in Pfeiffer and SU-DHL-6 cells. Further, compound 6 inhibited the activation of mouse B-cells. With support from in vivo pharmacokinetic studies, compound 6 demonstrated significant anticancer efficacy in a Pfeiffer xenograft mouse model. Overall, compound 6 is a promising PI3Kδ inhibitor worthy of further preclinical investigation for the treatment of B-cell malignancies.


Assuntos
Antineoplásicos , Neoplasias , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Linfócitos B/metabolismo , Proliferação de Células , Classe I de Fosfatidilinositol 3-Quinases , Humanos , Camundongos , Neoplasias/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas
9.
Acta Pharm Sin B ; 12(2): 774-786, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35256946

RESUMO

Glioblastoma is carcinogenesis of glial cells in central nervous system and has the highest incidence among primary brain tumors. Brain metastasis, such as breast cancer and lung cancer, also leads to high mortality. The available medicines are limited due to blood-brain barrier. Abnormal activation of phosphatidylinositol 3-kinases (PI3K) signaling pathway is prevalent in glioblastoma and metastatic tumors. Here, we characterized a 2-amino-4-methylquinazoline derivative XH30 as a potent PI3K inhibitor with excellent anti-tumor activity against human glioblastoma. XH30 significantly repressed the proliferation of various brain cancer cells and decreased the phosphorylation of key proteins of PI3K signaling pathway, induced cell cycle arrest in G1 phase as well. Additionally, XH30 inhibited the migration of glioma cells and blocked the activation of PI3K pathway by interleukin-17A (IL-17A), which increased the migration of U87MG. Oral administration of XH30 significantly suppressed the tumor growth in both subcutaneous and orthotopic tumor models. XH30 also repressed tumor growth in brain metastasis models of lung cancers. Moreover, XH30 reduced IL-17A and its receptor IL-17RA in vivo. These results indicate that XH30 might be a potential therapeutic drug candidate for glioblastoma migration and brain metastasis.

10.
J Nutr Biochem ; 103: 108950, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35121022

RESUMO

The ω-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been shown to attenuate inflammation processes, whereas the molecular mechanisms remain unclear. This study was aimed at figuring out the differential effects of EPA and DHA on fatal arrhythmias and whether the signaling pathway could be a target after myocardial infarction, an inflammatory status. Male Wistar rats after ligating coronary artery were randomized to either vehicle, EPA, or DHA for 4 weeks. Postinfarction was associated with increased myocardial norepinephrine levels and sympathetic innervation. Furthermore, infarction was associated with the activation of NLRP3 inflammasomes and increased the protein and expression of IL-1ß and nerve growth factor (NGF). These changes were blunted after adding either EPA or DHA with a greater extent of EPA than DHA. Immunoblotting and immunohistochemical analysis showed that EPA had significantly lower phosphorylation of PPARγ at Ser 112 compared with DHA. Arrhythmic severity during programmed stimulation in the infarcted rats treated with EPA was significantly lower than those treated with DHA. Specific inhibition of GPR120 by AH-7614 and PPARγ by T0070907 reduced the EPA-or DHA-related attenuation of IL-1ß and NGF release. Besides, AH-7614 treatment partially reduced the PPARγ levels, whereas T0070907 administration did not affect the GPR120 levels. These results suggest that EPA was more effective than DHA in prevention of fatal arrhythmias by inhibiting NLRP3 inflammasome and sympathetic innervation through activation of PPARγ-mediated GPR120-dependent and -independent signaling pathways in infarcted hearts.


Assuntos
Ácido Eicosapentaenoico , Infarto do Miocárdio , Animais , Ácidos Docosa-Hexaenoicos/metabolismo , Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/metabolismo , Ácido Eicosapentaenoico/farmacologia , Inflamassomos/metabolismo , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Fator de Crescimento Neural , PPAR gama/metabolismo , Ratos , Ratos Wistar
11.
Anal Chem ; 93(44): 14743-14747, 2021 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-34709796

RESUMO

A long-standing challenge has been the simultaneous sensing of intracellular temperature and norepinephrine (NE) variations to explore signaling pathways and depression pathogeny. Here, we designed a fluorescent probe using poly(N-isopropylacrylamide) and 1-[4-(7-nitro-benzo [1,2,5]oxadiazol-4-yl)-piperazin-1-yl]-propenone (PNIPAm-AANBD) and (E)-1-(4-boronobenzyl)-2-(2-(1,3-dioxo-1H,3H-benzo[de]isochromen-6-yl)vinyl)pyridin-1-ium bromide (PHE) for simultaneously measuring the temperature and NE with high selectivity. The fluorescence intensity of the PNIPAm-AANBD moiety exhibited a good response to temperature changes. The PHE moiety could selectively sense NE due to the naphthalic anhydride group in PHE, which formed naphthalimide upon bonding with the primary amino group of NE. The hydroxyl-terminated ligand recognized the phenolic hydroxyl group of NE through the formation of hydrogen bonds. Using the proposed fluorescent probe, variations in the intracellular temperature and NE during NE reuptake could be simultaneously measured. It was first discovered that with the inhibition of antidepressant drugs, the intracellular temperature increased by 1.2-2.1 °C, and the NE reuptake decreased by about 21.5 µM. The measured variations in intracellular temperature and NE during neurotransmitter reuptake can shed light on the underlying mechanism of neurotransmitter signaling pathways, which may facilitate the treatment of depression.


Assuntos
Corantes Fluorescentes , Norepinefrina , Antidepressivos , Naftalimidas , Temperatura
12.
J Cell Mol Med ; 25(17): 8546-8557, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34328702

RESUMO

Oxidative damage in the brain may lead to cognitive impairments. There was considerable debate regarding the beneficial effects of physical exercise on cognitive functions because exercise protocols have varied widely across studies. We investigated whether different exercise intensities alter performance on cognitive tasks. The experiment was performed on spontaneously hypertensive rats (6 months at the established phase of hypertension) distributed into 3 groups: sedentary, low-intensity exercise and high-intensity exercise. Systolic blood pressure measurements confirmed hypertension in spontaneously hypertensive rats. In comparison to normotensive Wistar-Kyoto rats, sedentary spontaneously hypertensive rats had similar escape latencies and a similar preference for the correct quadrant in the probe trial. Compared to the sedentary group, the low-intensity exercise group had significantly better improvements in spatial memory assessed by Morris water maze. Low-intensity exercise was associated with attenuated reactive oxygen species, as measured by dihydroethidine fluorescence and nitrotyrosine staining in the dentate gyrus of the hippocampus. This was coupled with increased numbers of neurons and dendritic spines as well as a significant upregulation of synaptic density. In contrast, the beneficial effects of low-intensity exercise are abolished in high-intensity exercise as shown by increased free radical levels and an impairment in spatial memory. We concluded that exercise is an effective strategy to improve spatial memory in spontaneously hypertensive rats even at an established phase of hypertension. Low-intensity exercise exhibited better improvement on cognitive deficits than high-intensity exercise by attenuating free radical levels and improving downstream synaptic plasticity.


Assuntos
Cognição , Hipertensão , Condicionamento Físico Animal , Animais , Hipocampo/fisiopatologia , Hipertensão/fisiopatologia , Hipertensão/terapia , Masculino , Plasticidade Neuronal , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
13.
J Med Chem ; 64(11): 7331-7340, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-33876637

RESUMO

Aberrant activation of the PI3K pathway has been intensively targeted for cancer therapeutics for decades, leading to more than 40 PI3K inhibitors advanced into clinical trials. However, it is increasingly noticed that PI3K inhibitors often showed limited efficacy as well as a number of serious on-target adverse effects during the clinical development. In this work, we designed and synthesized a novel photocaged PI3K inhibitor 1, which could be readily activated by UV irradiation to release a highly potent PI3K inhibitor 2. Upon UV irradiation, the photocaged inhibitor 1 demonstrated remarkably enhanced antiproliferative activity against multiple cancer cell lines and significant efficacy in the patient-derived tumor organoid model. Furthermore, 1 also showed favorable anticancer activity in an in vivo zebrafish xenograft model. Taken together, the photocaged PI3K inhibitor 1 represents a promising avenue for novel therapeutics toward precise cancer treatment.


Assuntos
Desenho de Fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/síntese química , Animais , Sítios de Ligação , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Cães , Estabilidade de Medicamentos , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Simulação de Dinâmica Molecular , Neoplasias/tratamento farmacológico , Fosfatidilinositol 3-Quinases/química , Inibidores de Fosfoinositídeo-3 Quinase/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Pirimidinas/química , Pirimidinas/metabolismo , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Ratos , Transdução de Sinais/efeitos dos fármacos , Raios Ultravioleta , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-Zebra/metabolismo
14.
Bioorg Med Chem ; 29: 115890, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33285407

RESUMO

As abnormal PI3K signaling is a feature of many types of cancer, the development of orally active PI3K inhibitors is of great significance for targeted cancer therapy. Through integrating strategies of reducing aromatic character/increasing the fraction of sp3 carbons together with scaffold hopping, we designed and synthesized two new series of thieno[2,3-d]pyrimidine and thiazolo[5,4-d]pyrimidine derivatives for use as PI3K inhibitors. Our structure-activity relationship studies led to the identification of thieno[2,3-d]pyrimidine 6a and thiazolo[5,4-d]pyrimidine 7a, which exhibited remarkable nanomolar PI3K potency, good antiproliferative activity, favorable pharmacokinetic properties and significant in vivo anti-cancer efficacy. Notably, thiazolo[5,4-d]pyrimidine 7a had better anti-cancer activity than thieno[2,3-d]pyrimidine 6a and is worthy of further pre-clinical evaluation for its use in cancer treatment.


Assuntos
Antineoplásicos/química , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/química , Pirimidinas/química , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Camundongos Nus , Modelos Moleculares , Estrutura Molecular , Inibidores de Fosfoinositídeo-3 Quinase/administração & dosagem , Inibidores de Fosfoinositídeo-3 Quinase/farmacocinética , Ligação Proteica , Conformação Proteica , Pirimidinas/farmacologia , Transdução de Sinais , Relação Estrutura-Atividade
15.
J Med Chem ; 62(19): 8873-8879, 2019 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-31335136

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease, and its molecular pathogenesis remains poorly understood. Recently, emerging evidence demonstrates that the PI3K signaling transduction pathway is linked to the pathology of IPF. In this work, we rationally designed a new series of 4-methylquinazoline derivatives as highly potent PI3K inhibitors that significantly suppress the phosphorylation of the main PI3K downstream effectors and displays marked antiproliferative activity in mouse MLg2908 lung fibroblasts. In a bleomycin-induced mouse pulmonary fibrosis model, 5d from the series improved mouse lung function and slowed the progression of pulmonary fibrosis. Overall, this work promises a therapeutic potential for PI3K inhibitors to treat IPF.


Assuntos
Fosfatidilinositol 3-Quinases/química , Inibidores de Fosfoinositídeo-3 Quinase/química , Quinazolinas/química , Animais , Bleomicina/toxicidade , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/patologia , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Conformação Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Fosforilação/efeitos dos fármacos , Quinazolinas/metabolismo , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade
16.
J Med Chem ; 62(15): 6992-7014, 2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31117517

RESUMO

Polypharmacology is a promising paradigm in modern drug discovery. Herein, we have discovered a series of novel PI3K and HDAC dual inhibitors in which the hydroxamic acid moiety as the zinc binding functional group was introduced to a quinazoline-based PI3K pharmacophore through an appropriate linker. Systematic structure-activity relationship studies resulted in lead compounds 23 and 36 that simultaneously inhibited PI3K and HDAC with nanomolar potencies and demonstrated favorable antiproliferative activities. Compounds 23 and 36 efficiently modulated the expression of p-AKT and Ac-H3, arrested the cell cycle, and induced apoptosis in HCT116 cancer cells. Following pharmacokinetic studies, 23 was further evaluated in HCT116 and HGC-27 xenograft models to show significant in vivo anticancer efficacies with tumor growth inhibitions of 45.8% (po, 150 mg/kg) and 62.6% (ip, 30 mg/kg), respectively. Overall, this work shows promise in discovering new anticancer therapeutics by the approach of simultaneously targeting PI3K and HDAC pathways with a single molecule.


Assuntos
Antineoplásicos/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Inibidores de Histona Desacetilases/metabolismo , Histona Desacetilases/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/metabolismo , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Células HCT116 , Células Hep G2 , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/farmacologia , Humanos , Células K562 , Células MCF-7 , Camundongos , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular/métodos , Inibidores de Fosfoinositídeo-3 Quinase/síntese química , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia
17.
J Med Chem ; 61(14): 6087-6109, 2018 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-29927604

RESUMO

Increased phosphatidylinositol 3-kinase (PI3K) signaling is among the most common alterations in cancer, spurring intensive efforts to develop new cancer therapeutics that target this pathway. In this work, we discovered a series of novel 2-amino-4-methylquinazoline derivatives through a hybridization and subsequent scaffold hopping approach that were highly potent class I PI3K inhibitors. Lead optimization resulted in several promising compounds (e.g., 19, 20, 37, and 43) with nanomolar PI3K potencies, prominent antiproliferative activities, favorable PK profiles, and robust in vivo antitumor efficacies. More interestingly, compared with 19 and 20, 37 and 43 demonstrated improved brain penetration and in vivo efficacy in an orthotopic glioblastoma xenograft model. Furthermore, preliminary safety assessments including hERG channel inhibition, AMES, CYP450 inhibition, and single-dose toxicity were performed to characterize their toxicological properties.


Assuntos
Desenho de Fármacos , Inibidores de Fosfoinositídeo-3 Quinase , Quinazolinas/química , Quinazolinas/farmacologia , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Simulação de Acoplamento Molecular , Fosfatidilinositol 3-Quinases/química , Fosfatidilinositol 3-Quinases/metabolismo , Conformação Proteica , Quinazolinas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade
18.
Bioorg Med Chem ; 26(3): 637-646, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29305298

RESUMO

A series of new thienopyrimidine derivatives has been discovered as potent PI3K inhibitors. The systematic SAR studies for these analogues are described. Among them, 8a and 9a exhibit nanomolar enzymatic potencies and sub-micromolar cellular anti-proliferative activities. 8a displays favorable pharmacokinetic profiles, while 9a easily undergoes deacetylation to yield a major metabolite 8a. Furthermore, 8a and 9a potently inhibit tumor growth in a dose-dependent manner in the NCI-H460 xenograft model with an acceptable safety profile.


Assuntos
Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Meia-Vida , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Microssomos Hepáticos/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , Relação Estrutura-Atividade , Transplante Heterólogo
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