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1.
ChemMedChem ; 17(6): e202100731, 2022 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-35146935

RESUMO

The epigenetic reader BRD4 is involved in chromatin remodelling and transcriptional regulation, making it a promising therapeutic target. However, over the past decades, many BRD4 inhibitors that entered clinical trials were, in the main, unsatisfactory, due to some therapeutic limitations such as off-target effects and drug resistance. Combining a BRD4 inhibitor with another drug was expected to be an ideal option to overcome these hurdles and to improve therapeutic outcomes. However, such combination therapy could trigger toxicity caused by drug-drug interactions, complex pharmacokinetics, and additive effects. Recently, the application of dual-target drugs targeting BRD4 and other kinases has become an attractive approach to remedy the defects of a single BRD4 inhibitor. This review focuses on recent advances in the discovery of dual BRD4-kinase inhibitors, with an emphasis on their co-crystal structures and structure-activity relationships (SARs), as well as future perspectives in this field.


Assuntos
Antineoplásicos , Proteínas de Ciclo Celular , Neoplasias , Fatores de Transcrição , Antineoplásicos/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Humanos , Neoplasias/tratamento farmacológico , Proteínas Nucleares , Polifarmacologia , Fatores de Transcrição/antagonistas & inibidores
2.
Bioorg Med Chem Lett ; 55: 128474, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34838651

RESUMO

BU-4664L is a naturally occurring N-farnesylated dibenzodiazepinone with important biological activities. Herein, we report the synthesis and antitumor evaluation of two series of BU-4664L derivatives bearing different substituent patterns on the dibenzodiazepinone core and with diverse side chains. All of the derivatives displayed micromolar activity against the human prostate cancer PC-3 cells, while lower or no activity against the human lung H460 cells. The most active derivatives were 10a and 16c which exerted antiproliferative activity against PC-3 cells with GI50 values of 5.66 and 5.94 µM, respectively, and thus represent promising lead compounds for further development.


Assuntos
Antineoplásicos/farmacologia , Dibenzazepinas/farmacologia , Sesquiterpenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dibenzazepinas/síntese química , Dibenzazepinas/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Sesquiterpenos/síntese química , Sesquiterpenos/química , Relação Estrutura-Atividade
3.
Eur J Med Chem ; 228: 114037, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34883290

RESUMO

Off-target toxicity is one of the main challenges faced by anticancer chemotherapeutics. For tumor targeted and precision chemotherapy, we take the advantages of the ligand directed tumor active targeting of small molecule drug conjugates (SMDCs) and the passive tumor targeting of nanoparticles via the enhanced penetration and retention (EPR) effects, put forward a branched small molecule drug conjugate (BSMDC) nanomedicine design concept. In a proof of concept, we used pentaerythritol as the branched moiety, galactosamine (GalN) as the hepatocellular carcinoma (HCC) directing ligands, PTX as a payload, and a stearoyl moiety as the amphiphilic property adjusting group, designed and synthesized BSMDC 1 and prepared its NPs. In cellular level, the BSMDC 1 NPs targeted asialoglycoprotein receptor (ASGPR)-overexpressing HepG2 cells, were effectively taken up in the cells and released in tumor microenvironments, inhibited the HepG2 cell proliferation, arrested HepG2 cell in G2/M phase and induced tumor cell apoptosis. In HepG2 xenograft nude mice, the BSMDC 1 NPs were high specific to target the tumor and demonstrated a higher antitumor efficiency than BSMDC 1, having no apparent influences on mice body weights and major organs, supporting our BSMDC nanomedicine design concept. Therefore, this new strategy may find applications for cancer targeted and precision chemotherapy.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Galactosamina/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Paclitaxel/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Antineoplásicos Fitogênicos/química , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Pontos de Checagem do Ciclo 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 , Galactosamina/química , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/patologia , Camundongos , Camundongos Nus , Estrutura Molecular , Nanomedicina , Paclitaxel/química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade
4.
Eur J Med Chem ; 225: 113821, 2021 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-34517222

RESUMO

Histone deacetylase 6 (HDAC6) is a potential target for Alzheimer's disease (AD). In this study, a series of novel phenothiazine-, memantine-, and 1,2,3,4-tetrahydro-γ-carboline-based HDAC6 inhibitors with a variety of linker moieties were designed and synthesized. As a hydrochloride salt, the phenothiazine-based hydroxamic acid W5 with a pyridyl-containing linker motif was identified as a high potent and selective HDAC6 inhibitor. It inhibited HDAC6 with an IC50 of 2.54 nM and was more than 290- to 3300-fold selective over other HDAC isoforms. In SH-SY5Y cells, W5 dose-dependently increased the acetylated α-tubulin levels and reduced the hyperphosphorylated tau proteins at Ser396. As an effective metal chelator, W5 inhibited Cu2+-induced Aß1-42 aggregation and disaggregated Cu2+-Aß1-42 oligomers, and showed protective effects on the SH-SY5Y cells against Aß1-42- as well as Cu2+-Aß1-42 induced cell damages, serving as a potential ligand to target AD metal dyshomeostasis. Moreover, W5 promoted the differentiated neuronal neurite outgrowth, increased the mRNA expression of the recognized neurogenesis markers, GAP43, N-myc, and MAP-2. Therefore, W5 might be a good lead for the development of novel HDAC6 inhibitors targeting multi-facets of AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Fármacos Neuroprotetores/farmacologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Cobre/metabolismo , Relação Dose-Resposta a Droga , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
5.
Bioorg Chem ; 113: 104995, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34034133

RESUMO

A series of novel 3-(1-benzotriazole)-nor-ß-lapachones 5a-5l were synthesized as the NQO1-targeted anticancer agents. Most of these compounds displayed good antiproliferative activity against the breast cancer MCF-7, lung cancer A549 and hepatocellular carcinoma HepG2 cells in agreements with their NQO1 activity. Among them, compound 5k was identified as a favorable NQO1 substrate. It could activate the ROS production in a NQO1-dependent manner, arrest tumor cell cycle at G0/G1 phase, promote tumor cell apoptosis, and decrease the mitochondrial membrane potential. In HepG2 xenograft models, 5k significantly suppressed the tumor growth with no influences on animal body weights. Therefore, 5k could be a good lead for further anticancer drug developments.


Assuntos
Antineoplásicos/farmacologia , Benzofuranos/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , NAD(P)H Desidrogenase (Quinona)/antagonistas & inibidores , Naftoquinonas/farmacologia , Triazóis/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Benzofuranos/síntese química , Benzofuranos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/patologia , Camundongos , Camundongos Nus , Modelos Moleculares , Estrutura Molecular , NAD(P)H Desidrogenase (Quinona)/metabolismo , Naftoquinonas/síntese química , Naftoquinonas/química , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química , Células Tumorais Cultivadas
6.
Curr Med Chem ; 28(8): 1585-1604, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32660395

RESUMO

BACKGROUND: The casein kinase 1 (CK1) family is involved in regulating many cellular processes, including membrane trafficking, DNA damage repair, cytoskeleton dynamics, cytoskeleton maintenance and apoptosis. CK1 isoforms, especially CK1δ and CK1ε have emerged as important therapeutic targets for severe disorders such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), familial advanced sleep phase syndrome and cancer. Due to the importance of CK1 for the pathogenesis of disorders, there are great interests in the development of CK1 inhibitors. METHODS: Using SciFinder® as a tool, the publications about the biology of CK1 and the recent developments of CK1 inhibitors were surveyed with an exclusion of those published as patents. RESULTS: This review presents the current state of knowledge on the development of CK1 inhibitors, including both synthetic small molecular inhibitors that were divided into 7 categories according to structural features, and the natural compounds. An overview of the advancement of CK1 inhibitors was given, with the introduction of various existing CK1 inhibitors, their inhibitory activities, and the structure-activity relationships. CONCLUSION: Through physicochemical characterization and biological investigations, it is possible to understand the structure-activity relationship of CK1 inhibitors, which will contribute to better design and discovery of potent and selective CK1 inhibitors as potential agents for severe disorders such as AD, ALS and cancer.


Assuntos
Caseína Quinase I , Neoplasias , Apoptose , Caseína Quinase I/metabolismo , Humanos , Neoplasias/tratamento farmacológico , Isoformas de Proteínas , Relação Estrutura-Atividade
7.
Future Med Chem ; 13(1): 45-62, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33242992

RESUMO

RET is a proto-oncogene encoding a receptor tyrosine kinase. RET regulates key aspects of cellular proliferation, differentiation and survival. The activation of RET via gene fusions or point mutations is closely related to lung, thyroid and other cancers. This review summarizes the developments of a diversity of small molecule RET protein kinase inhibitors in the past 10 years. These RET inhibitors are classified according to their hinge binder chemotypes as: pyrimidines, including the pyrazolopyrimidines, pyrimidine oxazines, quinazolines, 4-aminopyrimidines and 4-aminopyridines; indolinones; 5-aminopyrazole-4-carboxamides; 3-trifluoromethylanilines; imidazopyridines, imidazopyridazines and pyrazopyridines; nicotinonitriles; pyridones and 1,2,4-triazoles. In each section, the biological activities of the inhibitors, their structure-activity relationships and possible binding modes with the RET kinase are introduced.


Assuntos
Antineoplásicos/química , Inibidores de Proteínas Quinases/metabolismo , Proteínas Proto-Oncogênicas c-ret/metabolismo , Pirimidinas/química , Receptores Proteína Tirosina Quinases/química , Compostos de Anilina/química , Compostos de Anilina/farmacologia , Antineoplásicos/farmacologia , Descoberta de Drogas , Hemoglobina A/metabolismo , Humanos , Imidazóis/química , Imidazóis/farmacologia , Oxazinas/química , Oxazinas/farmacologia , Oxindóis/química , Oxindóis/farmacologia , Pirazóis/química , Pirazóis/farmacologia , Piridinas/química , Piridinas/farmacologia , Pirimidinas/farmacologia , Quinazolinas/química , Quinazolinas/farmacologia , Receptores Proteína Tirosina Quinases/farmacologia
8.
J Med Chem ; 63(23): 14840-14866, 2020 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-33201714

RESUMO

Taking the previously discovered 1-methyl-1,4-dihydroindeno[1,2c]pyrazol derivative LL01 as a lead, systematic structural modifications were made at the phenolic 6- and 7-positions and the aniline at the 3-position of the indenopyrazole core to investigate the SARs and to improve water solubility. Among the designed indenopyrazoles ID01-ID33, a series of potent MTAs were identified. As the hydrochloride salt(s), ID09 and ID33 showed excellent aqueous solubility and favorable Log P value and displayed noteworthily low nanomolar potency against a variety of tumor cells, including those taxol-resistant ones. They inhibited tubulin polymerization, disrupted cellular microtubule networks by targeting the colchicine site, and promoted HepG2 cell cycle arrest and cell apoptosis. In the HepG2 xenograft mouse model, ID09 and ID33 effectively inhibited tumor growth at an oral dose of 25 mg/kg. At an intravenous (iv) injection dose of 10 mg/kg every other day, ID09 suppressed tumor growth by 68% without obvious toxicity.


Assuntos
Antineoplásicos/uso terapêutico , Indenos/uso terapêutico , Neoplasias/tratamento farmacológico , Pirazóis/uso terapêutico , Moduladores de Tubulina/uso terapêutico , Animais , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Células Hep G2 , Humanos , Indenos/síntese química , Camundongos Endogâmicos BALB C , Estrutura Molecular , Pirazóis/síntese química , Solubilidade , Relação Estrutura-Atividade , Moduladores de Tubulina/síntese química , Água/química , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Bioorg Chem ; 101: 104005, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32599362

RESUMO

The clinical application of mitoxantrone (MTZ), a DNA-intercalating topoisomerase II (topo II) poison, has been largely limited by the risk of secondary tumor and severe myelosuppression. To develop more effective antineoplastic agents with less toxicity, a spectrum of anthraquinone analogues of MTZ were herein designed and synthesized based on the concept of 'enhancing protein backbone-binding', by rationally introducing hydrophobic long fatty acid chain (LFC) and hydrophilic polyamine (PA) components, which are reported to function as effective tumor-targeting tethers. The SAR exploration implicated that in our synthesized molecules, the introduction of both lipophilic LFC and hydrophilic PA fragment is plausibly beneficial to the anti-proliferative potency, with a certain degree of selectivity between the hematopoietic and solid malignant cells, which still need to be further accurately confirmed. Meanwhile, many compounds, the LFC-tethered 5d2 and PA-bridged 8c in particular, provided satisfactory topo IIα inhibition by acting as DNA non-intercalators, largely attributable to their strong adaptability to three binding regions (pocket I, II and III) and also the generated H-bonding interactions between inhibitors and key residues of topo IIα. In brief, 5d2 and 8c might be promising hits for further exploitation of more potent topo IIα inhibitors.


Assuntos
Antraquinonas/química , Antineoplásicos/farmacologia , Desenho de Fármacos , Mitoxantrona/análogos & derivados , Inibidores da Topoisomerase II/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Humanos , Mitoxantrona/química , Mitoxantrona/farmacologia , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/química
10.
Eur J Med Chem ; 198: 112396, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32464425

RESUMO

A novel series of 4-substituted-3,4-dihydrobenzo[h]quinoline-2,5,6(1H)-triones as NQO1-directed antitumor agents were designed, synthesized, biologically evaluated. Compounds 3n, 3o and 3j proved to be good NQO1 substrates that showed increased metabolic rates relative to that of ß-lapachone. In addition, 3n, 3o and 3j potently inhibited the growth of NQO1-rich breast cancer MCF-7 cell, liver hepatocellular HepG2 cell, and lung cancer A549 cell. In cellular mechanistic studies, the representative compound 3o triggered ROS generation depending on the NQO1 dose, and induce HepG2 cell apoptosis by the generated oxidative stress. In HepG2 xenografts mouse model, at the dose of 20 mg/kg, 3o remarkably suppressed the tumor growth without affecting the animal weights.


Assuntos
Antineoplásicos/síntese química , NAD(P)H Desidrogenase (Quinona)/metabolismo , Quinolinas/síntese química , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Xenoenxertos , Humanos , Camundongos , Modelos Moleculares , Terapia de Alvo Molecular , Naftoquinonas/farmacologia , Neoplasias Experimentais , Estresse Oxidativo , Quinolinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade
11.
Cells ; 9(3)2020 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-32155989

RESUMO

Due to the complicated pathogenesis of Alzheimer's disease (AD), the development of multitargeted agents to simultaneously interfere with multiple pathological processes of AD is a potential choice. Glycogen synthase kinase-3ß (GSK-3ß) plays a vital role in the AD pathological process. In this study, we discovered a novel 1H-pyrrolo[2,3-b]pyridine derivative B10 as a GSK-3ß inhibitor that features with a quinolin-8-ol moiety to target the metal dyshomeostasis of AD. B10 potently inhibited GSK-3ß with an IC50 of 66 ± 2.5 nM. At the concentration of 20 µM, B10 increased ß-catenin abundance (ß-catenin/GAPDH: 0.83 ± 0.086 vs. 0.30 ± 0.016), phosphorylated GSK-3ß at Ser9 (p-GSK-3ß/GAPDH: 0.53 ± 0.045 vs. 0.35 ± 0.012), and decreased the phosphorylated tau level (p-tau/GAPDH: 0.33 ± 0.065 vs. 0.83 ± 0.061) in SH-SY5Y cells. Unlike other GSK-3ß inhibitors, B10 had a direct effect on Aß by inhibiting Aß1-42 aggregation and promoting the Aß1-42 aggregate disassociation. It selectively chelated with Cu2+, Zn2+, Fe3+, and Al3+, and targeted AD metal dyshomeostasis. Moreover, B10 effectively increased the mRNA expression of the recognized neurogenesis markers, GAP43, N-myc, and MAP-2, and promoted the differentiated neuronal neurite outgrowth, possibly through the GSK-3ß and ß-catenin signal pathways. Therefore, B10 is a potent and unique GSK-3ß inhibitor that has a direct on Aß and serves as a multifunctional anti-AD agent for further investigations.


Assuntos
Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Neuritos/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Proteínas tau/efeitos dos fármacos , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Linhagem Celular Tumoral , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Neuritos/metabolismo , Crescimento Neuronal/efeitos dos fármacos , Neurônios/metabolismo , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
12.
Curr Med Chem ; 27(27): 4567-4576, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32175831

RESUMO

BACKGROUND: Microtubule Targeting Agents (MTAs) represent the most successful anticancer drugs for cancer chemotherapy. Through interfering with the tubulin polymerization and depolymerization dynamics, MTAs influence intracellular transport and cell signal pathways, inhibit cell mitosis and cell proliferation, and induce cell apoptosis and death. The tubulin maytansine site binding agents are natural or nature-derived products that represent one type of the MTAs that inhibit tubulin polymerization and exhibit potent antitumor activity both in vitro and in vivo. They are used as Antibody-Drug Conjugates (ADCs) in cancer chemotherapy. METHODS: Using SciFinder® as a tool, the publications about maytansine, its derivatives, maytansine binding site, maytansine site binding agents and their applications as MTAs for cancer therapy were surveyed with an exclusion on those published as patents. The latest progresses in clinical trials were obtained from the clinical trial web. RESULTS: This article presents an introduction about MTAs, maytansine, maytansine binding site and its ligands, the applications of these ligands as MTAs and ADCs in cancer therapy. CONCLUSION: The maytansine site binding agents are powerful MTAs for cancer chemotherapy. The maytansine site ligands-based ADCs are used in clinic or under clinical trials as cancer targeted therapy to improve their selectivity and to reduce their side effects. Further improvements in the delivery efficiency of the ADCs will benefit the patients in cancer targeted therapy.


Assuntos
Neoplasias , Antineoplásicos , Humanos , Imunoconjugados , Ligantes , Maitansina , Microtúbulos , Trastuzumab , Tubulina (Proteína)
13.
Eur J Med Chem ; 187: 111968, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31865012

RESUMO

Tubulin inhibitors that bind to the colchicine site are widely studied anticancer agents. In continuous our researches, we designed a series of novel indazole derivatives as microtubule-targeting agents (MTAs). The structure-activity relationships (SARs) investigations indicated that a 3,4,5-trimethoxyphenyl moiety and a methyl or methoxy substitution were preferred for the better antiproliferative activity. The indazole derivatives 3c and 3f showed noteworthy low nanomolar potency against HepG2, HCT116, SW620, HT29 and A549 tumor cells. In mechanism studies, 3c and 3f were proved to target the colchicine site, inhibited tubulin polymerization and disrupted cellular microtubule networks, arrested HCT116 cell in G2/M phase and induced cell apoptosis. In the HCT116 xenografts mouse model, 3c and 3f suppressed tumor growth by 45.3% and 58.9% at an orally dose of 25 mg/kg without causing obvious weight loss. The indazole 3f may serve as a good lead or drug candidate for colorectal cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Colchicina/farmacologia , Descoberta de Drogas , Indazóis/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Sítios de Ligação/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Colchicina/síntese química , Colchicina/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indazóis/síntese química , Indazóis/química , Camundongos , Camundongos Nus , Modelos Moleculares , Estrutura Molecular , Polimerização/efeitos dos fármacos , Relação Estrutura-Atividade , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química
14.
Invest New Drugs ; 38(1): 29-38, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-30887253

RESUMO

Through rational drug design, we previously identified an indenoprazole derivative, 2-(6-ethoxy-3-(3-ethoxyphenylamino)-1-methyl-1,4-dihydroindeno[1,2-c]pyrazol-7-yloxy)acetamide (LL01), as a potent tubulin polymerization inhibitor targeting the tubulin colchicine binding site. In this study, we further demonstrated that LL01 was not a P-gp substrate. It potently inhibited the growth of a variety of tumor cells, including those with multidrug resistance, with GI50 values in the low nanomole ranges. In vitro liver microsome stability assay, LL01 was modest stable in the liver microsomes of human, mouse and rat, but was fast metabolized in dog. After single oral administration of LL01 at a dose of 10 mg/kg in SD male rats, LL01 showed acceptable PK properties with a mean bioavailability of 41%. In human HepG2 hepatoma xenograft, at the oral doses of 25 mg/kg/day and 12.5 mg/kg/day, LL01 inhibited the tumor growth by 61.27%, and 43.74%, respectively, which is much better than the positive drug sorafenib (29.45%; 30 mg/kg/day). Therefore, LL01 might be a potential drug candidate for further investigation for hepatocellular carcinoma therapy.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Colchicina/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Animais , Antineoplásicos/química , Apoptose , Sítios de Ligação , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proliferação de Células , Resistência a Múltiplos Medicamentos , Feminino , Humanos , Técnicas In Vitro , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Ratos , Ratos Sprague-Dawley , Moduladores de Tubulina/química , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Molecules ; 24(23)2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31775363

RESUMO

In previous work, we applied the rotation-limiting strategy and introduced a substituent at the 3-position of the pyrazolo [3,4-d]pyrimidin-4-amine as the affinity element to interact with the deeper hydrophobic pocket, discovered a series of novel quinazolinones as potent PI3Kδ inhibitors. Among them, the indole derivative 3 is one of the most selective PI3Kδ inhibitors and the 3,4-dimethoxyphenyl derivative 4 is a potent and selective dual PI3Kδ/γ inhibitor. In this study, we replaced the carbonyl group in the quinazolinone core with a sulfonyl group, designed a series of novel 2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives as PI3Kδ inhibitors. After the reduction of nitro group in N-(2,6-dimethylphenyl)-2-nitrobenzenesulfonamide 5 and N-(2,6-dimethylphenyl)-2-nitro-5-fluorobenzenesulfonamide 6, the resulting 2-aminobenzenesulfonamides were reacted with trimethyl orthoacetate to give the 3-methyl-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives. After bromination of the 3-methyl group, the nucleophilic substitution with the 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine provided the respective iodide derivatives, which were further reacted with a series of arylboronic acids via Suzuki coupling to furnish the 2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives 15a-J and 16a-d. In agreement with the quinazolinone derivatives, the introduction of a 5-indolyl or 3,4-dimethoxyphenyl at the affinity pocket generated the most potent analogues 15a and 15b with the IC50 values of 217 to 266 nM, respectively. In comparison with the quinazolinone lead compounds 3 and 4, these 2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives exhibited much decreased PI3Kδ inhibitory potency, but maintained the high selectivity over other PI3K isoforms. Unlike the quinazolinone lead compound 4 that was a dual PI3Kδ/γ inhibitor, the benzthiadiazine 1,1-dioxide 15b with the same 3,4-dimethoxyphenyl moiety was more than 21-fold selective over PI3Kγ. Moreover, the introducing of a fluorine atom at the 7-position of the 2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide core, in general, was not favored for the PI3Kδ inhibitory activity. In agreement with their high PI3Kδ selectivity, 15a and 15b significantly inhibited the SU-DHL-6 cell proliferation.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Quinazolinonas/química , Tiadiazinas/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Classe I de Fosfatidilinositol 3-Quinases/química , Desenho de Fármacos , Humanos , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Quinazolinonas/síntese química , Quinazolinonas/farmacologia , Relação Estrutura-Atividade , Tiadiazinas/química , Tiadiazinas/farmacologia
16.
Eur J Med Chem ; 167: 211-225, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30772605

RESUMO

To target the multi-facets of Alzheimer's disease (AD), a series of novel GSK-3ß inhibitors containing the 2,3-diaminopyridine moiety were designed and synthesized. The amide derivatives 5a-f showed moderate potency against GSK-3ß with weak Cu2+, Zn2+ and Al3+ chelating ability. The imine derivatives 9a, 9b and 9e were potent GSK-3ß inhibitors and selective Cu2+and Al3+ chelators. The 1,2-diamine derivatives 10a-e were strong metal-chelators, but decreased or lost their GSK-3ß inhibitory potency. In vitro, compounds 9a, 9b and 9e, especially 9b, exhibited good Cu2+-induced Aß aggregation inhibition, Cu2+-Aß complex disaggregation, ROS formation inhibition, and antioxidant activities. In cells, compounds 9a, 9b and 9e can inhibit tau protein phosphorylation and protect neuro cells against Cu2+-Aß1-42 and H2O2-induced cell damage. Furthermore, compound 9b was predicted to have the ability to pass the BBB with drug likeness properties. Therefore, compound 9b might be a good lead for the development of novel GSK-3ß inhibitors targeting multi-facets of AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Amidas/química , Aminas/química , Animais , Antioxidantes/farmacologia , Barreira Hematoencefálica/metabolismo , Linhagem Celular , Quelantes , Desenho de Fármacos , Humanos , Células PC12 , Agregação Patológica de Proteínas/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Ratos , Relação Estrutura-Atividade , Proteínas tau/metabolismo
17.
Molecules ; 24(2)2019 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-30642134

RESUMO

To find novel antitumor agents, a series of 1H-benzofuro[3,2-c]pyrazole derivatives 4a-e were designed and synthesized. The treatment of 6-methoxybenzofuran-3(2H)-one 3 with LiHMDS in anhydrous tetrahydrofuran (THF) followed by reaction with 3-substitued phenyl isothiocyanate gave the thioamide intermediates, which underwent condensation with hydrazine monohydrate in dioxane/EtOH (1:1) to provide the benzofuropyrazole derivatives 4a⁻e as well as the unexpected pyrazole derivatives 5a⁻e. In tumor cell growth inhibitory assay, all the benzofuropyrazole derivatives were not active against the breast tumor MCF-7 cell, only 4a was highly active and more potent than ABT-751 against the leukemia K562 (GI50 = 0.26 µM) and lung tumor A549 cells (GI50 = 0.19 µM), while other benzofuropyrazoles showed very weak inhibitory activity. In contrast, the pyrazoles 5a-e were in general more potent than the benzofuropyrazoles 4a⁻e. Compound 5a exhibited a similar tendency to that of 4a with high potency against K562 and A549 cells but weak effects on MCF-7 cell. Both pyrazoles 5b and 5e exhibited high inhibitory activities against K562, MCF-7 and A549 cells. The most active compound 5b was much more potent than ABT-751 against K562 and A549 cells with GI50 values of 0.021 and 0.69 M, respectively. Moreover, 5b was identified as a novel tubulin polymerization inhibitor with an IC50 of 7.30 M.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Pirazóis/síntese química , Pirazóis/farmacologia , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Pirazóis/química , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia
18.
J Steroid Biochem Mol Biol ; 186: 66-73, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30253225

RESUMO

Two novel 1α,25-dihydroxyvitamin D3 derivatives containing a α,α-difluorocyclopentanone (3) or α,α-difluorocyclohexanone (4) moiety at the CD-ring side chains were designed, synthesized, and evaluated for their biological properties on restoring bone mass in ovariectomized (OVX) rats with established osteopenia. The synthesis of compounds 3 and 4 utilized the Wittig-Horner coupling to build up the vitamin D conjugated triene system, followed by the introduction of the cycloketone fragments at the side chain, and subsequent α,α-difluorination of the ketone by the treatment of the derived silyl enol ether with Selectfluor, as the key synthetic steps. In comparison with the natural 1α,25-dihydroxyvitamin D3 (calcitriol; 200 ng/kg/day), oral administration of compounds 3 and 4 at the dose of 25 ng/kg/day for 6 weeks led to much improved bone mass and bone density related parameters, while maintaining normal serum calcium and serum phosphorus levels. The immunohistochemistry results showed that both compounds remarkably decreased in osteoclast number and moderately decreased in osteoblast number on trabecular bone surface. Therefore, our findings suggested that compounds 3 and 4 successfully rescue bone loss by suppression on bone turnover in OVX rat models.


Assuntos
Doenças Ósseas Metabólicas/tratamento farmacológico , Vitamina D/análogos & derivados , Vitaminas/química , Vitaminas/uso terapêutico , Animais , Densidade Óssea/efeitos dos fármacos , Doenças Ósseas Metabólicas/sangue , Doenças Ósseas Metabólicas/patologia , Doenças Ósseas Metabólicas/fisiopatologia , Cálcio/sangue , Feminino , Halogenação , Osteogênese/efeitos dos fármacos , Ovariectomia , Ratos , Ratos Wistar , Vitamina D/síntese química , Vitamina D/química , Vitamina D/uso terapêutico , Vitaminas/síntese química
19.
Mini Rev Med Chem ; 19(2): 165-176, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29692249

RESUMO

Statins are currently the major therapeutic strategies to lower low-density lipoprotein cholesterol (LDL-C) levels. However, a number of hypercholesterolemia patients still have a residual cardiovascular disease (CVD) risk despite taking the maximum-tolerated dose of statins. Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to low-density lipoprotein receptor (LDLR), inducing its degradation in the lysosome and inhibiting LDLR recirculating to the cell membranes. The gain-offunction mutations in PCSK9 elevate the LDL-C levels in plasma. Therefore, PCSK9 inhibitors become novel therapeutic approaches in the treatment of hypercholesterolemia. Several PCSK9 inhibitors have been under investigation, and much progress has been made in clinical trials, especially for monoclonal antibodies (MoAbs). Two MoAbs, evolocumab and alirocumab, are now in clinical use. In this review, we summarize the development of PCSK9 inhibitors, including antisense oligonucleotides (ASOs), small interfering RNA (siRNA), small molecule inhibitor, MoAbs, mimetic peptides and adnectins, and the related safety issues.


Assuntos
Anticolesterolemiantes/uso terapêutico , LDL-Colesterol/antagonistas & inibidores , Inibidores Enzimáticos/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Animais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Anticolesterolemiantes/efeitos adversos , Anticolesterolemiantes/farmacologia , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , LDL-Colesterol/metabolismo , Descoberta de Drogas , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacologia , Humanos , Hipercolesterolemia/metabolismo , Pró-Proteína Convertase 9/metabolismo
20.
Expert Opin Ther Pat ; 28(8): 647-651, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30073889

RESUMO

INTRODUCTION: There are great potential in the development of selective HDAC6 inhibitors for the treatment of infectious diseases, neoplasms, endocrine diseases, and other diseases associated with HDAC6 activity. Areas covered: The application claims 1,3,4-oxadiazole sulfamide derivatives as selective HDAC6 inhibitors for the treatment of infectious diseases, neoplasms, endocrine, nutritional, and metabolic diseases; mental and behavioral disorders; neurological diseases; diseases of the eye and adnexa; cardiovascular diseases; respiratory diseases; digestive diseases; diseases of the skin and subcutaneous tissue; disease of the musculoskeletal system and connective tissue; or congenital malformations, deformations and chromosomal abnormalities. Many of the exemplified compounds showed nanomole potency against HDAC6 and were more than 5000-fold selectivity for HDAC6 over HDAC1. Expert opinion: These 1,3,4-oxadiazole sulfamide derivatives have a unique zinc-binding group (ZBG) that provide good leads for the discovery of potent selective HDAC6 inhibitors for the treatment of a variety of diseases associated with HDAC6 activity.


Assuntos
Inibidores de Histona Desacetilases/farmacologia , Oxidiazóis/farmacologia , Sulfonamidas/farmacologia , Desenho de Fármacos , Descoberta de Drogas/métodos , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Oxidiazóis/síntese química , Oxidiazóis/química , Patentes como Assunto , Sulfonamidas/síntese química , Sulfonamidas/química
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