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1.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 53(1): 133-136, 2022 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-35048613

RESUMO

OBJECTIVE: To analyze the effect of factors relevant to blastocyst transfer on the pregnancy outcome of in vitro fertilization-embryo transfer (IVF-ET). METHODS: The clinical data of 790 pregnant women who underwent IVF-ET in our hospital from July 2015 to July 2020 were retrospectively analyzed. The pregnancy outcome of blastocysts transferred on day 5 (D5, n=705) and those transferred on day 6 (D6, n=85) were compared. According to the pregnancy outcome, the cases were divided into a live birth group ( n=322) and a non-live birth group ( n=468), and multivariate logistic regression was conducted to study the effect of factors relevant to blastocyst transfer on the live birth outcome of IVF-ET. RESULTS: In the D5 group, the biochemical pregnancy rate, clinical pregnancy rate and live birth rate of blastocyst transfer were 69.93%, 64.96%, and 41.84%, respectively, which were significantly higher than those of the D6 group at 50.59%, 45.88%, and 30.59%, respectively. The difference was statistically significant ( P<0.05). There was no statistically significant difference in the miscarriage rate between the D5 group and the D6 group ( P>0.05). Multivariate logistic analysis revealed that age>35 years, years of infertility>5 years, endometrium thickness<9 mm on the day of blastocyst transfer, trophoblast cell rating of C, blastocyst transfer performed on D6, and multiparity were all risk factors for non-live birth outcome of IVF-ET ( P<0.05). CONCLUSION: The adverse pregnancy outcomes of IVF-ET were found to be associated with age, duration of infertility, endometrial thickness on the day of to blastocyst transfer, trophoblast cell rating, and blastocyst transfer performed after how many days of embryo development, and multiparity, which should be closely monitored, and effective measures should be adopted accordingly to prevent adverse outcomes of pregnancy.


Assuntos
Transferência Embrionária , Resultado da Gravidez , Adulto , Blastocisto , Feminino , Fertilização In Vitro , Humanos , Gravidez , Taxa de Gravidez , Estudos Retrospectivos
2.
J Med Chem ; 65(1): 163-190, 2022 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-34939411

RESUMO

DCN1, a co-E3 ligase, interacts with UBC12 and activates cullin-RING ligases (CRLs) by catalyzing cullin neddylation. Although DCN1 has been recognized as an important therapeutic target for human diseases, its role in the cardiovascular area remains unknown. Here, we first found that DCN1 was upregulated in isolated cardiac fibroblasts (CFs) treated by angiotensin (Ang) II and in mouse hearts after pressure overload. Then, structure-based optimizations for DCN1-UBC12 inhibitors were performed based on our previous work, yielding compound DN-2. DN-2 specifically targeted DCN1 at molecular and cellular levels as shown by molecular modeling studies, HTRF, cellular thermal shift and co-immunoprecipitation assays. Importantly, DN-2 effectively reversed Ang II-induced cardiac fibroblast activation, which was associated with the inhibition of cullin 3 neddylation. Our findings indicate a potentially unrecognized role of DCN1 inhibition for anticardiac fibrotic effects. DN-2 may be used as a lead compound for further development.


Assuntos
/farmacologia , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Fibrose/tratamento farmacológico , Cardiopatias/tratamento farmacológico , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Pirimidinas/química , Enzimas de Conjugação de Ubiquitina/antagonistas & inibidores , Animais , Proteínas Culina/metabolismo , Inibidores Enzimáticos/química , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Fibrose/metabolismo , Fibrose/patologia , Cardiopatias/metabolismo , Cardiopatias/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína NEDD8/metabolismo , Ratos , Ratos Sprague-Dawley , Ubiquitinas
3.
Acta Pharmacol Sin ; 2021 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-34893686

RESUMO

The response rate of topotecan, as a second-line chemotherapeutic drug for small cell lung cancer, is ~20%. DNA/RNA helicase SLFN11 (schlafen family member 11), a member of the Schlafen (SLFN) family, is a crucial determinant of response to many DNA damaging agents, expression of SLFN11 tends to augment the antitumor effects of the commonly used DNA-targeting agents. In the present study we investigated how SLFN11 expression regulated the sensitivity of small cell lung cancer to topotecan. We showed that SLFN11 expression levels were positively associated with the sensitivity to topotecan in a panel of seven SCLC cell lines. Topotecan treatment induced different patterns of the DNA response network in SCLC cells: DNA damage response (DDR) was more prominently activated in SLFN11-deficient SCLC cell line H82 than in SLFN11-plentiful SCLC cell line DMS273, whereas topotecan induced significant accumulation of p-Chk1, p-RPA2 and Rad51 in H82 cells, but not in DMS273 cells. We unraveled that SLFN11 expression was highly negatively correlated to the methylation of the SLFN11 promoter. HDAC inhibitors FK228 and SAHA dose-dependently increased SLFN11 expression through suppressing DNA methylation at the SLFN11 promoter, thereby sensitizing SCLC cells to topotecan. Finally, we assessed the methylation status of the SLFN11 promoter in 27 SCLC clinical specimens, and found that most of the clinical samples (24/27) showed DNA methylation at the SLFN11 promoter. In conclusion, it is feasible to combine topotecan with FK228 to improve the response rate of topotecan in SCLC patients.

4.
Exp Cell Res ; 405(2): 112728, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34246653

RESUMO

ATP-binding cassette (ABC) transporter C10 (ABCC10), also named multidrug resistance protein 7 (MRP7), is a member of ABC transporter superfamily and has been revealed to transport a wide range of chemotherapeutic agents including taxanes, epothilone B, Vinca alkaloids, and anthracyclines. In our previous study, a 5-cyano-6-phenylpyrimidin derivative CP55 was synthesized and found significantly reversal effect of multidrug resistance (MDR) mediated by ABCB1. In this study, we found CP55 also efficiently reversed MDR mediated by ABCC10. Our in vitro study showed that co-treatment with CP55 significantly increased the efficacy of ABCC10-substrate anticancer drugs in MDR cells overexpressing ABCC10. Furthermore, we showed that treatment with CP55 increased the intracellular accumulation of [3H]-labeled anticancer drugs and in-turn decreasing drug efflux by inhibiting the transport activity, without altering ABCC10 protein ex-pression level or cellular localization. Potential CP55-ABCC10 interactions were predicted via docking analysis using human ABCC10 homology model and obtained high docking score. Therefore, CP55 represents a promising therapeutic agent in the combinational treatment of chemo-resistant cancer related to ABCC10.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Trifosfato de Adenosina/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/fisiologia , Humanos , Proteínas de Neoplasias/metabolismo , Sensibilidade e Especificidade
5.
Biochem Pharmacol ; 190: 114652, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34126072

RESUMO

Multidrug resistance-associated protein 7 (MRP7) is an important member of ABC transporter superfamily and has been revealed to mediate the cross-membrane translocation of a wide range of chemotherapeutic agents including taxanes, epothilones, Vinca alkaloids, Anthracyclines and Epipodophyllotoxins.In our previous study, a 1,2,3-triazole-pyrimidine hybridCMP25was synthesized and found able to efficiently reverse multidrug resistance (MDR) mediated by P-glycoprotein. In this study, we evaluated the efficacy of compound CMP25in reversing MDR mediated by MRP7in vitro. The results showed that CMP25significantly sensitized MRP7-overexpressing cells to anticancer drugs that are MRP7 substrates. Mechanistic study showed that CMP25reversed MRP7-mediated MDR by increasing the intracellular accumulation of anticancer drugs and decreasing drug efflux, without altering protein expression level or subcellular localization. Currently, very few studies on synthetic MRP7 modulators have been published. Our findings provide a valuable prototype for designing drugs to combine with conventional anticancer drugs to overcome MDR-mediated by MRP7.


Assuntos
Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Sistemas de Liberação de Medicamentos , Quimioterapia Combinada , Regulação da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Modelos Moleculares , Simulação de Dinâmica Molecular , Estrutura Molecular , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Conformação Proteica
6.
Eur J Med Chem ; 218: 113392, 2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-33831778

RESUMO

Histone deacetylase 6 (HDAC6) has emerged as a critical regulator of many cellular pathways in tumors due to its unique structure basis and abundant substrate types. Over the past few decades, the role played by HDAC6 inhibitors as anticancer agents has sparked great interest of biochemists worldwide. However, they were less reported for gastric cancer therapy. In this paper, with the help of bioisosteric replacement, in-house library screening, and lead optimization strategies, we designed, synthesized and verified a series of 1,3-diaryl-1,2,4-triazole-capped HDAC6 inhibitors with promising anti-gastric cancer activities. Amongst, compound 9r displayed the best inhibitory activity towards HDAC6 (IC50 = 30.6 nM), with 128-fold selectivity over HDAC1. Further BLI and CETSA assay proved the high affinity of 9r to HDAC6. In addition, 9r could dose-dependently upregulate the levels of acetylated α-tubulin, without significant effect on acetylated histone H3 in MGC803 cells. Besides, 9r exhibited potent antiproliferative effect on MGC803 cells, and promoted apoptosis and suppressed the metastasis without obvious toxicity, suggesting 9r would serve as a potential lead compound for the development of novel therapeutic agents of gastric cancer.


Assuntos
Antineoplásicos/farmacologia , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Triazóis/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química
7.
Bioorg Chem ; 109: 104754, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33677416

RESUMO

Tumor immunotherapy is currently subject of intense scientific and clinical developments. In previous decade, therapists used natural immune system from the human body to treat several diseases. Although tumor immune disease is a big challenge, combinatorial therapeutic strategy has been succeeded to show the clinical significance. In this context, we discuss the HDAC6 and tumor immune diseases relationship. Also, we summarized the current state of knowledge that based on the combination treatments of the HDAC6 inhibitors (HDAC6is) with antitumor immunomodulatory agents. We observed that, the combination therapies slow down the tumor immune diseases by blocking the aggresome and proteasome pathway. The combination therapy was able to reduce M2 macrophage and increasing PD-L1 blockade sensitivity. Most importantly, multiple combinations of HDAC6is with other agents may consider as potential strategies to treat tumor immune diseases, by reducing the side effects and improve efficacy for the future clinical development.


Assuntos
Antineoplásicos/farmacologia , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Fatores Imunológicos/farmacologia , Imunoterapia , Neoplasias/terapia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Desacetilase 6 de Histona/química , Desacetilase 6 de Histona/imunologia , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Fatores Imunológicos/síntese química , Fatores Imunológicos/química , Estrutura Molecular , Neoplasias/imunologia , Neoplasias/patologia
8.
J Med Chem ; 64(3): 1362-1391, 2021 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-33523672

RESUMO

Histone deacetylases (HDACs) are essential for maintaining homeostasis by catalyzing histone deacetylation. Aberrant expression of HDACs is associated with various human diseases. Although HDAC inhibitors are used as effective chemotherapeutic agents in clinical practice, their applications remain limited due to associated side effects induced by weak isoform selectivity. HDAC6 displays unique structure and cellular localization as well as diverse substrates and exhibits a wider range of biological functions than other isoforms. HDAC6 inhibitors have been effectively used to treat cancers, neurodegenerative diseases, and autoimmune disorders without exerting significant toxic effects. Progress has been made in defining the crystal structures of HDAC6 catalytic domains which has influenced the structure-based drug design of HDAC6 inhibitors. This review summarizes recent literature on HDAC6 inhibitors with particular reference to structural specificity and functional diversity. It may provide up-to-date guidance for the development of HDAC6 inhibitors and perspectives for optimization of therapeutic applications.


Assuntos
Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/química , Animais , Inibidores de Histona Desacetilases/química , Humanos , Modelos Moleculares , Relação Estrutura-Atividade
9.
Eur J Med Chem ; 210: 112970, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33153765

RESUMO

To discover novel anticancer agents with potent and low toxicity, we designed and synthesized a range of new thiosemicarbazone-indole analogues based on lead compound 4 we reported previously. Most compounds displayed moderate to high anticancer activities against five tested tumor cells (PC3, EC109, DU-145, MGC803, MCF-7). Specifically, the represented compound 16f possessed strong antiproliferative potency and high selectivity toward PC3 cells with the IC50 value of 0.054 µM, compared with normal WPMY-1 cells with the IC50 value of 19.470 µM. Preliminary mechanism research indicated that compound 16f could significantly suppress prostate cancer cells (PC3, DU-145) growth and colony formation in a dose-dependent manner. Besides, derivative 16f induced G1/S cycle arrest and apoptosis, which may be related to ROS accumulation due to the activation of MAPK signaling pathway. Furthermore, molecule 16f could effectively inhibit tumor growth through a xenograft model bearing PC3 cells and had no evident toxicity in vivo. Overall, based on the biological activity evaluation, analogue 16f can be viewed as a potential lead compound for further development of novel anti-prostate cancer drug.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Indóis/farmacologia , Tiossemicarbazonas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indóis/química , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Tiossemicarbazonas/química , Células Tumorais Cultivadas
10.
Eur J Med Chem ; 209: 112861, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33045661

RESUMO

CBP/p300, functioning as histone acetyltransferases and transcriptional co-factors, represents an attractive target for various diseases, including malignant tumor. The development of small-molecule inhibitors targeting the bromodomain and HAT domains of CBP/p300 has aroused broad interests of medicinal chemist in expectation of providing new hope for anti-cancer treatment. In particular, the CBP/p300 bromodomain inhibitor CCS1477, identified by CellCentric, is currently undergone clinical evaluation for the treatment of haematological malignancies and prostate cancer. In this review, we depict the development of CBP/p300 inhibitors reported from 2010 to 2020 and particularly highlight their structure-activity relationships (SARs), binding modes, selectivity and pharmacological functions with the aim to facilitate rational design and development of CBP/p300 inhibitors.


Assuntos
Histona Acetiltransferases/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Fatores de Transcrição de p300-CBP/antagonistas & inibidores , Animais , Descoberta de Drogas , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Histona Acetiltransferases/química , Histona Acetiltransferases/metabolismo , Humanos , Modelos Moleculares , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Domínios Proteicos/efeitos dos fármacos , Fatores de Transcrição de p300-CBP/química , Fatores de Transcrição de p300-CBP/metabolismo
11.
Eur J Med Chem ; 209: 112946, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33129590

RESUMO

Identification of potent anticancer agents with high selectivity and low toxicity remains on the way to human health. Pyridazine featuring advantageous physicochemical properties and antitumor potential usually is regarded as a central core in numerous anticancer derivatives. There are several approved pyridazine-based drugs in the market and analogues currently going through different clinical phases or registration statuses, suggesting pyridazine as a promising drug-like scaffold. The current review is intended to provide a comprehensive and updated overview of pyridazine derivatives as potential anticancer agents. In particular, we focused on their structure-activity relationship (SAR) studies, design strategies, binding modes and biological activities in the hope of offering novel insights for further rational design of more active and less toxic anticancer drugs.


Assuntos
Antineoplásicos/síntese química , Inibidores Enzimáticos/síntese química , Piridazinas/síntese química , Sequência de Aminoácidos , Animais , Antineoplásicos/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Modelos Moleculares , Ligação Proteica , Conformação Proteica , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Piridazinas/farmacologia , Pirofosfatases/antagonistas & inibidores , Relação Estrutura-Atividade
12.
Bioorg Chem ; 107: 104549, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33383324

RESUMO

Gramine is a natural indole alkaloid with a wide range of biological activities, but its anti-gastric cancer activity is poor. Herein, a pharmacophore fusion strategy was adopted to design and synthesize a new series of indole-azole hybrids on the structural basis of gramine. Based on our previous studies, different nitrogen-containing five-membered heterocyclic rings and terminal alkyne group were introduced into the indole-based scaffold to investigate their effect on improving the anti-gastric cancer activity of gramine derivatives. Structure-activity relationship (SAR) studies highlighted the role played by terminal alkyne in enhancing the inhibitory effect, and compound 16h displayed the best antiproliferative activity against gastric cancer MGC803 cells with IC50 value of 3.74 µM. Further investigations displayed compound 16h could induce mitochondria-mediated apoptosis, and caused cell cycle arrest at G2/M phase. Besides, compound 16h could inhibit the metastasis ability of MGC803 cells. Our studies may provide a new strategy for structural optimization of gramine to enhance anti-gastric cancer activity, and provide a potential candidate for the treatment of gastric cancer.


Assuntos
Antineoplásicos/química , Alcaloides Indólicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Alcaloides Indólicos/farmacologia , Alcaloides Indólicos/uso terapêutico , Mitocôndrias/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Relação Estrutura-Atividade
13.
Eur J Med Chem ; 200: 112458, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32497962

RESUMO

The multidrug resistance (MDR) phenomenon in cancer cells is the major obstacle leading to failure of chemotherapy accompanied by the feature of intractable and recurrence of cancers. As significant contributors that cause MDR, ABC superfamily proteins can transport the chemotherapeutic drugs out of the tumor cells by the energy of adenosine triphosphate (ATP) hydrolysis, thereby reducing their intracellular accumulation. The ABC transports like ABCB1, ABCC1 and ABCG2 have been extensively studied to develop modulators for overcoming MDR. To date, no reversal agents have been successfully marketed for clinical application, and little information about the ABC proteins bound to specific inhibitors is known, which make the design of MDR inhibitors with potency, selectivity and low toxicity a major challenge. In recent years, it has been increasingly recognized that pyrimidine-based derivatives have the potential for reversing ABC-mediated MDR. In this review, we summarized the pyrimidine-based inhibitors of ABC transporters, and mainly focused on their structure optimizations, development strategies and structure-activity relationship studies in hope of providing a reference for medicinal chemists to develop new modulators of MDR with highly potency and fewer side effects.


Assuntos
Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Pirimidinas/farmacologia , Transportadores de Cassetes de Ligação de ATP/metabolismo , Humanos , Estrutura Molecular , Pirimidinas/química
14.
Eur J Med Chem ; 199: 112349, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32438199

RESUMO

In this paper, a series of thiosemicarbazone derivatives containing different aromatic heterocyclic groups were synthesized and the tridentate donor system of the lead compound was optimized. Most of the target compounds showed improved antiproliferative activity against MGC803 cells. SAR studies revealed that compound 5d displayed significant advantages in inhibition effect with an IC50 value of 0.031 µM, and better selectivity between cancer and normal cells than 3-AP and DpC (about 15- and 5-fold improved respectively). Besides, compound 5d showed selective antiproliferative activity in not only other cancer cells but also different gastric cancer cell lines. In-depth mechanism studies showed that compound 5d could induce mitochondria-related apoptosis which might be related to the elevation of intracellular ROS level, and cause cell cycle arrest at S phase. Moreover, 5d could evidently suppress the cell migration and invasion by blocking the EMT (epithelial-mesenchymal transition) process. Consequently, our studies provided a lead optimization strategy of thiosemicarbazone derivatives which would contribute to discover high-efficiency and low-toxicity agents for the treatment of gastric cancer.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Neoplasias Gástricas/tratamento farmacológico , Tiossemicarbazonas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Estrutura Molecular , Neoplasias Gástricas/patologia , Relação Estrutura-Atividade , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/química , Células Tumorais Cultivadas , Cicatrização/efeitos dos fármacos
15.
Eur J Med Chem ; 192: 112161, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32155529

RESUMO

KDM5B (also known as PLU-1 and JARID1B) is 2-oxoglutarate and Fe2+ dependent oxygenase that acts as a histone H3K4 demethylase, which is a key participant in inhibiting the expression of tumor suppressors as a drug target. Here, we present the discovery of pyrazole derivatives compound 5 by structure-based virtual screening and biochemical screening with IC50 of 9.320 µM against KDM5B, and its subsequent optimization to give 1-(4-methoxyphenyl)-N-(2-methyl-2-morpholinopropyl)-3-phenyl-1H-pyrazole-4-carboxamide (27 ab), a potent KDM5B inhibitor with IC50 of 0.0244 µM. In MKN45 cells, compound 27 ab can bind and stabilize KDM5B and induce the accumulation of H3K4me2/3, bona fide substrates of KDM5B, while keep the amount of H3K4me1, H3K9me2/3 and H3K27me2 without change. Further biological study also indicated that compound 27 ab is a potent cellular active KDM5B inhibitor that can inhibit MKN45 cell proliferation, wound healing and migration. In sum, our finding gives a novel structure for the discovery of KDM5B inhibitor and targeting KDM5B may be a new therapeutic strategy for gastric cancer treatment.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Pirazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Movimento Celular/efeitos dos fármacos , 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 , Histona Desmetilases com o Domínio Jumonji , Estrutura Molecular , Proteínas Nucleares , Pirazóis/síntese química , Pirazóis/química , Proteínas Repressoras , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Cicatrização/efeitos dos fármacos
16.
Eur J Pharmacol ; 863: 172611, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31476282

RESUMO

Multidrug resistance (MDR) lead to inadequate response to chemotherapy and cause failure in cancer treatment. One of the targeted approaches to overcome MDR in cancer cells is interfering or inhibiting ATP binding cassette (ABC) transporters. Among all members in ABC transporters superfamily, ABCB1 (ABC transporter subfamily B #1) and ABCG2 (ABC transporter subfamily G #2) play an important role in the development of cancer MDR. In this study, we synthesized a novel 5-cyano-6-phenylpyrimidin derivative 479, which exhibited selective dual-activity in reversing MDR mediated by ABCB1 and ABCG2, without affecting MDR mediated by ABCC1 (ABC transporter subfamily C #1) and ABCC10 (ABC transporter subfamily C #10). Further mechanism studies demonstrated that 479 increased the accumulation of paclitaxel and mitoxantrone in cancer cells by interrupting the efflux function of transporters and stimulating ABCB1/ABCG2 ATPase activity. In silico study provided evidence that 479 formed multiple physiochemical bonds with the drug-binding pocket of ABCB1 and ABCG2. Overall, our results provide a promising prototype in designing potent dual reversal agents targeting ABCB1- and ABCG2-meidated MDR.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Pirimidinas/química , Pirimidinas/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/química , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/química , Linhagem Celular Tumoral , Humanos , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Mitoxantrona/metabolismo , Simulação de Acoplamento Molecular , Paclitaxel/metabolismo , Conformação Proteica , Pirimidinas/síntese química , Pirimidinas/metabolismo
17.
Bioorg Chem ; 91: 103167, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31398599

RESUMO

Three new alkaloids, iizukines C-E (1-3), including two aspochalasins (1 and 2), and one brasiliamide derivative (3), along with two known aspochalasins, rosellichalasin (4) and cytochalasin Z17 (5), were isolated from the culture of Aspergillus iizukae. Compound 1 was the first aspochalasin uniquely featuring a 1,2,4-triazole functionality, and 3 showed a pair of NMR signals in CDCl3 with a ratio of about 2:1 due to the existence of conformational isomers. Their structures were determined by extensive spectroscopic analyses and single-crystal X-ray diffractions. In particular, the 1,2,4-triazole moiety in 1 was assigned on the basis of extremely valuable 1H-15N HMBC spectrum. Compound 1 exhibited cytotoxic effect towards HL-60 and A549 cell lines with IC50 values of 3.8 and 7.2 µM, respectively.


Assuntos
Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Aspergillus/química , Proliferação de Células , Citocalasinas/química , Neoplasias/tratamento farmacológico , Solo/química , Alcaloides/química , Antineoplásicos/química , Humanos , Estrutura Molecular , Neoplasias/patologia , Células Tumorais Cultivadas
18.
Molecules ; 24(14)2019 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-31330867

RESUMO

Three new γ-hydroxyl butenolides (1-3), a pair of new enantiomeric spiro-butenolides (4a and 4b), a pair of enantiomeric cyclopentenones (5a new and 5b new natural), and six known compounds (6-11), were isolated from Aspergillus sclerotiorum. Their structures were established by spectroscopic data and electronic circular dichroism (ECD) spectra. Two pairs of enantiomers [(+)/(-)-6c and (+)/(-)-6d] obtained from the reaction of 6 with acetyl chloride (AcCl) confirmed that 6 was a mixture of two pairs of enantiomers. In addition, the X-ray data confirmed that 7 was also a racemate. The new metabolites (1-5) were evaluated for their inhibitory activity against cancer and non-cancer cell lines. As a result, compound 1 exhibited moderate cytotoxicity to HL60 and A549 with IC50 values of 6.5 and 8.9 µM, respectively, and weak potency to HL-7702 with IC50 values of 17.6 µM. Furthermore, compounds 1-9 were screened for their antimicrobial activity using the micro-broth dilution method. MIC values of 200 µg/mL were obtained for compounds 2 and 3 towards Staphylococcus aureus and Escherichia coli, while compound 8 exhibited a MIC of 50 µ/mL towards Candida albicans.


Assuntos
4-Butirolactona/análogos & derivados , Aspergillus/química , Ciclopentanos/química , Microbiologia do Solo , Solo/química , 4-Butirolactona/química , 4-Butirolactona/farmacologia , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclopentanos/farmacologia , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Análise Espectral , Relação Estrutura-Atividade
19.
Eur J Med Chem ; 161: 493-505, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30388465

RESUMO

To explore anti-gastric cancer agents with high efficacy and selectivity, we report the design, synthesis and optimization of a novel series of 3-(2,6,9-trisubstituted-9H-purine)-8-chalcone derivatives starting from the compound PCA-15 reported by us previously. Most of the target compounds demonstrated significant antiproliferative effects on MGC803 cancer cell line, and more potent than the positive control (PCA-15 and 5-Fu). Among them, compound 6o was identified to be the most active compound against MGC803 cell line with an IC50 value of 0.84 µM. Additionally, high selectivity was also observed between cancer and normal cells (23.35 µM against GES-1). Further mechanism studies confirmed that compound 6o could inhibit colony formation and migration, induce the apoptosis of MGC803 cells through both the mitochondrial-mediated intrinsic pathway and death receptor-mediated extrinsic pathway, which were evidenced by the up-regulation of Bax, cleaved-caspase 9/3/8, cleaved PARP and down-regulation of Bcl-2. Our systematic studies implied a new scaffold targeting gastric cancer cells for further development of small-molecule compounds with improved potency and selectivity.


Assuntos
Antineoplásicos/farmacologia , Chalconas/farmacologia , Desenho de Fármacos , Neoplasias Gástricas/tratamento farmacológico , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Chalconas/síntese química , Chalconas/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Neoplasias Gástricas/patologia , Relação Estrutura-Atividade
20.
Mar Drugs ; 16(11)2018 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-30445748

RESUMO

Five new (1⁻5) and two known xanthones (6 and 7), one of the latter (6) obtained for the first time as a natural product, together with three known anthraquinones, questin, penipurdin A, and questinol, were isolated from the coastal saline soil-derived Aspergillus iizukae by application of an OSMAC (one strain many compounds) approach. Their structures were determined by interpretation of nuclear magnetic resonance (NMR) and high-resolution electrospray ionization mass spectroscopy (HRESIMS) data, as well as comparison of these data with those of related known compounds. Antiviral activity of xanthones 1-7 was evaluated through the cytopathic effect (CPE) inhibition assay, and compound 2 exhibited distinctly strong activity towards influenza virus (H1N1), herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) with IC50 values of 44.6, 21.4, and 76.7 µM, respectively, which indicated that it was worth to further investigate it as a potential lead compound. The preliminary structure-activity relationship of the xanthones is discussed.


Assuntos
Antivirais/farmacologia , Aspergillus/química , Xantonas/farmacologia , Animais , Antivirais/química , Antivirais/isolamento & purificação , Cães , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 2/efeitos dos fármacos , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Concentração Inibidora 50 , Células Madin Darby de Rim Canino , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Solo/química , Microbiologia do Solo , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade , Xantonas/química , Xantonas/isolamento & purificação
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