RESUMEN
Fourteen new compounds with 2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline or 2,3,5,9b-tetrahydro-1H-pyrrolo[3,2-c]quinoline scaffold were designed and synthesized, and their inhibitory activities against Kv2.1 were evaluated. As a result,2,3-dihydro-1H-pyrrolo[3,2-c]quinoline derivatives 3a and 5a were identified as potent inhibitors of Kv2.1 with IC(50) values of 10.2 and 9.0 µmol·L(-1), respectively.
Asunto(s)
Quinolinas/química , Canales de Potasio Shab/antagonistas & inhibidores , Humanos , Relación Estructura-ActividadRESUMEN
Poly(ADP-ribose)polymerase-1 (PARP-1) plays a significant role in the DNA repair process by catalyzing the transfer of ADP-ribose from NAD+ to its receptors. It is a promising anticancer drug target and many PARP-1 inhibitors have been developed and used in the clinical trial. In this work, a series of 3-(2-oxo-2-substituted acetamido)benzamides have been synthesized and their inhibitory activities against PARP-1 were evaluated. Of all the tested compounds, six compounds displayed inhibitory activities with IC50 values ranging from 0.23 to 5.78 µmol.L-1 . The binding pose of compound 5a was predicted using molecular docking to facilitate further structural modification.
Asunto(s)
Benzamidas/química , Diseño de Fármacos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/síntesis química , Antineoplásicos , Reparación del ADN , Humanos , Simulación del Acoplamiento Molecular , Inhibidores de Poli(ADP-Ribosa) Polimerasas/química , Poli(ADP-Ribosa) PolimerasasRESUMEN
Poly(ADP-ribose) polymerase-1 (PARP-1) has emerged as a promising anticancer drug target due to its key role in the DNA repair process. It can polymerize ADP-ribose units on its substrate proteins which are involved in the regulation of DNA repair. In this work, a novel series of para-substituted 1-benzyl-quinazoline-2, 4 (1H, 3H)-diones was designed and synthesized, and the inhibitory activities against PARP-1 of compounds 7a-7e, 8a-8f, 9a-9c and 10a-10c were evaluated. Of all the tested compounds, nine compounds displayed inhibitory activities with IC50 values ranging from 4.6 to 39.2 micromol x L(-1). In order to predict the binding modes of the potent molecules, molecular docking was performed using CDOCKER algorithm, and that will facilitate to further develop more potent PARP-1 inhibitors with a quinazolinedione scaffold.
Asunto(s)
Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Quinazolinonas/síntesis química , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Simulación del Acoplamiento Molecular , Estructura Molecular , Poli(ADP-Ribosa) Polimerasa-1 , Poli(ADP-Ribosa) Polimerasas , Quinazolinonas/química , Quinazolinonas/farmacología , Relación Estructura-ActividadRESUMEN
WYK431, a novel synthetic quinazoline derivative, showing potent inhibition of proliferation activity against a broad spectrum of human cancer cell lines. We investigated the anticancer effects of WYK431 on BGC823 cells both in vitro and in vivo. The results showed that WYK431 inhibited proliferation, arrested the cell cycle at the G(2)/M phase, which was related to CDK1 and CDC25C, and induced apoptosis associated with activation of caspase-3 and caspase-9 rather than caspase-8 in BGC823 cells. Treatment of BGC823 cells with WYK431 resulted in upregulation of Bax, release of cytochrome c from the mitochondria to the cytosol and disruption of mitochondrial membrane potential. Western blot analysis showed that WYK431 downregulated the levels of the PI3K/Akt signaling pathway. Moreover, WYK431 effectively suppressed tumor growth in xenograft models in BALB/c athymic nude mice without major side action. TUNEL analysis showed that WYK431 induced BGC823 cell apoptosis in vivo. Collectively, WYK431 is a novel small molecule agent which inhibits BGC823 cell proliferation inducing G(2)/M phase arrest and apoptosis via the mitochondrial apoptotic pathway. To assess its potential as a promising anticancer agent requires further investigation.
Asunto(s)
Adenocarcinoma/patología , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Quinazolinas/farmacología , Neoplasias Gástricas/patología , Animales , Western Blotting , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Humanos , Etiquetado Corte-Fin in Situ , Puntos de Control de la Fase M del Ciclo Celular/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
Pin1 (peptidyl-prolyl cis-trans isomerase NIMA-interacting 1) belongs to peptidyl-prolyl cis-trans isomerase (PPIase) and is a novel promising anticancer target. Based on the lead structure of benzophenone, a series of novel diarylether derivatives containing a pyrimidine ring were designed and synthesized. The inhibitory activities on Pin1 of compounds 5a-5d and 6a-6i were evaluated by a protease-coupled enzyme assay. Of all the evaluated compounds, 6 compounds displayed inhibitory activities. Molecular docking was performed using FlexX algorithm to explore the binding mode of the active molecules.
Asunto(s)
Diseño de Fármacos , Inhibidores Enzimáticos/química , Éteres/química , Isomerasa de Peptidilprolil/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Éteres/síntesis química , Éteres/farmacología , Humanos , Concentración 50 Inhibidora , Simulación del Acoplamiento Molecular , Estructura Molecular , Peptidilprolil Isomerasa de Interacción con NIMA , Isomerasa de Peptidilprolil/metabolismo , Pirimidinas/química , Relación Estructura-ActividadRESUMEN
This study is to investigate the mechanism and action characteristics of 6-chloro-3-methyl-4-(2-methyoxycarbonylthiophene-3-sulfonyl)-3, 4-dihydroquinoxa-lin-2-(1 H)-one (XU07011) against HIV-1 replication. XU07011 anti-HIV activity was tested by using VSVG/HIV pseudotype viral system and confirmed by HIV-1 live viruses' infectious assay. Time of addition was used to test HIV-1 reverse transcription process. RNA-dependent DNA polymerase activity and RNase H activity were tested by using enzyme linked immunoabsorbent assay and fluorescence method. Wild type and nine NNRTIs-resistant reverse transcriptase enzymatic models and cell-based pharmacological models were used to evaluate XU07011 bio-characteristics. The results showed that XU07011 inhibited HIV-1 replication with IC50 of (0.057 +/- 0.01) micromol x L(-1) which was comparable to nevirapine [IC50: (0.046 +/- 0.01) micromol x L(-1)]. Mechanism study data indicated that XU07011 blocked HIV-1 reverse transcription process through acting on reverse transcriptase RNA-dependent DNA polymerase with IC 50 of (1.1 +/- 0.3) micromol x L(-1). The compound showed no effect on RNase H activity. XU07011 exhibited better activities comparing with nevirapine on K103N mutated NNRTIs-resistant HIV-1 strains. This study could provide a theoretical basis for novel anti-HIV reagents development.
Asunto(s)
Fármacos Anti-VIH/farmacología , Quinoxalinas/farmacología , ADN Polimerasa Dirigida por ARN/metabolismo , Tiofenos/farmacología , Replicación Viral/efectos de los fármacos , Fármacos Anti-VIH/química , Farmacorresistencia Viral , Células HEK293 , VIH-1/fisiología , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Nevirapina/farmacología , Ribonucleasa H/metabolismoRESUMEN
PARP [poly(ADP-ribose)polymerase] represents a novel potential target in cancer therapy. It is involved in a DNA repair process by catalyzing the transfer of ADP-ribose units from NAD to a number of its substrate proteins. In this work, a series of novel azaindole derivatives was designed and synthesized. Moreover, 16 target molecules were screened and 8 compounds displayed inhibitory activity against PARP-1. It has been demonstrated that these azaindoles bearing cycloamine substituents at 2-position were active to both PARP-1 and PARP-2.
Asunto(s)
Antineoplásicos/síntesis química , Compuestos Aza/síntesis química , Indoles/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Compuestos Aza/química , Compuestos Aza/farmacología , Indoles/química , Indoles/farmacología , Poli(ADP-Ribosa) Polimerasa-1 , Poli(ADP-Ribosa) Polimerasas/metabolismoRESUMEN
A variety of novel 2-(1-substituted-piperidine-4-ylamino)quinazoline derivatives were prepared and their antiproliferative activities on five cancer cell lines were evaluated by MTT assay. Quinazolines 4j-4l, 5a, 5b and 5d bearing a small hydrophobic alkyl group on piperidine ring exhibited potent antitumor activities with IC50 values at micromolar level. Compound 41 displayed significant in vivo antitumor activity with 72.9% inhibition on H22 tumor growth and 80% inhibition on Lewis lung cancer growth at a dose of 200 mg x kg(-1).
Asunto(s)
Antineoplásicos/síntesis química , Quinazolinas/síntesis química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Carcinoma Pulmonar de Lewis/patología , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Concentración 50 Inhibidora , Neoplasias Hepáticas/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Trasplante de Neoplasias , Quinazolinas/química , Quinazolinas/farmacologíaRESUMEN
Two series of novel benzoimidazole sulfonamides as combretastatin A-4 analogs were synthesized. The cytotoxicities of the title compounds were evaluated against five different cancer cell lines. Among the tested compounds, four compounds displayed cytotoxicities against the HCT8 cell line. Compound 6a has shown the strongest potency against the tested human tumor cell lines with an IC50 value ranging from submicromolar to micromolar level.
Asunto(s)
Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos Fitogénicos/farmacología , Imidazoles/síntesis química , Imidazoles/farmacología , Estilbenos/síntesis química , Estilbenos/farmacología , Sulfonamidas/síntesis química , Sulfonamidas/farmacología , Antineoplásicos Fitogénicos/química , Combretum/química , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Imidazoles/química , Estructura Molecular , Estilbenos/química , Sulfonamidas/químicaRESUMEN
Fructose-1, 6-bisphosphatase (FBPase), a rate-limiting enzyme involved in the pathway of gluconeogenesis, can catalyze the hydrolysis of fructose-1, 6-bisphosphate to fructose-6-phosphate. Upon inhibiting the activity of FBPase, the production of endogenous glucose can be decreased and the level of blood glucose lowered. Therefore, inhibitors of FBPase are expected to be novel potential therapeutics for the treatment of type II diabetes. Recent research efforts were reviewed in the field of developing allosteric inhibitors interacting with the AMP binding site of FBPase.
Asunto(s)
Adenosina Monofosfato/química , Inhibidores Enzimáticos/química , Fructosa-Bifosfatasa/antagonistas & inhibidores , Fructosa-Bifosfatasa/química , Sitio Alostérico , Animales , Sitios de Unión , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/sangre , Inhibidores Enzimáticos/farmacología , Fructosa-Bifosfatasa/metabolismo , Fructosadifosfatos/metabolismo , Fructosafosfatos/metabolismo , HumanosRESUMEN
Pin1 is a phosphorylation-dependent peptidyl-prolyl cis/trans isomerase, which specifically catalyzes the amide bond isomerization of phosphoserine-proline or phosphothreonine-proline in mitotic phosphoproteins. Pin1 induces the conformational changes to control the function of phosphoproteins. Depletion of Pinl on various human cancer cell lines cause mitotic arrest and apoptosis. Pin1 is an attracting therapeutic target for anticancer and its inhibitors might be potential anticancer drug. In this review, Pin1 inhibitors and the catalytic mechanism, the biological function of Pin1 and its role in oncogenesis are summarized.