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1.
Acta Pharmaceutica Sinica ; (12): 1784-1796, 2018.
Artículo en Chino | WPRIM | ID: wpr-780059

RESUMEN

Indoleamine 2,3-dioxygenase 1 (IDO1) is a key enzyme of L-tryptophan metabolic oxidation pathway, in which the L-tryptophan is transformed into N-formyl kynurenine by oxidative cleavage. IDO1 is considered as a potential target for the development of cancer immunotherapeutic molecules. Up to now, at least 10 drug candidates have been advanced into clinical research. In this review, the binding mode and structure-activity relationships of the representative IDO1 small molecule inhibitors were summarized according the characteristics of chemical structures. Hopefully, this review could provide some insights for further development of novel IDO1 inhibitors.

2.
Acta Pharmaceutica Sinica ; (12): 938-943, 2018.
Artículo en Chino | WPRIM | ID: wpr-779954

RESUMEN

Poly(ADP-ribose) polymerase (PARP)-1 and PARP2 function as ADP-ribosylases involved in DNA repair. PARP1/2 is highly expressed in cancers and emerged as an attractive target for antitumor drug. In this study, we investigated the antitumor activity of a novel PARP1/2 inhibitor YHP-743 in vitro and in vivo. The results showed that YHP-743 had potent enzymatic inhibitory activity against PARP1 and PARP2 to down-regulate the PAR level. YHP-743 not only inhibited breast cancer cells with genes deficiency of homologous recombination repair, but also potentiated chemotherapy agent's cytotoxicity, such as temozolomide, topotecan, cisplatin and doxorubicin. YHP-743 elicited good antitumor activity in combination with temo-zolomide in vivo.

3.
Acta Pharmaceutica Sinica ; (12): 762-2016.
Artículo en Chino | WPRIM | ID: wpr-779234

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 IC50 values of 10.2 and 9.0 μmol·L-1, respectively.

4.
Acta Pharmaceutica Sinica ; (12): 738-745, 2015.
Artículo en Chino | WPRIM | ID: wpr-257074

RESUMEN

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)
Humanos , Antineoplásicos , Benzamidas , Química , Reparación del ADN , Diseño de Fármacos , Simulación del Acoplamiento Molecular , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Química , Poli(ADP-Ribosa) Polimerasas
5.
Acta Pharmaceutica Sinica ; (12): 497-503, 2014.
Artículo en Chino | WPRIM | ID: wpr-245056

RESUMEN

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)
Antineoplásicos , Química , Farmacología , Diseño de Fármacos , Inhibidores Enzimáticos , Química , Farmacología , Simulación del Acoplamiento Molecular , Estructura Molecular , Poli(ADP-Ribosa) Polimerasa-1 , Poli(ADP-Ribosa) Polimerasas , Quinazolinonas , Química , Farmacología , Relación Estructura-Actividad
6.
Acta Pharmaceutica Sinica ; (12): 1792-1799, 2013.
Artículo en Chino | WPRIM | ID: wpr-298009

RESUMEN

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 , Química , Farmacología , Compuestos Aza , Química , Farmacología , Indoles , Química , Farmacología , Poli(ADP-Ribosa) Polimerasa-1 , Poli(ADP-Ribosa) Polimerasas , Metabolismo
7.
Acta Pharmaceutica Sinica ; (12): 860-865, 2013.
Artículo en Chino | WPRIM | ID: wpr-259539

RESUMEN

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)
Humanos , Fármacos Anti-VIH , Química , Farmacología , Farmacorresistencia Viral , Células HEK293 , VIH-1 , Fisiología , Concentración 50 Inhibidora , Estructura Molecular , Nevirapina , Farmacología , Quinoxalinas , Farmacología , ADN Polimerasa Dirigida por ARN , Metabolismo , Ribonucleasa H , Metabolismo , Tiofenos , Farmacología , Replicación Viral
8.
Acta Pharmaceutica Sinica ; (12): 1266-1272, 2013.
Artículo en Chino | WPRIM | ID: wpr-259484

RESUMEN

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)
Humanos , Diseño de Fármacos , Inhibidores Enzimáticos , Química , Farmacología , Éteres , Química , Farmacología , Concentración 50 Inhibidora , Simulación del Acoplamiento Molecular , Estructura Molecular , Peptidilprolil Isomerasa de Interacción con NIMA , Isomerasa de Peptidilprolil , Metabolismo , Pirimidinas , Química , Relación Estructura-Actividad
9.
Acta Pharmaceutica Sinica ; (12): 1164-1178, 2012.
Artículo en Inglés | WPRIM | ID: wpr-274682

RESUMEN

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)
Animales , Masculino , Ratones , Antineoplásicos , Química , Farmacología , Carcinoma Pulmonar de Lewis , Patología , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Concentración 50 Inhibidora , Neoplasias Hepáticas , Patología , Ratones Endogámicos C57BL , Trasplante de Neoplasias , Quinazolinas , Química , Farmacología
10.
Acta Pharmaceutica Sinica ; (12): 1291-1300, 2011.
Artículo en Chino | WPRIM | ID: wpr-232995

RESUMEN

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)
Animales , Humanos , Adenosina Monofosfato , Química , Sitio Alostérico , Sitios de Unión , Glucemia , Metabolismo , Diabetes Mellitus Tipo 2 , Sangre , Inhibidores Enzimáticos , Química , Farmacología , Fructosa-Bifosfatasa , Química , Metabolismo , Fructosadifosfatos , Metabolismo , Fructosafosfatos , Metabolismo
11.
Acta Pharmaceutica Sinica ; (12): 9-17, 2008.
Artículo en Chino | WPRIM | ID: wpr-268180

RESUMEN

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.


Asunto(s)
Humanos , Apoptosis , Inhibidores Enzimáticos , Farmacología , Mitosis , Peptidilprolil Isomerasa de Interacción con NIMA , Neoplasias , Isomerasa de Peptidilprolil , Metabolismo , Fosfoproteínas , Química , Metabolismo , Fosforilación , Transducción de Señal
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