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1.
Biomed Pharmacother ; 170: 116018, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38113628

RESUMEN

Hepatocellular carcinoma (HCC) is one of the most fatal solid malignancies worldwide. Evidence suggests that thrombin stimulates tumor progression via fibrin formation and platelet activation. Meanwhile, we also found a correlation between thrombin and HCC through bioinformatics analysis. Dabigatran is a selective, direct thrombin inhibitor that reversibly binds to thrombin. Dabigatran was used as the lead agent in this study, and 19 dabigatran derivatives were designed and synthesized based on docking mode. The thrombin-inhibitory activity of the derivative AX-2 was slightly better than that of dabigatran. BX-2, a prodrug of AX-2, showed a fairly strong inhibitory effect on thrombin-induced platelet aggregation, and effectively antagonized proliferation of HCC tumor cells induced by thrombin at the cellular level. Furthermore, BX-2 reduced tumor volume, weight, lung metastasis, and secondary tumor occurrence in nude mouse models. BX-2 combined with sorafenib increased sorafenib efficacy. This study lays the foundation for discovering new anti-HCC mechanism based on thrombin. BX-2 can be used as an anti-HCC drug lead for further research.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Ratones , Animales , Dabigatrán/farmacología , Dabigatrán/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Trombina/metabolismo , Sorafenib/farmacología , Neoplasias Hepáticas/tratamiento farmacológico
2.
J Med Chem ; 66(4): 2524-2541, 2023 02 23.
Artículo en Inglés | MEDLINE | ID: mdl-36739537

RESUMEN

The current global issue of antibiotic resistance is serious, and there is an urgent requirement of developing novel antibiotics. Octapeptins have recently regained interest because of their activities against resistant Gram-negative bacteria. We synthesized four natural octapeptins and 33 derivatives with diverse polarity, amphiphilicity, and acid-base properties by solid-phase synthesis and investigated their in vitro antibacterial activity and renal cytotoxicity. We also assessed the structure-activity relationship and structure-toxicity relationship of the cyclic lipopeptide compounds. Some compounds showed increased activity against Gram-negative and/or Gram-positive bacteria, with improved renal cytotoxicity. C-02 showed remarkable in vitro antibacterial activity and low renal cytotoxicity. We found that C-02 showed high antibacterial activity against Escherichia coli in vivo and manifested its effects preliminarily by increasing outer membrane permeability. Therefore, C-02 might be a new antibiotic lead compound with not only high efficacy but also low renal cytotoxicity.


Asunto(s)
Aminoácidos , Antibacterianos , Antibacterianos/farmacología , Aminoácidos/química , Lipopéptidos , Bacterias Gramnegativas , Relación Estructura-Actividad , Pruebas de Sensibilidad Microbiana
3.
J Med Chem ; 66(3): 1742-1760, 2023 02 09.
Artículo en Inglés | MEDLINE | ID: mdl-36662031

RESUMEN

Most patients with senile osteoporosis (SOP) are severely deficient in bone mass, and treatments using bone resorption inhibitors, such as bisphosphonates, have shown limited efficacy. Small-molecule osteogenesis-promoting drugs are required to improve the treatment for this disease. Previously, we demonstrated that a compound with a benzofuran-like structure promoted bone formation by upregulating BMP-2, and it exhibited a therapeutic effect in SAMP-6 mice, glucocorticoid-induced osteoporosis rats, and ovariectomized rats. In this study, aged C57 and SAMP-6 mice models were used to investigate the therapeutic and preventive effects of compound 125 on SOP. scRNA-seq analysis showed that BMP-2 upregulation is the mechanism through which 125 accelerates bone turnover and increases the proportion of osteoblasts. We evaluated the structure-activity relationship of the candidate drugs and found that the derivative I-9 showed significantly higher efficacy than 125 and teriparatide in the zebrafish osteoporosis model. This study provides a foundation for the development of SOP drugs.


Asunto(s)
Benzofuranos , Osteoporosis , Ratas , Ratones , Animales , Pez Cebra , Osteoporosis/tratamiento farmacológico , Osteoporosis/prevención & control , Osteogénesis , Osteoblastos , Benzofuranos/farmacología , Benzofuranos/uso terapéutico , Benzofuranos/química , Relación Estructura-Actividad
4.
Eur J Med Chem ; 244: 114877, 2022 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-36334454

RESUMEN

FOXM1 signalling pathways are highly expressed in multiple human cancers. Based on the crystal structure of the FOXM1 DNA binding domain, our preliminary research found ethylene glycol (4-benzyloxyphenyl) cyclopentylaminoethyl ether XST20, which could inhibit ovarian cancer cell proliferation and showed a medium affinity for the truncated protein FOXM1. This study intended to develop a FOXM1 inhibitor with stronger affinity and higher efficiency to be utilized as a molecular tool and drug candidate. We evaluated the optimization direction through molecular docking and systematically modified the structure of XST20. A novel class of ethylene glycol phenyl aminoethyl ether derivatives were synthesized, their anticancer activity and mechanism were evaluated, and the structure-activity relationship was summarized. Compound S2 showed a stronger affinity for FOXM1 and improved its activity with a broad-spectrum anticancer effect. S2 displayed selective antiproliferative activity against cancer cells with high expression levels of FOXM1 proteins. S2 should be a good chemobiological tool and a potential leading compound for future studies of anticancer drugs targeting FOXM1.


Asunto(s)
Antineoplásicos , Neoplasias Ováricas , Femenino , Humanos , Simulación del Acoplamiento Molecular , Antineoplásicos/química , Proliferación Celular , Glicoles de Etileno/farmacología , Éteres/farmacología , Línea Celular Tumoral , Proteína Forkhead Box M1
5.
Future Med Chem ; 14(4): 207-219, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34809496

RESUMEN

Aim: Given the importance of FOXM1 in the treatment of ovarian cancer, we aimed to identify an excellent specific inhibitor and examined its underlying therapeutic effect. Materials & methods: The binding statistics for FDI-6 with FOXM1 were calculated through computer-aided drug design. We selected XST-119 through virtual screening, performed surface plasmon resonance and in vitro cell antiproliferative activity analysis and evaluated its antitumor efficacy in a mouse model. Results: XST-119 had significantly higher affinity for FOXM1 and antiproliferative activity than FDI-6. XST-119 had a definite inhibitory activity in a xenograft mouse model. Conclusion: We identified XST-119, a FOXM1 inhibitor, with better efficacy for treatment of ovarian cancer. FOXM1 binding sites for small molecules are also highlighted, which may provide the foundation for further drug discovery.


Asunto(s)
Proteína Forkhead Box M1/antagonistas & inhibidores , Animales , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Sitios de Unión , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Proteína Forkhead Box M1/metabolismo , Humanos , Ligandos , Ratones , Simulación del Acoplamiento Molecular , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Relación Estructura-Actividad , Termodinámica
6.
Eur J Med Chem ; 200: 112465, 2020 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-32480301

RESUMEN

The bone morphogenetic protein (BMP) pathway is a promising new target for the design of therapeutic agents for the treatment of low bone mass. This study optimized the structure of the anti-osteoporosis compound 38 by balancing its lipophilicity and improving its stability. Twenty derivatives which were not reported in the literature were designed and synthesized. The ovariectomized rat model of osteoporosis was selected to evaluate the therapeutic effects. Compound 125 showed better therapeutic efficacy than that of 38. We verified the anti-osteoporosis activity and BMP-2 protein upregulation after treatment with 125 in a zebrafish osteoporosis model. We found that 125 improved the ADME properties, therapeutic efficacy, and pharmacokinetics of the drug. Overall, we evaluated the anti-osteoporosis effects of the compounds of this type, preliminarily determined the target patient population, verified the mechanism of action, clarified the level of toxicity, and provided preliminary ADME data. We believe that these compounds can both correct bone loss that is already occurring in patients and have broad clinical applicability.


Asunto(s)
Benzofuranos/farmacología , Proteína Morfogenética Ósea 2/metabolismo , Modelos Animales de Enfermedad , Osteoporosis/tratamiento farmacológico , Tiofenos/farmacología , Animales , Células CACO-2 , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Ratones Endogámicos BALB C , Estructura Molecular , Osteoporosis/cirugía , Ovariectomía , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Pez Cebra
7.
Biomolecules ; 10(1)2019 12 19.
Artículo en Inglés | MEDLINE | ID: mdl-31861703

RESUMEN

The voltage-gated potassium channel Kv1.5, which mediates the cardiac ultra-rapid delayed-rectifier (IKur) current in human cells, has a crucial role in atrial fibrillation. Therefore, the design of selective Kv1.5 modulators is essential for the treatment of pathophysiological conditions involving Kv1.5 activity. This review summarizes the progress of molecular structures and the functionality of different types of Kv1.5 modulators, with a focus on clinical cardiovascular drugs and a number of active natural products, through a summarization of 96 compounds currently widely used. Furthermore, we also discuss the contributions of Kv1.5 and the regulation of the structure-activity relationship (SAR) of synthetic Kv1.5 inhibitors in human pathophysiology. SAR analysis is regarded as a useful strategy in structural elucidation, as it relates to the characteristics that improve compounds targeting Kv1.5. Herein, we present previous studies regarding the structural, pharmacological, and SAR information of the Kv1.5 modulator, through which we can assist in identifying and designing potent and specific Kv1.5 inhibitors in the treatment of diseases involving Kv1.5 activity.


Asunto(s)
Fibrilación Atrial/metabolismo , Canal de Potasio Kv1.5/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/química , Animales , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/genética , Humanos , Canal de Potasio Kv1.5/genética , Canal de Potasio Kv1.5/metabolismo , Potasio/metabolismo , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacología , Relación Estructura-Actividad
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