RESUMO
HDAC8 is a therapeutic target with great promise for breast cancer. Here, we reported a novel compound corallorazine D from Nocardiopsis sp. XZB108, selectively inhibited HDAC8 (IC50 = 0.90 ± 0.014 µM), suggesting that it may be a promising nonhydroxamate HDAC8 inhibitor. Upon additional modifications of corallorazine D, a candidate compound 5k, demonstrated remarkable inhibitory potency against HDAC8 (IC50 = 0.12 ± 0.01 nM), 89-fold superior to PCI-34051. The selectivity of 5k was at least 439-fold, superior to corallorazine D, confirming the efficacy of our modifications. In an orthotopic mouse model of breast cancer, 5k displayed nearly 4-fold superior antitumor activity than SAHA. Furthermore, 5k triggered antitumor immunity by activating T cells. Treatment with 5k significantly increased the proportion of M1 macrophages and decreased the proportion of M2 macrophages (M1/M2 ratio = 2.67 ± 0.25). 5k represents a promising compound for further investigation as a potential treatment for breast cancer.
Assuntos
Antineoplásicos , Neoplasias da Mama , Inibidores de Histona Desacetilases , Histona Desacetilases , Animais , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Humanos , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/uso terapêutico , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Antineoplásicos/uso terapêutico , Histona Desacetilases/metabolismo , Linhagem Celular Tumoral , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/metabolismo , Relação Estrutura-Atividade , Camundongos Endogâmicos BALB C , Proliferação de Células/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Based on the structure of caerulomycin A, 90 novel bipyridine derivatives were designed and synthesized. Among these, compound B19 exerted strong antitumor effects in vivo and in vitro. Importantly, NOP2/Sun RNA methyltransferase 3 (NSUN3) protein was identified as the target specific binding to B19, which inhibits oxidative phosphorylation of mitochondrial energy metabolism and enhances glycolytic activity by binding to NSUN3. Knockdown of NSUN3 inhibited both proliferation and migration of colorectal cancer (CRC) cells by activating AMPK-related signaling and inhibiting downstream STAT3 signaling to exert antiproliferative and pro-apoptotic effects. Our findings support the use of NSUN3 inhibitors as promising therapeutic strategies against CRC.
Assuntos
Antineoplásicos , Proliferação de Células , Neoplasias Colorretais , Humanos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Antineoplásicos/uso terapêutico , Camundongos , Linhagem Celular Tumoral , Metiltransferases/antagonistas & inibidores , Metiltransferases/metabolismo , Apoptose/efeitos dos fármacos , Piridinas/farmacologia , Piridinas/química , Piridinas/síntese química , Camundongos Nus , Relação Estrutura-Atividade , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/uso terapêutico , Camundongos Endogâmicos BALB C , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/metabolismo , Movimento Celular/efeitos dos fármacosRESUMO
Two new alpiniamide-type polyketides, alpiniamides H-I (1-2), in addition to four recognized compounds, were discovered in Streptomyces sp. ZSA65 derived from the marine sediments. The planar structure and absolute configuration of alpiniamides H-I were elucidated using a combination of 1D, 2D NMR, HRESIMS data analysis, Mosher's method and ECD calculations. The antibiofilm and antibacterial activities against P. aeruginosa were evaluated using the microdilution method. Notably, Compound 2 exhibited strong antibiofilm property.
Assuntos
Policetídeos , Streptomyces , Policetídeos/farmacologia , Policetídeos/química , Streptomyces/química , Antibacterianos/farmacologia , Espectroscopia de Ressonância Magnética , Biofilmes , Estrutura MolecularRESUMO
A novel staurosporine derivate, streptomholyrine A (1), along with 6â known compounds were identified from the rice-based solid fermentation of marine-derived Streptomyces sp. ZS-A121. The planar structure and absolute configuration of streptomholyrine A were elucidated using a combination of 1D, 2D NMR, HRESIMS data analysis, chemical transformation, ECD and NMR calculations. Screening of all these compounds revealed their cytotoxic activity against HCT-116â cell lines, with IC50 values ranging from 0.012 to 11.67â µM, except for the known 1H-indole-3-hydroxyacetyl, which showed no inhibition activity. Furthermore, streptomholyrine A, along with two known staurosporine derivatives, k252d and staurosporine, exhibited activities against Candida albicans, with MICs of 12.5, 25.0 and 50.0â µg/ml, respectively.
Assuntos
Actinobacteria , Antineoplásicos , Streptomyces , Humanos , Estaurosporina/farmacologia , Estaurosporina/metabolismo , Antifúngicos/farmacologia , Antifúngicos/metabolismo , Streptomyces/química , Antineoplásicos/química , Estrutura MolecularRESUMO
Nine new compounds, including streptothiomycin A-E (1-5), two cyclopentenones (6, 7), one α-pyrone (8), wailupemycin Q (20), along with sixteen known compounds were identified from a rhizosphere strain Streptomyces sp. DS-27 derived from the marine cordgrass Spartina alterniflora under two different culture conditions. All of the structures were elucidated by extensive analysis of 1D/2D NMR and HR-ESI-MS data. The absolute configurations were determined by NOESY analysis, ECD, specific rotation and GIAO NMR calculations, and DP4+ probability analysis. Bioactivity investigation showed that compounds 5 and 7 exhibited significant inhibitory effects on LPS-induced NO production in a dose-dependent manner, which indicates their anti-inflammatory potential.
Assuntos
Antineoplásicos , Streptomyces , Antineoplásicos/farmacologia , Streptomyces/química , Espectroscopia de Ressonância Magnética , Pironas/química , Estrutura MolecularRESUMO
Alpiniamides E-G, three previously unreported linear polyketide derivatives, along with two known compounds, were isolated from Streptomyces sp. QHA48, which was isolated from the saline lakes of Qinghai-Tibet Plateau. The structures of these compounds were determined through analysis of their spectroscopic data, as well as density functional theory prediction of NMR chemical shifts, application of the DP4+ algorithm and electronic circular dichroism (ECD) calculations. In a cell-based lipid-lowering assay, all five alpiniamides exhibited significant inhibition of lipid accumulation in HepG2 cells without inducing cytotoxic effects at a concentration of 27â µM.
Assuntos
Lagos , Streptomyces , Streptomyces/química , Dicroísmo Circular , Espectroscopia de Ressonância Magnética , Lipídeos/farmacologia , Estrutura MolecularRESUMO
Two novel di-tert-butyl-type structures (1-2), and five known compounds (3-7) were isolated from the chemical investigations of a saline lake actinomycete, Streptomyces sp. XZB42. The structures of the new compounds were elucidated by extensive NMR spectroscopic analysis, HRESIMS data, GIAO (gauge-including atomic orbitals) NMR and specific optical rotation (SOR).
RESUMO
Bioinformatic annotation of protein function is essential but extremely sophisticated, which asks for extensive efforts to develop effective prediction method. However, the existing methods tend to amplify the representativeness of the families with large number of proteins by misclassifying the proteins in the families with small number of proteins. That is to say, the ability of the existing methods to annotate proteins in the 'rare classes' remains limited. Herein, a new protein function annotation strategy, PFmulDL, integrating multiple deep learning methods, was thus constructed. First, the recurrent neural network was integrated, for the first time, with the convolutional neural network to facilitate the function annotation. Second, a transfer learning method was introduced to the model construction for further improving the prediction performances. Third, based on the latest data of Gene Ontology, the newly constructed model could annotate the largest number of protein families comparing with the existing methods. Finally, this newly constructed model was found capable of significantly elevating the prediction performance for the 'rare classes' without sacrificing that for the 'major classes'. All in all, due to the emerging requirements on improving the prediction performance for the proteins in 'rare classes', this new strategy would become an essential complement to the existing methods for protein function prediction. All the models and source codes are freely available and open to all users at: https://github.com/idrblab/PFmulDL.