RESUMEN
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.
Asunto(s)
Antineoplásicos , Neoplasias de la Mama , Inhibidores de Histona Desacetilasas , Histona Desacetilasas , Animales , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Humanos , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/uso terapéutico , Ratones , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Antineoplásicos/uso terapéutico , Histona Desacetilasas/metabolismo , Línea Celular Tumoral , Proteínas Represoras/antagonistas & inhibidores , Proteínas Represoras/metabolismo , Relación Estructura-Actividad , Ratones Endogámicos BALB C , Proliferación Celular/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
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.
Asunto(s)
Antineoplásicos , Proliferación Celular , Neoplasias Colorrectales , Humanos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Animales , Proliferación Celular/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Antineoplásicos/uso terapéutico , Ratones , Línea Celular Tumoral , Metiltransferasas/antagonistas & inhibidores , Metiltransferasas/metabolismo , Apoptosis/efectos de los fármacos , Piridinas/farmacología , Piridinas/química , Piridinas/síntesis química , Ratones Desnudos , Relación Estructura-Actividad , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/uso terapéutico , Ratones Endogámicos BALB C , Factor de Transcripción STAT3/antagonistas & inhibidores , Factor de Transcripción STAT3/metabolismo , Movimiento Celular/efectos de los fármacosRESUMEN
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.
Asunto(s)
Actinobacteria , Antineoplásicos , Streptomyces , Humanos , Estaurosporina/farmacología , Estaurosporina/metabolismo , Antifúngicos/farmacología , Antifúngicos/metabolismo , Streptomyces/química , Antineoplásicos/química , Estructura MolecularRESUMEN
Psoriasis, a prevalent chronic skin disorder, remains a significant therapeutic obstacle. This study centers on rho-associated coiled-coil-containing kinase2 (ROCK2) as an advantageous target for treating psoriasis and identifies five potent and selective ROCK2 inhibitors (A31-35). Notably, A32-35 outperform KD025 in ROCK2/ROCK1 selectivity by up to 216-fold. Among these candidates, A31 emerged as an exceedingly promising molecule, showcasing remarkable inhibitory potency (IC50 = 3.7 ± 0.8 nM), 19-fold ROCK2/ROCK1 selectivity, and favorable pharmacokinetics. Insights from the binding mode study further underscored the pivotal role of interactions with Phe103 on the P-loop in determining the selectivity between ROCK1 and ROCK2. In an imiquimod-induced psoriasis-like mouse model, oral administration of A31 notably ameliorated symptoms by targeting the IL-23/Th17 axis. Based on these compelling findings, A31 was selected as a highly promising compound for further investigation as a potential treatment for psoriasis.
Asunto(s)
Psoriasis , Animales , Ratones , Psoriasis/inducido químicamente , Psoriasis/tratamiento farmacológico , Quinasas Asociadas a rhoRESUMEN
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.
Asunto(s)
Antineoplásicos , Streptomyces , Antineoplásicos/farmacología , Streptomyces/química , Espectroscopía de Resonancia Magnética , Pironas/química , Estructura MolecularRESUMEN
Breast cancer metastasis is a major challenge in clinical therapy because of the absence of effective treatments. Rho-associated coiled-coil kinase (ROCK), which is essential for cell invasion and migration, has recently been suggested as a potential target for the treatment of cancer metastasis. Herein, we report the structure-activity relationships (SAR) of indolocarbazoles against ROCK2 and reveal the crucial role of the C-3 hydroxyl for ROCK2 inhibition. The most potent unglycosylated aglycone THK01 was demonstrated to bind to and stabilize ROCK2 with potent anti-metastatic effects in breast cancer in vitro and in vivo with no obvious toxicities. Further mechanistic studies revealed that the anti-metastatic effect of THK01 was closely related to the suppression of STAT3Y705 activation. Moreover, THK01 exhibited excellent selectivity over the isoform protein ROCK1 (>100-fold). Taken together, with low toxicity, the ROCK2 inhibitor THK01 potently inhibited breast cancer metastasis through the ROCK2-STAT3 signaling pathway, which offers a new opportunity for the treatment of metastatic breast cancer.
Asunto(s)
Neoplasias de la Mama , Neoplasias Cutáneas , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Quinasas Asociadas a rho , Isoformas de Proteínas , Melanoma Cutáneo MalignoRESUMEN
Four dimeric diketopiperazine stereoisomers (1-4) including two new ones (1-2) had been isolated from the culture broth of one marine-derived fungus Aspergillus sp. Z3, which was found in the gut of a marine isopod Ligia exotica. The planner structures and absolute configurations of the new compounds were determined by combination of NMR, HRESIMS, electronic circular dichroism calculation, Marfey's method as well as single-crystal X-ray diffraction. Their cytotoxicity against the prostate cancer PC3 cell line was assayed by the MTT method.
RESUMEN
Lipid-lowering is one of the most effective methods of prevention and treatment for cardiovascular diseases. However, most clinical lipid-lowering drugs have adverse effects and cannot achieve the desired efficacy in some complex hyperlipidemia patients, so it is of great significance to develop safe and effective novel lipid-lowering drugs. In the course of our project aimed at discovering the chemical novelty and bioactive natural products of marine-derived actinomycetes, we found that the organic crude extracts (OCEs) of Nocardiopsis sp. ZHD001 exhibited strong in vivo efficacies in reducing weight gain, lowering LDL-C, TC, and TG levels, and improving HDL-C levels in high-fat-diet-fed mice models. Chemical investigations of the active OCEs led to identifying two new sphydrofuran-derived compounds (1-2) and one known 2-methyl-4-(1-glycerol)-furan (3). Their structures were elucidated by the analysis of HRESIMS, 1D and 2D NMR spectroscopic data, and ECD calculations. Among these compounds, compound 1 represents a novel rearranged sphydrofuran-derived derivative. Bioactivity evaluations of these pure compounds showed that all the compounds exhibited significant lipid-lowering activity with lower cytotoxicity in vitro compared to simvastatin. Our results demonstrate that sphydrofuran-derived derivatives might be promising candidates for lipid-lowering drugs.
Asunto(s)
Glicerol , Nocardiopsis , Ratones , Animales , Hipolipemiantes/uso terapéutico , Extractos Vegetales/química , LípidosRESUMEN
Twelve new tanzawaic acid derivatives, penitanzacids A-F (1-6), and G-J (9-12), and hatsusamides C-D (13-14), together with two revised structures [tanzawaic acids I-J (7-8)] and three known compounds (15-17) were isolated from the deep-sea-derived fungus Penicillium sp. KWF32. Their structures including absolute configurations were elucidated by spectroscopic data analysis, HRESIMS data, modified Mosher's method, chemical degradation studies, ECD calculations, single crystal X-ray diffraction, and biogenic considerations in comparison with reported known analogues. Penitanzacids H-J (10-12) represent the first examples of this family with a C3 side chain and support the proposed biosynthetic pathway in which the side chain is connected to the decalin backbone. Hatsusamides C-D (13-14) have a hybrid skeleton formed by linking a tanzawaic acid and a diketopiperazine through an ester bond. Compounds 13 and 14 exhibit weak cytotoxicity against the A549 cell line.
Asunto(s)
Penicillium , Cristalografía por Rayos X , Hongos , Estructura Molecular , Penicillium/químicaRESUMEN
Lamellarin D, a marine natural product, acts as a potent inhibitor of DNA topoisomerase I (Topo I). To modify its physicochemical property and biological activity, a series of mono- and di-glycosylated derivatives were designed and synthesized through 22-26 multi-steps. Their inhibition of human Topo I was evaluated, and most of the glycosylated derivatives exhibited high potency in inhibiting Topo I activity as well as lamellarin D. All the 15 target compounds were evaluated for their cytotoxic activities against five human cancer cell lines. The typical lamellarin derivative ZL-3 exhibited the best activity with IC50 values of 3 nM, 10 nM, and 15 nM against human lung cancer A549 cells, human colon cancer HCT116 cells and human hepatocellular carcinoma HepG2 cells. Compound ZL-1 exhibited anti-cancer activity with IC50 of 14 nM and 24 nM against human colon cancer HCT116 cells and human hepatocellular carcinoma HepG2 cells, respectively. Cell cycle analysis in MDA-MB-231 suggested ZL-3 inhibited cell growth through arresting cells at the G2/M phase of the cell cycle. Further tests showed a significant improvement in aqueous solubility of ZL-1 and ZL-7. This study suggested that glycosylation could be utilized as a useful strategy to optimize lamellarin D derivatives as Topo I inhibitors and anticancer agents.
Asunto(s)
Antineoplásicos/farmacología , Productos Biológicos/farmacología , Cumarinas/farmacología , Diseño de Fármacos , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Isoquinolinas/farmacología , Inhibidores de Topoisomerasa I/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Productos Biológicos/síntesis química , Productos Biológicos/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cumarinas/síntesis química , Cumarinas/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Glicosilación , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Compuestos Heterocíclicos de 4 o más Anillos/química , Humanos , Isoquinolinas/síntesis química , Isoquinolinas/química , Estructura Molecular , Relación Estructura-Actividad , Inhibidores de Topoisomerasa I/síntesis química , Inhibidores de Topoisomerasa I/química , Células Tumorales CultivadasRESUMEN
Two new alkaloids (1,2) and one new enoic acid (3), together with three known piericidins (4-6), were isolated from the liquid fermentation of the salt lake derived Streptomyces sp. QHA10. The structures of 1-3 were elucidated based on extensive spectroscopic data (NMR, HRESIMS) as well as single-crystal X-ray diffraction. Compound 3 showed potential anti-inflammatory activity by inhibiting the production of nitric oxide (NO) in lipopolysaccharide (LPS)-induced RAW 264.7 mouse macrophages with the IC50 value of 24.5 µM.
Asunto(s)
Streptomyces , Animales , Antiinflamatorios/farmacología , Lagos , Lipopolisacáridos/farmacología , Ratones , Estructura Molecular , Óxido NítricoRESUMEN
Four new polyketides including two arthrinic acid derivatives (1-2), one phenolic derivative (3) and (S)-3-hydroxy-6-(2-hydroxypropyl)-5-methyl-2H-pyran-2-one (4) along with one methyl ester of arthrinic acid (5) were isolated from the culture broth of Arthrinium sp., which was an entophytic fungus of clam worm. Their structures were identified on the basis of HR-ESI-MS and NMR spectral analyses together with advanced Mosher's method. In the assay of inhibiting the prostate cancer PC3 cell line, none of the isolated compounds showed significant cytotoxicity.
Asunto(s)
Policétidos , Xylariales , Humanos , Espectroscopía de Resonancia Magnética , Estructura Molecular , Policétidos/farmacología , Piranos , Xylariales/químicaRESUMEN
Fungi are a prospective resource of bioactive compounds, but conventional methods of drug discovery are not effective enough to fully explore their metabolic potential. This study aimed to develop an easily attainable method to elicit the metabolic potential of fungi using Aspergillus nidulans laeA as a transcription regulation tool. In this study, functional analysis of Aspergillus nidulans laeA (AnLaeA) and Aspergillus sp. Z5 laeA (Az5LaeA) was done in the fungus Aspergillus sp. Z5. Heterologous AnLaeA-and native Az5LaeA-overexpression exhibited similar phenotypic effects and caused an increase in production of a bioactive compound diorcinol in Aspergillus sp. Z5, which proved the conserved function of this global regulator. In particular, heteroexpression of AnLaeA showed a significant impact on the expression of velvet complex genes, diorcinol synthesis-related genes, and different transcription factors (TFs). Moreover, heteroexpression of AnLaeA influenced the whole genome gene expression of Aspergillus sp. Z5 and triggered the upregulation of many genes. Overall, these findings suggest that heteroexpression of AnLaeA in fungi serves as a simple and easy method to explore their metabolic potential. In relation to this, AnLaeA was overexpressed in the fungus Penicillium sp. LC1-4, which resulted in increased production of quinolactacin A.
Asunto(s)
Aspergillus nidulans/genética , Aspergillus nidulans/metabolismo , Regulación Fúngica de la Expresión Génica/fisiología , Metabolismo Secundario/fisiología , Regulación hacia Arriba/fisiología , Animales , Biología Computacional/métodos , Caracol Conus , Proteínas Fúngicas/biosíntesis , Proteínas Fúngicas/genética , Perfilación de la Expresión Génica/métodosRESUMEN
Protein kinases C (PKCs) are a family of serine/threonine kinases involved in various cellular processes, including proliferation, differentiation, cell survival, and apoptosis. Here, we report the identification, structure-activity relationship (SAR), and 3D-QSAR studies of 69 natural indolocarbazoles, including 15 new compounds, from marine streptomyces strains. Interestingly, we found that the chair conformational isomer of 7-oxo-staurosporine (compound 15) inhibited PKCθ more potently than the corresponding boat isomer. An evaluation of kinase selectivity and antitumor efficacy revealed that 15 was a potent dual PKCθ/δ inhibitor and that it could efficiently inhibit tumor growth in pancreatic cancer (PC) by inducing cellular apoptosis and suppressing the NF-κB/p-P65 pathway. In addition, we demonstrated that overexpression of p-PKCδ and p-P65 was associated with poor survival rates in patients with PC, and p-PKCθ expression also showed significant positive correlations with p-PKCδ and p-P65 levels. Finally, the PC patient-derived xenograft model further confirmed the potential anti-PC efficacy of 15.
Asunto(s)
Carbazoles/química , Proteína Quinasa C-delta/antagonistas & inhibidores , Proteína Quinasa C-theta/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Animales , Apoptosis/efectos de los fármacos , Sitios de Unión , Carbazoles/metabolismo , Carbazoles/farmacología , Carbazoles/uso terapéutico , Línea Celular Tumoral , Cristalografía por Rayos X , Humanos , Ratones , Ratones Endogámicos BALB C , Simulación del Acoplamiento Molecular , FN-kappa B/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Proteína Quinasa C-delta/metabolismo , Proteína Quinasa C-theta/metabolismo , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Agua de Mar/microbiología , Transducción de Señal/efectos de los fármacos , Streptomyces/química , Streptomyces/metabolismo , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Colon cancer is still a major disease plaguing humans. In this study, we evaluated the synergistic antitumor effects of the combination of BRD4 inhibitor JQ1 and docosahexaenoic acid (DHA) in colon cancer. We demonstrated that simultaneous exposure to JQ1 and DHA resulted in strong synergistic antiproliferative and proapoptotic effects related to inhibition of expression of c-Myc and activation of NF-κB in colon cancer cell lines. At the same time, the synergetic anticancer effect had been confirmed in vivo. For in vivo experiments, JQ1 and DHA resulted in more significant tumor growth inhibition (53.7%) in a human colon cancer HCT116 xenograft model, comparing with the moderate inhibition in JQ1-treated (31.9%) or DHA-treated groups (20.3%). Because DHA is the predominant component of fish oil, our data suggest that this nontoxic dietary supplement could be administered with BRD4 inhibitor during therapy for CRC, which lay an important foundation for the development of therapeutic regimens for CRC.
Asunto(s)
Antineoplásicos/uso terapéutico , Azepinas/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Ácidos Docosahexaenoicos/uso terapéutico , Triazoles/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Proteínas de Ciclo Celular/antagonistas & inhibidores , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Sinergismo Farmacológico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Ratones , FN-kappa B/efectos de los fármacos , Proteínas Proto-Oncogénicas c-myc/antagonistas & inhibidores , Factores de Transcripción/antagonistas & inhibidores , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Gephyromycin C (GC), a natural compound isolated from a marine-derived actinomycete Streptomyces sp. SS13I, which exerts anti-proliferative effect on PC3 cells. However, its underlying mechanism of the anti-cancer effect remains unknown. The results of SRB assays showed that GC inhibited the proliferation of PC3 cells with an IC50 value of 1.79 ± 0.28 µM. GC also induced G2/M cell cycle arrest which was accompanied by declining levels of cyclin proteins. Possible mechanisms were investigated and it was found that GC bound to Hsp90 and caused the degradation of Hsp90 client proteins (AKT, CHK1, P53, CDK4, Raf-b, and Raf-1). The fluorescent polarization assay with FITC-labeled geldanamycin (FITC-GA) demonstrated that GC was able to compete with FITC-GA in binding to wild type Hsp90 with an IC50 of 2.15 µM. Results of a docking study also suggested that GC interacted with the N-terminal domain of Hsp90. Our results showed that GC could bind to Hsp90, which resulted in down-regulation of Hsp90 client proteins and G2/M arrest in PC3 cells. Since the antitumor effects of this kind of angucycline via targeting Hsp90 has not been reported before, our results indicate that GC is a novel inhibitor of Hsp90 from marine resources and worthy of further study.
Asunto(s)
Antraquinonas/farmacología , Apoptosis/efectos de los fármacos , Hidrocarburos Aromáticos con Puentes/farmacología , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Puntos de Control de la Fase M del Ciclo Celular/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/farmacología , Antraquinonas/química , Hidrocarburos Aromáticos con Puentes/química , Proteínas de Ciclo Celular/metabolismo , Proliferación Celular/efectos de los fármacos , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Modelos Moleculares , Células PC-3 , Proteolisis/efectos de los fármacosRESUMEN
As part of our efforts toward search for structurally new and bioactive natural products from marine-derived microorganisms, one new compound (1) was characterized from a marine-derived actinomycete Streptomyces sp. SS13M. The structure of new compound was elucidated by the analysis of HRESIMS, 1D, and 2D NMR spectroscopic data, and the absolute configuration was determined by ECD calculations.[Formula: see text].
Asunto(s)
Productos Biológicos , Streptomyces , Espectroscopía de Resonancia Magnética , Estructura MolecularRESUMEN
Marine-derived fungi have been reported to have great potential to produce structurally unique metabolites. Our investigation on secondary metabolites from marine-derived fungi resulted in the isolation of seven new polyketides (phomopsiketones D-G (1-4) and letendronols A-C (5-7)) as well as one known xylarinol (8) in the cultural broth of Letendraea sp. Their structures and absolute configurations were elucidated using a set of spectroscopic and chemical methods, including HRESIMS, NMR, single-crystal X-ray diffraction, ECD calculation, and a modified version of Mosher's method. Compound 2 showed weak inhibition against nitric oxide production in lipopolysaccaride-activated macrophages with an IC50 value of 86 µM.
Asunto(s)
Ascomicetos/química , Policétidos/química , Policétidos/aislamiento & purificación , Animales , Antibacterianos/farmacología , Línea Celular Tumoral/efectos de los fármacos , Cristalografía por Rayos X , Decápodos/microbiología , Bacterias Gramnegativas/efectos de los fármacos , Espectroscopía de Resonancia Magnética , Ratones , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Océanos y Mares , Policétidos/farmacología , Células RAW 264.7RESUMEN
Six new (1-6) and nine known (7-15) staurosporine derivatives were isolated from the rice solid fermentation of the marine-derived Streptomyces sp. NB-A13. The structures of the new staurosporine derivatives were established by extensive spectroscopic data interpretation. The absolute configurations of 1 and 2 were assigned by quantum chemical calculations of the electronic circular dichroism (ECD) spectra. All of these compounds were screened for their cytotoxic activities against PC-3 and SW-620 cell lines. Compound 7 exhibited stronger inhibitory activity against SW-620 cell lines than the positive control staurosporine (25.10â¯nM), with IC50 values of 9.99â¯nM. Moreover, compounds 1-5, 8-13 and 15 also showed significant cytotoxicities with IC50 values ranging from 0.02 to 16.60⯵M, while 6 exhibited no cytotoxic potency. Additionally, compounds 1-7 were also tested for enzyme inhibition activities of Protein kinase C theta (PKC-θ), and showed activity with IC50 values ranging from 0.06 to 9.43⯵M except for compound 6, which has no inhibition activity.
Asunto(s)
Antineoplásicos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Estaurosporina/análogos & derivados , Estaurosporina/farmacología , Streptomyces/química , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Proteína Quinasa C-theta/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/aislamiento & purificación , Estaurosporina/aislamiento & purificación , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A new medermycin analog (1) was isolated from the marine-derived actinomycetes Streptomyces sp. ZS-A45. The structure elucidation of compound 1 was determined by the HRESIMS and extensive NMR analysis. And compound 1 exhibited significant cytotoxicity against PC3 cell lines with IC50 values of 0.81 ± 0.42 µm.