RESUMEN
Makaluvamine J, a pyrroloiminoquinone alkaloid of marine sponge origin, and its analogs were synthesized and assessed for their potential to develop as a novel and selective growth inhibitor targeting human pancreatic cancer PANC-1 cells. Ts-damirone B, a common precursor featuring a pyrroloiminoquinone core structure, was synthesized through Bartoli indole synthesis and IBX-mediated oxidation. Late-stage diversification at N-5 and N-9 yielded makaluvamine J and several analogs. A structure-activity relationship (SAR) analysis highlighted the significance of the lipophilic side chain at N-9 for the growth inhibitory activity of PANC-1 cells. The modest alkyl group at N-5 was found to improve selectivity against other cancer cells. Among the prepared analogs, the tryptamine analog 24 showed potent and selective cytotoxicity (IC50 = 0.029 µM, selective index = 13.1), exceeding those of natural products.
Asunto(s)
Alcaloides , Antineoplásicos , Poríferos , Pirroliminoquinonas , Animales , Humanos , Pirroliminoquinonas/química , Pirroliminoquinonas/farmacología , Relación Estructura-Actividad , Poríferos/química , Antineoplásicos/farmacología , Antineoplásicos/química , Alcaloides/químicaRESUMEN
A shorter synthesis of the demethyl(oxy)aaptamine skeleton was developed via oxidative intramolecular cyclization of 1-(2-azidoethyl)-6-methoxyisoquinolin-7-ol followed by dehydrogenation with a hypervalent iodine reagent. This is the first example of oxidative cyclization at the ortho-position of phenol that does not involve spiro-cyclization, resulting in the improved total synthesis of 3-(phenethylamino)demethyl(oxy)aaptamine, a potent anti-dormant mycobacterial agent.
Asunto(s)
Fenol , Ciclización , Estrés Oxidativo , Fenoles , Naftiridinas/químicaRESUMEN
The current tuberculosis treatment regimen is long and complex, and its failure leads to relapse and emergence of drug resistance. One of the major reasons underlying the extended chemotherapeutic regimen is the ability of Mycobacterium tuberculosis to attain a dormant state. Therefore, the identification of new lead compounds with chemical structures different from those of conventional anti-tuberculosis drugs is essential. The compound 3-(phenethylamino)demethyl(oxy)aaptamine (PDOA, 1), isolated from marine sponge of Aaptos sp., is known as an anti-dormant mycobacterial substance, and has been reported to be effective against the drug resistant strains of M. tuberculosis. However, its target protein still remains unclear. This study aims to clarify the structure-activity relationship of 1 using 15 synthetic analogues, in order to prepare a probe molecule for detecting the target protein of 1. We succeeded in creating the compound 15 with a photoaffinity group that retained antimicrobial activity, which proved to be a suitable probe molecule for identifying the target protein of 1.
Asunto(s)
Antituberculosos/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Naftiridinas/farmacología , Poríferos/metabolismo , Animales , Antituberculosos/química , Antituberculosos/aislamiento & purificación , Farmacorresistencia Bacteriana , Sondas Moleculares , Naftiridinas/química , Naftiridinas/aislamiento & purificación , Relación Estructura-ActividadRESUMEN
The synthesis and evaluation of simplified analogs of marine sponge-derived alkaloid 3-(phenethylamino)demethyl(oxy)aaptamine were performed to develop novel anti-mycobacterial substances. Ring truncation of the tricyclic benzo[de][1,6]-naphthyridine skeleton effectively weakened the cytotoxicity of the natural product, and the resulting AC-ring analog exhibited good anti-mycobacterial activity. A structure-activity relationship (SAR) study, synthesizing and evaluating some analogs, demonstrated the specificity and importance of the N-(2-arylethyl)quinolin-3-amine skeleton as a promising scaffold for anti-mycobacterial lead compounds.
Asunto(s)
Alcaloides , Antineoplásicos , Poríferos , Animales , Alcaloides/farmacología , Antineoplásicos/farmacología , Relación Estructura-ActividadRESUMEN
3-(Phenethylamino)demethyl(oxy)aaptamine (1) was re-discovered from the marine sponge of Aaptos sp. as an anti-dormant mycobacterial substance through the bioassay-guided separation. Compound 1 showed potent anti-microbial activity against Mycobacterium bovis BCG with a minimum inhibitory concentration of 0.75 µg/mL under both aerobic conditions and hypoxic conditions inducing dormant state. Compound 1 was also effective against pathogenic M. tuberculosis strains including clinical multidrug-resistant strains. Furthermore, the successful total syntheses of 1 and its analog 3-aminodemethyl(oxy)aaptamine (2) afford sufficient quantities for further biological studies.
RESUMEN
Hypoxia-adapted cancer cells in tumors contribute to the pathological progression of cancer. The marine spongean sesquiterpene phenols dictyoceratin-A (1) and -C (2) have been shown to induce hypoxia-selective growth inhibition in cultured cancer cells and exhibit in vivo antitumor effects. These compounds inhibit the accumulation of hypoxia-inducible factor-1α (HIF-1α), which is a drug target in hypoxia-adapted cancer cells, under hypoxic conditions. However, the target molecules of compounds 1 and 2, which are responsible for decreasing HIF-1α expression under hypoxic conditions, remain unclear. In this study, we synthesized probe molecules for compounds 1 and 2 to identify their target molecules and found that both compounds bind to RNA polymerase II-associated protein 3 (RPAP3), which is a component of the R2TP/Prefoldin-like (PEDL) complex. In addition, RPAP3-knockdown cells showed a phenotype similar to that of compound-treated cells.
Asunto(s)
Antineoplásicos/farmacología , Productos Biológicos/farmacología , Proteínas Portadoras/antagonistas & inhibidores , Poríferos , Animales , Proteínas Reguladoras de la Apoptosis , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Hipoxia de la Célula/efectos de los fármacos , Línea Celular Tumoral , Técnicas de Silenciamiento del Gen , Humanos , Hidroxibenzoatos/farmacología , Terapia Molecular Dirigida/métodos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , ARN Interferente Pequeño/metabolismo , Sesquiterpenos/farmacologíaRESUMEN
The tumor microenvironment is considered as one of the important targets for anticancer drug discovery. In particular, nutrient deficiency may be observed in tumor microenvironment; biakamides A-D (1-4) isolated from marine sponge Petrosaspongia sp. as growth inhibitors against cancer cells adapted to glucose-deprived conditions have potential as new drugs and tools for elucidating adaptation mechanisms to these conditions. In this paper, we investigated structure-activity relationship (SAR) of biakamide to create easily accessible analog and gain insights about participation of the substructures to growth-inhibitory activity toward development of anticancer drug. This work revealed that 14,15-dinor-biakamide C (5), which is easily accessible, has similar activity to natural biakamide C (3). In addition, detailed SAR study showed the terminal acyl chain is important for interacting with target molecule and amide part including thiazole ring has acceptability to convert structures without losing activity.
Asunto(s)
Antineoplásicos/química , Policétidos/química , Poríferos/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Policétidos/síntesis química , Policétidos/farmacología , Poríferos/metabolismo , Estereoisomerismo , Relación Estructura-Actividad , Tiazoles/químicaRESUMEN
Biakamides A-D, novel unusually unique polyketides, were isolated from an Indonesian marine sponge (Petrosaspongia sp.) with a constructed bioassay using PANC-1 human pancreatic cancer cells. Through detailed analyses of the one- and two-dimensional NMR spectra of biakamides, planar chemical structures possessing a terminal thiazole, two N-methyl amides, a chloromethylene, and a substituted butyryl moiety were obtained. After elucidation of the configuration of the secondary alcohol moiety in biakamides A and B, the absolute stereostructures of the two secondary methyl groups in biakamides A-D were determined by the asymmetric total syntheses of all possible stereoisomers from the optically pure monoprotected 2,4-dimethyl-1,5-diol. Biakamides A-D showed selective antiproliferative activities against PANC-1 cells cultured under glucose-deficient conditions in a concentration-dependent manner. The primary mode of action of biakamides was found to be inhibition of complex I in the mitochondrial electron transport chain.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias Pancreáticas/tratamiento farmacológico , Policétidos/farmacología , Poríferos/química , Inanición/tratamiento farmacológico , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Conformación Molecular , Neoplasias Pancreáticas/patología , Policétidos/síntesis química , Policétidos/química , Inanición/patología , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Hypoxia-adapted cancer cells in tumors contribute to the pathological progression of cancer. Cancer research has therefore focused on the identification of molecules responsible for hypoxia adaptation in cancer cells, as well as the development of new compounds with action against hypoxia-adapted cancer cells. The marine natural product furospinosulin-1 (1) has displayed hypoxia-selective growth inhibition against cultured cancer cells, and has shown in vivo anti-tumor activity, although its precise mode of action and molecular targets remain unclear. In this study, we found that 1 is selectively effective against hypoxic regions of tumors, and that it directly binds to the transcriptional regulators p54(nrb) and LEDGF/p75, which have not been previously identified as mediators of hypoxia adaptation in cancer cells.
Asunto(s)
Péptidos y Proteínas de Señalización Intercelular/química , Proteínas Asociadas a Matriz Nuclear/química , Factores de Transcripción de Octámeros/química , Proteínas de Unión al ARN/química , Sesterterpenos/química , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Hipoxia de la Célula/efectos de los fármacos , Cisplatino/farmacología , Cisplatino/uso terapéutico , Proteínas de Unión al ADN , Técnica del Anticuerpo Fluorescente , Técnicas de Silenciamiento del Gen , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Ratones , Estructura Molecular , Neoplasias/tratamiento farmacológico , Unión Proteica/efectos de los fármacos , Sesterterpenos/farmacología , Sesterterpenos/uso terapéuticoRESUMEN
As angiogenesis is critical for tumor growth and metastasis, potent and selective anti-angiogenic agents with novel modes of action are highly needed for anti-cancer drug discovery. In this review, our studies focusing on the search for anti-angiogenic substances from natural sources, such as bastadins, globostellatic acid X methyl esters and cortistatins from marine sponges, and pyripyropenes from marine-derived fungus, together with senegasaponins from medicinal plant, are summarized.
Asunto(s)
Inhibidores de la Angiogénesis/aislamiento & purificación , Inhibidores de la Angiogénesis/farmacología , Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Productos Biológicos/aislamiento & purificación , Productos Biológicos/farmacología , Neoplasias/tratamiento farmacológico , Neovascularización Patológica/tratamiento farmacológico , Inhibidores de la Angiogénesis/química , Animales , Antineoplásicos Fitogénicos/química , Productos Biológicos/química , Humanos , Neoplasias/irrigación sanguíneaRESUMEN
In the course of searching for selective growth inhibitors of the cancer cells adapted to nutrient starvation, a new 3-alkylpyridine alkaloid named N-methylniphatyne A (1) was isolated from an Indonesian marine sponge of Xestospongia sp. The chemical structure of 1 was determined on the basis of the spectroscopic analysis and comparison with the synthesized 1 and its analogues. Compound 1 showed the cytotoxic activity against PANC-1 cells under the condition of glucose starvation with IC50 value of 16 µM, whereas no growth-inhibition was observed up to 100 µM under the general culture conditions.
Asunto(s)
Alquinos/farmacología , Antineoplásicos/farmacología , Piridinas/farmacología , Xestospongia/química , Alquinos/química , Alquinos/aislamiento & purificación , Animales , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Indonesia , Estructura Molecular , Piridinas/química , Piridinas/aislamiento & purificación , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Total syntheses of (+)-dictyoceratin-C (1) and (+)-dictyoceratin-A (smenospondiol) (2), hypoxia-selective growth inhibitors isolated from marine sponge, were executed. The absolute stereochemistry of the each compound was determined through the enantioselective total syntheses of them. It revealed that the unnatural enantiomers of them also exhibited the hypoxia-selective growth inhibitory activity against human prostate cancer DU-145 cells.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Inhibidores de Crecimiento/síntesis química , Inhibidores de Crecimiento/farmacología , Hidroxibenzoatos/síntesis química , Hidroxibenzoatos/farmacología , Poríferos/química , Sesquiterpenos/síntesis química , Sesquiterpenos/farmacología , Animales , Hipoxia de la Célula , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores de Crecimiento/química , Humanos , Hidroxibenzoatos/química , Masculino , Biología Marina , Neoplasias de la Próstata/patología , Sesquiterpenos/química , EstereoisomerismoRESUMEN
In the course of our search for anti-dormant Mycobacterial substances, nybomycin (1) was re-discovered from the culture broth of a marine-derived Streptomyces sp. on the bioassay-guided separation. Compound 1 showed anti-microbial activity against Mycobacterium smegmatis and Mycobacterium bovis BCG with the MIC of 1.0µg/mL under both actively growing aerobic conditions and dormancy inducing hypoxic conditions. Compound 1 is also effective to Mycobacterium tuberculosis including the clinically isolated strains. The mechanistic analysis indicated that 1 bound to DNA and induces a unique morphological change to mycobacterial bacilli leading the bacterial cell death.
Asunto(s)
Antituberculosos/farmacología , ADN Bacteriano/antagonistas & inhibidores , Mycobacterium tuberculosis/efectos de los fármacos , Streptomyces/química , Antituberculosos/química , Antituberculosos/aislamiento & purificación , Organismos Acuáticos , Técnicas de Cultivo de Célula , Cósmidos/química , Cósmidos/metabolismo , ADN Bacteriano/química , Farmacorresistencia Bacteriana/genética , Pruebas de Sensibilidad Microbiana , Viabilidad Microbiana/efectos de los fármacos , Mycobacterium bovis/efectos de los fármacos , Mycobacterium bovis/genética , Mycobacterium bovis/metabolismo , Mycobacterium bovis/ultraestructura , Mycobacterium smegmatis/efectos de los fármacos , Mycobacterium smegmatis/genética , Mycobacterium smegmatis/metabolismo , Mycobacterium smegmatis/ultraestructura , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/metabolismo , Mycobacterium tuberculosis/ultraestructura , Quinolonas/química , Quinolonas/aislamiento & purificación , Quinolonas/farmacología , Streptomyces/metabolismoRESUMEN
Oral dictyoceratin-C (1) and A (2), hypoxia-selective growth inhibitors, showed potent in vivo antitumor effects in mice subcutaneously inoculated with sarcoma S180 cells. Structurally modified analogs were synthesized to assess the structure-activity relationship of the natural compounds 1 and 2 isolated from a marine sponge. Biological evaluation of these analogs showed that the exo-olefin and hydroxyl and methyl ester moieties were important for the hypoxia-selective growth inhibitory activities of 1 and 2. Thus far, only substitution of the methyl ester with propargyl amide in 1 was found to be effective for the synthesis of probe molecules for target identification.
Asunto(s)
Antineoplásicos/farmacología , Hidroxibenzoatos/farmacología , Sarcoma 180/tratamiento farmacológico , Sesquiterpenos/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Femenino , Hidroxibenzoatos/química , Hidroxibenzoatos/aislamiento & purificación , Ratones , Poríferos/metabolismo , Sarcoma 180/patología , Sesquiterpenos/química , Sesquiterpenos/aislamiento & purificación , Relación Estructura-ActividadRESUMEN
Xylarianaphthol-1, a novel dinaphthofuran derivative, was isolated from a marine sponge-derived fungus of order Xylariales on the guidance of a bioassay using the transfected human osteosarcoma MG63 cells (MG63(luc+)). The chemical structure of xylarianaphthol-1 was determined from the (1)H and (13)C NMR analysis and was further confirmed by the total synthesis. Xylarianaphthol-1 activated p21 promoter stably transfected in MG63 cells dose-dependently. Expression of p21 protein in the wild-type MG63 cells was also increased by xylarianaphthol-1 treatment.
Asunto(s)
Benzofuranos/farmacología , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Benzofuranos/química , Benzofuranos/aislamiento & purificación , Línea Celular Tumoral , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Relación Dosis-Respuesta a Droga , Humanos , Relación Estructura-Actividad , Xylariales/química , Xylariales/metabolismoRESUMEN
The synthesis and evaluation of a photoaffinity probe molecule for furospinosulin-1, a hypoxia-selective growth inhibitor that we identified from marine sponge, was studied. An analogue carrying an alkyne tail showed potent hypoxia-selective inhibitory activity exceeding that of the parent molecule, and exhibited in vivo anti-tumor activity following oral administration. The alkyne moiety in the analogue was also found to be a good anchoring group for the preparation of probe molecules; a photoaffinity probe molecule having an optimized spacer length was selected through the systematic synthesis of several probes and the evaluation of their hypoxia-selective growth inhibitory activity and electrophoretic mobility shift properties.
Asunto(s)
Antineoplásicos/farmacología , Hipoxia , Etiquetas de Fotoafinidad/farmacología , Sesterterpenos/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Estructura Molecular , Etiquetas de Fotoafinidad/síntesis química , Etiquetas de Fotoafinidad/química , Sesterterpenos/síntesis química , Sesterterpenos/química , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Syntheses of analogue compounds of cortistatin A (1), an anti-angiogenic steroidal alkaloid from Indonesian marine sponge, were investigated by utilizing the CD-ring fragment of vitamin D2. The incidental preparation of a new analogue having CD-cis-fused skeleton and its biological evaluation revealed the importance of the CD-trans-fused structure for the potent and selective antiproliferative activity of 1 against human umbilical vein endothelial cells (HUVECs).
Asunto(s)
Ergocalciferoles/química , Compuestos Policíclicos/química , Animales , Proliferación Celular/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Isomerismo , Conformación Molecular , Compuestos Policíclicos/síntesis química , Compuestos Policíclicos/farmacología , Poríferos/química , Poríferos/metabolismoRESUMEN
A route for the asymmetric synthesis of (-)-stenine, a member of the Stemona alkaloid family used as folk medicine in Asian countries, is described. The key features of the sequence employed include stereoselective transformations on a cyclohexane ring controlled by a chiral auxiliary unit and an intramolecular Mitsunobu reaction to construct the perhydroindole ring system. By using an intermediate in the route to (-)-stenine, an asymmetric synthesis of 9a-epi-stenine was also executed. The C(9a) stereocenter in 9a-epi-stenine was installed by using a Staudinger/aza-Wittig reaction of a keto-azide precursor followed by reduction of the resulting imine. The results of this effort demonstrate the applicability of the chiral auxiliary based strategy to the preparation of naturally occurring alkaloids that contain highly functionalized cyclohexane cores.
Asunto(s)
Alcaloides/síntesis química , Alcoholes/química , Alcaloides/química , Ciclización , Ciclohexanos/química , Stemonaceae/química , EstereoisomerismoRESUMEN
Malignant pleural mesothelioma (MPM) is a highly aggressive malignant tumor, and the effective therapeutic drugs are limited. Thus, the establishment of novel therapeutic method is desired. Considerable proportion of MPMs are shown to express cell adhesion molecule 1 (CADM1), and to use CADM1 to bind to and proliferate on the pleural mesothelial surface, suggesting that CADM1 is a possible therapeutic target. Here, anti-CADM1 ectodomain chicken monoclonal antibodies, 3E1 and 9D2, were examined for their possible therapeutic utility. The full-length form of CADM1 was expressed in eight out of twelve human MPM cell lines. MPM cell lines were cultured on a confluent monolayer of mesothelial MeT-5A cells in the presence of 9D2, the neutralizing antibody. 9D2 suppressed the cell growth of CADM1-positive MPM cells with the loss and aggregation of CADM1 molecules on the MPM cell membrane, but not of CADM1-negative MPM cells. Co-addition of 3E1, lacking the neutralizing action, enhanced the growth-suppressive effect of 9D2. The two antibodies were tested as drug delivery vectors. 3E1 was converted into a humanized antibody (h3E1) and conjugated with monomethyl auristatin E (MMAE), a tubulin polymerization inhibitor. When the resulting h3E1-MMAE antibody-drug conjugate (ADC) was added to the standard cultures of CADM1-positive MPM cells, it suppressed the cell growth in a dose-dependent manner. Co-addition of 9D2 enhanced the growth-suppressive effect of h3E1-MMAE ADC. Anti-CADM1 ectodomain antibodies were suggested to serve as both antibody drugs and drug vectors in the treatment of MPM.
RESUMEN
Syntheses of biotinylated probe molecules of L-glutathione (GSH) equipped with boronic acid moiety and evaluation of their binding affinities against glutathione-S-transferase (GST) were described. It revealed that the presence of boronic acid moiety in an appropriate position enhances binding affinity of GSH probe toward GST probably by forming a reversible cross-link. Among prepared, the boronate-containing probe 8b exhibited the highest recovering ability of GST from Escherichia coli cell lysate.