RESUMEN
Introducing a second chiral center on our previously described 1,2,4-triazole, allowed us to increase diversity and elongate the 'C-terminal part' of the molecule. Therefore, we were able to explore mimics of the substance P analogs described as inverse agonists. Some compounds presented affinities in the nanomolar range and potent biological activities, while one exhibited a partial inverse agonist behavior similar to a Substance P analog.
Asunto(s)
Receptores de Ghrelina/metabolismo , Triazoles/química , Transferencia Resonante de Energía de Fluorescencia , Indoles/química , Indoles/farmacología , Concentración 50 Inhibidora , Ligandos , Receptores de Ghrelina/agonistas , Relación Estructura-Actividad , Sustancia P/química , Triptófano/análogos & derivados , Triptófano/química , Triptófano/farmacologíaRESUMEN
Ghrelin receptor ligands based on a trisubstituted 1,2,4-triazole scaffold were recently synthesized and evaluated for their in vitro affinity for the GHS-R1a receptor and their biological activity. In this study, replacement of the α-aminoisobutyryl (Aib) moiety (a common feature present in numerous growth hormone secretagogues described in the literature) by aromatic and heteroaromatic groups was explored. We found potent antagonists incorporating the picolinic moiety in place of the Aib moiety. In an attempt to increase affinity and activity of our lead compound 2, we explored the modulation of the pyridine ring. Herein we report the design and the structure-activity relationships study of these new ghrelin receptor ligands.
Asunto(s)
Receptores de Ghrelina/antagonistas & inhibidores , Receptores de Ghrelina/metabolismo , Triazoles/síntesis química , Triazoles/metabolismo , Animales , Línea Celular , Humanos , Ratones , Unión Proteica/fisiología , Relación Estructura-Actividad , Triazoles/farmacologíaRESUMEN
A novel series of (7-aryl-1,5-naphthyridin-2-yl)ureas was discovered as dual ERK2 and Aurora B kinases inhibitors. Several analogues were active at micromolar and submicromolar range against ERK2 and Aurora B, associated with very promising antiproliferative activity toward various cancer cell lines. Synthesis, structure activity relationship and docking study are reported. In vitro ADME properties and safety data are also discussed.
Asunto(s)
Antineoplásicos/farmacología , Aurora Quinasa B/antagonistas & inhibidores , Descubrimiento de Drogas , Proteína Quinasa 1 Activada por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Urea/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Aurora Quinasa B/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HCT116 , Humanos , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad , Urea/análogos & derivados , Urea/químicaRESUMEN
In recent years, a novel treatment method for cancer has emerged, which is based on the starvation of tumors of amino acids like arginine. The deprivation of arginine in serum is based on enzymatic degradation and can be realized by arginine deaminases like the l-amino acid oxidase found in the ink toxin of the sea hare Aplysia punctata. Previously isolated from the ink, the l-amino acid oxidase was described to oxidate the essential amino acids l-lysine and l-arginine to their corresponding deaminated alpha-keto acids. Here, we present the recombinant production and functionalization of the amino acid oxidase Aplysia punctata ink toxin (APIT). PEGylated APIT (APIT-PEG) increased the blood circulation time. APIT-PEG treatment of patient-derived xenografted mice shows a significant dose-dependent reduction of tumor growth over time mediated by amino acid starvation of the tumor. Treatment of mice with APIT-PEG, which led to deprivation of arginine, was well tolerated.
Asunto(s)
Aplysia , Arginina , Lisina , Polietilenglicoles , Animales , Arginina/farmacología , Arginina/química , Lisina/farmacología , Lisina/química , Polietilenglicoles/química , Polietilenglicoles/farmacología , Humanos , Ratones , Ensayos Antitumor por Modelo de Xenoinjerto , Toxinas Marinas/farmacología , Toxinas Marinas/uso terapéutico , Toxinas Marinas/química , Proteínas Recombinantes/farmacología , Proteínas Recombinantes/uso terapéutico , L-Aminoácido Oxidasa/farmacología , L-Aminoácido Oxidasa/metabolismo , L-Aminoácido Oxidasa/química , Femenino , Línea Celular TumoralRESUMEN
A new series of substituted tri-/tetraazabenzo[3,2-a]fluorene-5,6-diones and their corresponding oxime derivatives have been synthesized and spectroscopically characterized. The antiproliferative activities of all compounds were evaluated on at least three different cell lines.
Asunto(s)
Antineoplásicos/síntesis química , Compuestos Aza/síntesis química , Fluorenos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Compuestos Aza/química , Derivados del Benceno/síntesis química , Derivados del Benceno/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Estructura MolecularRESUMEN
A series of indazolo[4,3-gh]isoquinolinones derivatives have been synthesized to decrease cardiotoxic side effects in comparison to Mitoxantrone. The antiproliferative effects of different side chains were investigated and tested on at least four different cell lines of cervix, ovarian, CNS, NSCLC (non-small-cell lung cancer) and colon carcinoma. In addition to antiproliferative activities, influence on cell cycle and intercalation behavior have been tested.
Asunto(s)
Antineoplásicos/síntesis química , Indazoles/química , Quinolonas/química , Antineoplásicos/química , Antineoplásicos/toxicidad , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , ADN/química , ADN/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa , Humanos , Mitoxantrona/química , Mitoxantrona/toxicidad , Quinolonas/síntesis química , Quinolonas/toxicidad , Puntos de Control de la Fase S del Ciclo Celular/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
A series of 6-azanaphthoquinone pyrrolo-annelated derivatives carrying different basic side chains have been synthesized. The antiproliferative activities of all compounds were evaluated on at least four different cell lines with Mitoxantrone as reference compound. Cytotoxic effects and DNA intercalation behavior were investigated.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Pirroles/síntesis química , Pirroles/farmacología , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Naftoquinonas/química , Pirroles/química , Relación Estructura-ActividadRESUMEN
A novel series of phenylimino-10H-anthracen-9-ones and 9-(phenylhydrazone)-9,10-anthracenediones were synthesized and evaluated for interaction with tubulin and for cytotoxicity against a panel of human tumor cell lines. The 10-(3-hydroxy-4-methoxy-phenylimino)-10H-anthracen-9-one 15h and its dichloro analog 16b were identified as potent inhibitors of tumor cell growth (16b, IC(50) K562 0.11 µM), including multidrug resistant phenotypes. Compound 15h had excellent activity as an inhibitor of tubulin polymerization. Concentration-dependent cell cycle analyzes by flow cytometry confirmed that KB/HeLa cells treated by 15h and 16b were arrested in the G2/M phases of the cell cycle. In competition experiments, 15h strongly displaced radiolabeled colchicine from its binding site on tubulin, showing IC(50) values similar to that of colchicine. The results obtained demonstrate that the antiproliferative activity is related to the inhibition of tubulin polymerization.
Asunto(s)
Antracenos/farmacología , Antineoplásicos/farmacología , Microtúbulos/efectos de los fármacos , Bases de Schiff/farmacología , Tubulina (Proteína)/metabolismo , Antracenos/síntesis química , Antracenos/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Bases de Schiff/síntesis química , Bases de Schiff/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Disorazoles are macrocyclic polyketides first isolated from the fermentation broth of the myxobacterium Sorangium cellulosum. Both the major fermentation product disorazole A(1) and its much rarer companion disorazole C(1) exhibit potent cytotoxic activity against many human tumor cells. Furthermore, the disorazoles appear to bind tubulin uniquely among known antimitotic agents, promoting apoptosis or premature senescence. It is uncertain what conveys tumor cell sensitivity to these complex natural products. Therefore, we generated and characterized human tumor cells resistant to disorazole C(1). Resistant cells proved exceedingly difficult to generate and required single step mutagenesis with chronic stepwise exposure to increasing concentrations of disorazole C(1). Compared with wild-type HeLa cells, disorazole C(1)-resistant HeLa/DZR cells were 34- and 8-fold resistant to disorazole C(1) and disorazole A(1) growth inhibition, respectively. HeLa/DZR cells were also remarkably cross-resistant to vinblastine (280-fold), paclitaxel (2400-fold), and doxorubicin (47-fold) but not cisplatin, suggesting a multidrug-resistant phenotype. Supporting this hypothesis, MCF7/MDR cells were 10-fold cross-resistant to disorazole C(1). HeLa/DZR disorazole resistance was not durable in the absence of chronic compound exposure. Verapamil reversed HeLa/DZR resistance to disorazole C(1) and disorazole A(1). Moreover, HeLa/DZR cells expressed elevated levels of the drug resistance ATP-binding cassette ABCB1 transporter. Loss of ABCB1 by incubation with short interfering RNA restored sensitivity to the disorazoles. Thus, the multidrug resistance transporter ABCB1 can affect the cytotoxicity of both disorazole C(1) and A(1). Disorazole C(1), however, retained activity against cells resistant against the clinically used microtubule-stabilizing agent epothilone B.
Asunto(s)
Antibióticos Antineoplásicos/farmacología , Línea Celular Tumoral , Macrólidos/farmacología , Oxazoles/farmacología , Moduladores de Tubulina/farmacología , Subfamilia B de Transportador de Casetes de Unión a ATP , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/biosíntesis , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Proliferación Celular/efectos de los fármacos , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Epotilonas/farmacología , Humanos , ARN Interferente Pequeño/genéticaRESUMEN
A series of azanaphthoquinone pyrrolo-annelated derivatives attached to basic side chains have been synthesized. The antiproliferative activities of all compounds were evaluated on at least four different cell lines. The effects on cell cycle and intercalation were investigated.
Asunto(s)
Antineoplásicos/farmacología , Naftoquinonas/farmacología , Pirroles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa , Humanos , Estructura Molecular , Naftoquinonas/síntesis química , Naftoquinonas/química , Pirroles/síntesis química , Pirroles/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The synthesis and study of the structure-activity relationships of cytotoxic compounds based on N-pyridinyl or N-aryl-2-(1-benzylindol-3-yl)glyoxamide skeleton, represented by the lead structures D-24241 and D-24851, are described. The presence of N-(pyridin-4-yl) moiety was crucial for activity and 2-[1-(4-chloro-3-nitrobenzyl)-1H-indol-3-yl]-2-oxo-N-(pyridin-4-yl)acetamide (55), the most potent derivative, showed IC(50)=39 nM, 51 nM and 11 nM against HeLa/KB (human cervix carcinoma), L1210 (murine leukemia) and SKOV3 (human ovarian carcinoma) cell lines proliferation assay, respectively, as active as the lead compounds.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Indoles/química , Indoles/farmacología , Compuestos de Sulfonilurea/química , Compuestos de Sulfonilurea/farmacología , Animales , Antineoplásicos/síntesis química , Carcinoma/tratamiento farmacológico , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Células HeLa , Humanos , Indoles/síntesis química , Leucemia/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Relación Estructura-Actividad , Compuestos de Sulfonilurea/síntesis química , Neoplasias del Cuello Uterino/tratamiento farmacológicoRESUMEN
New series of analogues of N-(pyridin-4-yl)-2-[1-(4-chlorobenzyl)-indol-3-yl]glyoxamide D-24851 were synthesized, characterized and tested for their in vitro anticancer properties. In the first series, an amino acid spacer was introduced in the glyoxamide chain of D-24851. In the second series, the glyoxamide chain was moved to positions 4 and 5 of indole skeleton. These new compounds were tested on four cancer cell lines (KB, SK-OV-3, NCI-H460 and SF-268), with promising activity for the glycine derivative.
Asunto(s)
Acetamidas/química , Acetamidas/farmacología , Antineoplásicos/síntesis química , Indoles/química , Indoles/farmacología , Antineoplásicos/farmacología , Línea Celular Tumoral , Glicina , Humanos , Relación Estructura-ActividadRESUMEN
Benzenesulfonate derivatives of naphtho[2,3-b]thiophen-4(9H)-one and 9(10H)-anthracenone were prepared and found to inhibit microtubule formation by an in vitro tubulin polymerization assay. Several analogues showed potent cytotoxic activity in an assay based on K562 leukemia cells with IC50 values of <100 nM. The methylamino analogue 14i was the most active compound in this assay (14i, IC50 K562: 0.05 muM). Antiproliferative activities of selected compounds were additionally evaluated against a panel of 12 tumor cell lines, including multi-drug-resistant phenotypes. All resistant cell lines were sensitive to these compounds. Concentration-dependent flow cytometric studies showed that KB/HeLa cells treated with selected compounds were arrested in the G2/M phases of the cell cycle. In competition experiments, these compounds strongly displaced radiolabeled colchicine from its binding site in the tubulin, showing IC50 values lower than that of colchicine. The results demonstrate that the antiproliferative activity is related to the inhibition of tubulin polymerization.
Asunto(s)
Antracenos/síntesis química , Naftalenos/síntesis química , Tiofenos/síntesis química , Moduladores de Tubulina/síntesis química , Tubulina (Proteína)/metabolismo , Antracenos/química , Antracenos/farmacología , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Colchicina/farmacología , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Naftalenos/química , Naftalenos/farmacología , Nocodazol/farmacología , Podofilotoxina/farmacología , Relación Estructura-Actividad , Tiofenos/química , Tiofenos/farmacología , Tubulina (Proteína)/química , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologíaRESUMEN
Tubulin-binding 9-benzylidene-naphtho[2,3-b]thiophen-4-ones 1a and 1b and benzylidene-9(10H)-anthracenone 2 were evaluated for their ability to induce cell death. We examined the effect of the molecules on cell cycle progression, organization of microtubule networks, and apoptosis induction. As determined by flow cytometry, cancer cells were predominantly arrested in metaphase with 4N DNA before cell death occurred. By using indirect immunofluorescence techniques we visualized microtubule depolymerization recognizable by short microtubule fragments scattered around the nucleus. The incubation with 1a and 2 resulted in chromatin condensation, nuclear fragmentation, and cell shrinkage, which are, among others, typical features of apoptotic cell death. Furthermore, time- and dose-dependent induction of apoptosis in SH-SY5Y cells was detected via cleavage of Ac-DEVD-AMC, a fluorigenic substrate for caspase-3. We observed a lower apoptotic activity in neuroblastoma cells overexpressing Bcl-xL, suggesting activation of the mitochondrial apoptosis pathway. Western blot analysis demonstrated that caspase-3, an apoptosis mediator, was activated in a time-dependent manner after exposure of SH-SY5Y cells to drugs 1a and 2. Taken together, the agents investigated in the present study display strong apoptosis-inducing activity and therefore show promise for the development of novel chemotherapeutics.
Asunto(s)
Antracenos/farmacología , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Compuestos de Bencilideno/farmacología , Naftalenos/farmacología , Tiofenos/farmacología , Moduladores de Tubulina/farmacología , Western Blotting , Caspasa 3/metabolismo , Cromatina/metabolismo , Relación Dosis-Respuesta a Droga , Citometría de Flujo , Técnica del Anticuerpo Fluorescente Directa , Humanos , Microtúbulos/metabolismo , Mitocondrias/metabolismo , Neuroblastoma/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Células Tumorales CultivadasRESUMEN
A novel series of 9-benzylidene-naphtho[2,3-b]thiophen-4-ones and structurally related compounds were synthesized and evaluated for their ability to inhibit tubulin polymerization. The 4-hydroxy-3,5-dimethoxy-benzylidene analogue 15d was identified as a potent cytotoxic agent in an assay based on K562 leukemia cells. Antiproliferative activity of 15d and the 2,4-dimethoxy-3-hydroxy-benzylidene analogue 15e was additionally evaluated against a panel of 12 tumor cell lines, including multidrug resistant phenotypes. All resistant cell lines were sensitive to these compounds. Concentration-dependent flow cytometric studies showed that K562 cells as well as KB/HeLa cells treated by 15d were arrested in the G2/M phases of the cell cycle. Moreover, four compounds strongly inhibited tubulin polymerization with activities higher or comparable to those of the reference compounds. In competition experiments, the most active compounds strongly displaced radiolabeled colchicine from its binding site in the tubulin, showing IC50 values virtually 3- to 4-fold lower than that of colchicine.
Asunto(s)
Antineoplásicos/farmacología , Tiofenos/síntesis química , Tiofenos/farmacología , Moduladores de Tubulina/farmacología , Tubulina (Proteína)/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Colchicina/farmacología , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Citometría de Flujo , Humanos , Concentración 50 Inhibidora , Células K562/efectos de los fármacos , Leucemia P388/tratamiento farmacológico , Ratones , Estructura Molecular , Relación Estructura-Actividad , Tiofenos/química , Moduladores de Tubulina/síntesis química , Moduladores de Tubulina/química , Células Tumorales CultivadasRESUMEN
A novel series of 10-benzylidene-9(10H)-anthracenones and 10-(phenylmethyl)-9(10H)-anthracenones were synthesized and evaluated for antiproliferative activity in an assay based on K562 leukemia cells. The 3-hydroxy-4-methoxybenzylidene analogue 9h was found to be the most active compound (IC(50) K562: 20 nM). Structure-activity relationships are also considered. The highly active compound 9h and the 2,4-dimethoxy-3-hydroxybenzylidene analogue 9l were tested against five tumor cell lines using the XTT assay, including multidrug resistant phenotypes. Induction of cell death in a variety of tumor cell lines was determined in a monolayer assay using propidium iodide. Noteworthy, all compounds within the series induced elongations in K562 cells similar to vinblastine-treated cells. The effect of the lead compound 9h on K562 cell growth was associated with cell cycle arrest in G2/M. Concentrations for 50% KB/HeLa cells arrested in G2/M after treatment with 9h and 9l were determined and found to be in the range of 0.2 microM. Additionally, we monitored the dose dependent caspase-3-like protease activity in K562 cells and MCF-7/Casp-3 cells treated with 9h, indicating induction of apoptosis. Western blotting analysis demonstrated that 9h caused a shift in tubulin concentration from the polymerized state found in the cell pellet to the unpolymerized state found in the cell supernatant. Seven compounds strongly inhibited tubulin polymerization with activities higher or comparable to those of the reference compounds such as colchicine, podophyllotoxin, and nocodazole. In general, the antiproliferative activity correlated with inhibition of tubulin polymerization. The most active compounds strongly displaced [(3)H]colchicine from its binding site in the tubulin, yielding IC(50) values 3- to 4-fold lower than that of colchicine. The novel benzylidene-9(10H)-anthracenones described in the present study constitute an interesting group of highly active and easily accessible antimitotic agents that inhibit tubulin polymerization.
Asunto(s)
Antracenos/síntesis química , Antineoplásicos/síntesis química , Tubulina (Proteína)/química , Antracenos/química , Antracenos/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Apoptosis , Biopolímeros , Western Blotting , Ciclo Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Células K562 , Microscopía Electrónica , Relación Estructura-ActividadRESUMEN
From a strain of the fungus Emericella variecolor derived from the marine sponge Haliclona valliculata, two new natural products, evariquinone and isoemericellin, were isolated after HPLC-UV, -MS, and -NMR studies of the extract and their structures were elucidated by mass spectrometry and NMR experiments. Evariquinone showed antiproliferative activity towards KB and NCI-H460 cells at a concentration of 3.16 microg/ml. Furthermore, the fungus was found to produce the known metabolites stromemycin, shamixanthone, and 7-hydroxyemodin. Chemical degradation, NMR decoupling experiments, and spin-system simulation provided evidence for the double bonds in stromemycin to be all E-configured. ROESY experiments established the monosaccharide moiety to be glucose.
Asunto(s)
Benzoquinonas/aislamiento & purificación , Alcoholes Bencílicos/aislamiento & purificación , Emericella/química , Animales , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/aislamiento & purificación , Antibióticos Antineoplásicos/farmacología , Benzoquinonas/química , Benzoquinonas/farmacología , Alcoholes Bencílicos/química , Alcoholes Bencílicos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Emericella/metabolismo , Humanos , Isomerismo , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Poríferos/microbiología , Células Tumorales CultivadasRESUMEN
As part of our research projects to identify new chemical entities of biological interest, we developed a synthetic approach and the biological evaluation of (7-aryl-1,5-naphthyridin-4-yl)ureas as a novel class of Aurora kinase inhibitors for the treatment of malignant diseases based on pathological cell proliferation. 1,5-Naphthyridine derivatives showed excellent inhibitory activities toward Aurora kinases A and B, and the most active compound, 1-cyclopropyl-3-[7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-4-yl]urea (49), displayed IC50 values of 13 and 107â nM against Aurora kinases A and B, respectively. In addition, the selectivity toward a panel of seven cancer-related protein kinases was highlighted. In vitro ADME properties were also determined in order to rationalize the difficulties in correlating antiproliferative activity with Aurora kinase inhibition. Finally, the good safety profile of these compounds imparts promising potential for their further development as anticancer agents.
Asunto(s)
Aurora Quinasa A/antagonistas & inhibidores , Aurora Quinasa B/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/análogos & derivados , Urea/análogos & derivados , Animales , Aurora Quinasa A/genética , Aurora Quinasa A/metabolismo , Aurora Quinasa B/genética , Aurora Quinasa B/metabolismo , Células CACO-2 , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Células HCT116 , Semivida , Humanos , Ratones , Microsomas Hepáticos/metabolismo , Naftiridinas/química , Unión Proteica , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Relación Estructura-Actividad , Urea/farmacocinética , Urea/farmacologíaRESUMEN
A total of 53 N-benzoylated phenoxazines and phenothiazines, including their S-oxidized analogues, were synthesized and evaluated for antiproliferative activity, interaction with tubulin, and cell cycle effects. Potent inhibitors of multiple cancer cell lines emerged with the 10-(4-methoxybenzoyl)-10H-phenoxazine-3-carbonitrile (33b, IC(50) values in the range of 2-15 nM) and the isovanillic analogue 33c. Seventeen compounds strongly inhibited tubulin polymerization with activities higher than or comparable to those of the reference compounds such as colchicine. Concentration-dependent flow cytometric studies revealed that inhibition of K562 cell growth was associated with an arrest in the G2/M phases of the cell cycle, indicative of mitotic blockade. Structure-activity relationship studies showed that best potencies were obtained with agents bearing a methoxy group placed para at the terminal phenyl ring and a 3-cyano group in the phenoxazine. A series of analogues highlight not only the phenoxazine but also the phenothiazine structural scaffold as valuable pharmacophores for potent tubulin polymerization inhibitors, worthy of further investigation.
Asunto(s)
Antineoplásicos/síntesis química , Oxazinas/síntesis química , Fenotiazinas/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Biopolímeros , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Especificidad de Órganos , Oxazinas/química , Oxazinas/farmacología , Fenotiazinas/química , Fenotiazinas/farmacología , Relación Estructura-Actividad , Tubulina (Proteína)/química , Moduladores de Tubulina/síntesis química , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologíaRESUMEN
A novel series of 1,5- and 1,8-disubstituted 10-benzylidene-10H-anthracen-9-ones and 10-(2-oxo-2-phenylethylidene)-10H-anthracen-9-ones was synthesized to assess the substituent effects on biological activity. The 3-hydroxy-2,4-dimethoxy-benzylidene analogue 16 h displayed strong antiproliferative activity against several tumor cell lines, including multi-drug resistant phenotypes. Flow cytometric studies showed that KB/HeLa cells treated by elected compounds were arrested in the G2/M phases of the cell cycle. Among the compounds tested for inhibition of tubulin polymerization, 14 compounds proved to be exceptionally active with IC(50) values < 1 microM. In the 1,5-dichloro-derived series of benzylideneanthracenones, E/Z isomers were separated and biological effects were monitored. We found that the olefinic geometry had no significant effect on biological activity. Furthermore, the E isomeric 1,5-dichloro-substituted phenacylidenes entirely proved to be more potent inhibitors of tubulin polymerization than the recently described 10-(2-oxo-2-phenylethylidene)-10H-anthracen-9-ones. In conclusion, the present study improves understanding of the action of anthracenone-based tubulin polymerization inhibitors and contributes to the design of further potent anti-tubulin drugs.