RESUMEN
In the present study, we newly synthesized four types of novel fullerene derivatives: pyridinium/ethyl ester-type derivatives 3b-3l, pyridinium/carboxylic acid-type derivatives 4a, 4e, 4f, pyridinium/amide-type derivative 5a, and pyridinium/2-morpholinone-type derivative 6a. Among the assessed compounds, cis-3c, cis-3d, trans-3e, trans-3h, cis-3l, cis-4e, cis-4f, trans-4f, and cis-5a were found to inhibit HIV-1 reverse transcriptase (HIV-RT), HIV-1 protease (HIV-PR), and HCV NS5B polymerase (HCV NS5B), with IC50 values observed in the micromolar range. Cellular uptake of pyridinium/ethyl ester-type derivatives was higher than that of corresponding pyridinium/carboxylic acid-type derivatives and pyridinium/amide-type derivatives. This result might indicate that pyridinium/ethyl ester-type derivatives are expected to be lead compounds for multitargeting drugs to treat HIV/HCV coinfection.
Asunto(s)
Fármacos Anti-VIH/farmacología , Fulerenos/farmacología , Inhibidores de la Proteasa del VIH/farmacología , Compuestos de Piridinio/farmacología , Inhibidores de la Transcriptasa Inversa/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/toxicidad , Línea Celular Tumoral , Fulerenos/química , Fulerenos/toxicidad , Proteasa del VIH/metabolismo , Inhibidores de la Proteasa del VIH/síntesis química , Inhibidores de la Proteasa del VIH/toxicidad , Transcriptasa Inversa del VIH/antagonistas & inhibidores , VIH-1/enzimología , Hepacivirus/enzimología , Humanos , Ratones , Estructura Molecular , Células 3T3 NIH , Compuestos de Piridinio/síntesis química , Compuestos de Piridinio/toxicidad , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/toxicidad , Relación Estructura-ActividadRESUMEN
In the present study, we newly synthesized three types of novel fullerene derivatives: pyridinium-type derivatives trans-3a and 4a-5b, piperidinium-type derivative 9, and proline-type derivatives 10a-12. Among the assessed compounds, 5a, 10e, 10f, 10i, 11a-d, and 12 were found to inhibit both HIV reverse transcriptase and HIV protease (HIV-PR), with IC50 values in the low micromolar range being observed. Regarding HIV-PR inhibition activity, proline-type derivatives 11a-11d and 12, bearing an alkyl chain between the hydroxylmethylcarbonyl (HMC) moiety and pyrrolidine ring, were more potent than other derivatives. This result might indicate that connecting HMC moieties with proline-type fullerene derivatives through properly sized alkyl chain leads to improved HIV-PR inhibitory activity.
Asunto(s)
Fulerenos/farmacología , Inhibidores de la Proteasa del VIH/farmacología , Proteasa del VIH/metabolismo , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Compuestos de Piridinio/farmacología , Inhibidores de la Transcriptasa Inversa/farmacología , Relación Dosis-Respuesta a Droga , Fulerenos/química , Inhibidores de la Proteasa del VIH/síntesis química , Inhibidores de la Proteasa del VIH/química , Transcriptasa Inversa del VIH/metabolismo , Estructura Molecular , Compuestos de Piridinio/química , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/química , Relación Estructura-ActividadRESUMEN
In the present study, we describe the synthesis of a novel set of pyridine/pyridinium-type fullerene derivatives. The products were assessed for human immunodeficiency virus-reverse transcriptase inhibition activities. All novel fullerene derivatives showed potent human immunodeficiency virus-reverse transcriptase inhibition without cytotoxicity.
Asunto(s)
Fármacos Anti-VIH/farmacología , Fulerenos/farmacología , Piridinas/farmacología , Compuestos de Piridinio/farmacología , Inhibidores de la Transcriptasa Inversa/farmacología , Fármacos Anti-VIH/síntesis química , Supervivencia Celular/efectos de los fármacos , Fulerenos/química , Transcriptasa Inversa del VIH , Células HL-60 , Humanos , Piridinas/síntesis química , Compuestos de Piridinio/síntesis química , Inhibidores de la Transcriptasa Inversa/síntesis químicaRESUMEN
Primary effusion lymphoma (PEL) is defined as a rare subtype of nonHodgkin's B cell lymphoma, which is caused by Kaposi's sarcomaassociated herpesvirus (KSHV) in immunosuppressed patients. PEL is an aggressive type of lymphoma and is frequently resistant to conventional chemotherapeutics. Therefore, the discovery of novel drug candidates for the treatment of PEL is of utmost importance. In order to discover potential novel antitumor compounds against PEL, the authors previously developed a pyrrolidiniumtype fullerene derivative, 1,1,1',1'tetramethyl [60]fullerenodipyrrolidinium diiodide (derivative #1), which induced the apoptosis of PEL cells via caspase9 activation. In the present study, the growth inhibitory effects of pyrrolidiniumtype (derivatives #1 and #2), pyridiniumtype (derivatives #3 and #5 to #9) and aniliniumtype fullerene derivatives (derivative #4) against PEL cells were evaluated. This analysis revealed a pyridiniumtype derivative (derivative #5; 3â5'(etho xycarbonyl)1',5'dihydro2'H[5,6]fullerenoC60Ih[1,9c]pyrrol2'yl]1methylpyridinium iodide), which exhibited antitumor activity against PEL cells via the downregulation of Wnt/ßcatenin signaling. Derivative #5 suppressed the viability of KSHVinfected PEL cells compared with KSHVuninfected Blymphoma cells. Furthermore, derivative #5 induced the destabilization of ßcatenin and suppressed ßcateninTCF4 transcriptional activity in PEL cells. It is known that the constitutive activation of Wnt/ßcatenin signaling is essential for the growth of KSHVinfected cells. The Wnt/ßcatenin activation in KSHVinfected cells is mediated by KSHV latencyassociated nuclear antigen (LANA). The data demonstrated that derivative #5 increased ßcatenin phosphorylation, which resulted in ßcatenin polyubiquitination and subsequent degradation. Thus, derivative #5 overcame LANAmediated ßcatenin stabilization. Furthermore, the administration of derivative #5 suppressed the development of PEL cells in the ascites of SCID mice with tumor xenografts derived from PEL cells. On the whole, these findings provide evidence that the pyridiniumtype fullerene derivative #5 exhibits antitumor activity against PEL cells in vitro and in vivo. Thus, derivative #5 may be utilized as a novel therapeutic agent for the treatment of PEL.
Asunto(s)
Antineoplásicos/farmacología , Fulerenos/farmacología , Herpesvirus Humano 8/efectos de los fármacos , Linfoma de Efusión Primaria/tratamiento farmacológico , Vía de Señalización Wnt/efectos de los fármacos , beta Catenina/efectos de los fármacos , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Regulación hacia Abajo , Humanos , Ratones , Compuestos de Piridinio/farmacologíaRESUMEN
PURPOSE: We have previously reported that some cationic fullerene derivatives exhibited anticancer activity, and they are expected to be a potential lead compound for an anti-drug resistant cancer agent. However, they are bis-adducts and a mixture of multiple regioisomers, which cannot be readily separated due to the variability of substituent positions on the fullerene cage. To overcome this issue, we evaluated the antiproliferative activities of a set of mono-adduct derivatives and examined their structure-activity relationship. In addition, the in vivo antitumor activity of selected derivatives was also examined. METHODS: Nineteen pyridinium fullerene derivatives were newly designed and synthesized in this study. Their antiproliferative activities were evaluated using several cancer cell lines including drug-resistant cells. Furthermore, in vivo antitumor activity of several derivatives was investigated in mouse xenograft model of human lung cancer. RESULTS: The derivatives inhibited the proliferation of cancer cell lines, including cisplatin-resistant cells and doxorubicin-resistant cells. It was also shown that compound 10 (10 µM), 13 (10 µM) and cis-14 (10 µM) induced the intracellular oxidative stress. In addition, compound 13 (20 mg/kg) and cis-14 (15 mg/kg) significantly exhibited antitumor activity in mouse xenograft model of human lung cancer. CONCLUSION: We synthesized a novel set of mono-adduct fullerene derivatives functionalized with pyridinium groups and found that most of them show potent antiproliferative activities against cancer cell lines and some of them show significant antitumor activities in vivo. We propose that these fullerene derivatives serve as the lead compounds for a novel type of antitumor agents.