RESUMEN
A series of N-mustards, which was conjugated to mono- or bis-naphthalimides with a flexible amine link, were synthesized and evaluated for cytotoxicity against five cancer cell lines (HCT-116, PC-3, U87 MG, Hep G2 and SK-OV-3). Several compounds displayed better activities than the control compound amonafide. Further evaluations by fluorescence spectroscopy studies and DNA-interstrand cross-linking assays revealed that the derivatives showed both alkylating and intercalating properties. Among the derivatives, the bis-naphthalimide N-mustard derivative 11b was found to exhibit the highest cytotoxic activity and DNA cross-linking ability. Both 11b and 7b induce HCT-116 cell apoptosis by S phase arrest.
Asunto(s)
Antineoplásicos Alquilantes/síntesis química , Naftalimidas/síntesis química , Mostazas de Fosforamida/síntesis química , Antineoplásicos Alquilantes/farmacología , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Células HCT116 , Células Hep G2 , Humanos , Concentración 50 Inhibidora , Naftalimidas/farmacología , Mostazas de Fosforamida/farmacología , Poli(ADP-Ribosa) Polimerasa-1 , Poli(ADP-Ribosa) Polimerasas/metabolismoRESUMEN
We have developed a new KI-catalyzed method for the imidation of an sp(3) C-H bond adjacent to an amide nitrogen atom by using TBHP (tert-butyl hydroperoxide, 70% aqueous solution) as the oxidant. This novel procedure tolerated air and moisture and provided a series of novel products in moderate to excellent yields under mild conditions.
Asunto(s)
Amidas/química , Imidas/síntesis química , Yoduro de Potasio/química , Catálisis , Imidas/química , Estructura Molecular , EstereoisomerismoRESUMEN
Pirfenidone, a pyridone compound, is an effective and novel antifibrotic agent. In this article, we describe the design, synthesis and activity evaluation of novel antifibrotic agents, 1-(substituted aryl)-5-trifluoromethyl-2(1H) pyridones modified with carbohydrate. Most of the title compounds exhibited comparable or better inhibitory activity than fluorofenidone. Notably, compound 19a demonstrated the highest cell-based inhibitory activity against NIH 3T3 (IC(50) = 0.17 mM).
Asunto(s)
Proliferación Celular/efectos de los fármacos , Monosacáridos/química , Piridonas/síntesis química , Piridonas/farmacología , Animales , Diseño de Fármacos , Fibrosis/tratamiento farmacológico , Interacciones Hidrofóbicas e Hidrofílicas , Concentración 50 Inhibidora , Ratones , Células 3T3 NIH , Piridonas/química , SolubilidadRESUMEN
An unusual reductive ring-opening reaction in the title compounds, of the phthalimide group with sodium hydride in anhydrous DMF is observed for the first time and the presumed mechanism is described in detail. An unexpected hydrogenation of the phthalimide group was also observed.
Asunto(s)
Ftalimidas/química , Anhídridos/química , Secuencia de Carbohidratos , Dimetilformamida/química , Hidrogenación , Oxidación-Reducción , Sodio/químicaRESUMEN
A disulfated tetrasaccharide fragment with a spacer arm of human hepatocellular carcinoma carbohydrate antigen SB(1a), namely, 2-aminoethyl 3-O-sulfo-beta-D-galactopyranosyl-(1 --> 3)-2-acetamido-2-deoxy-beta-D-galactopyranosyl-(1 --> 4)-3-O-sulfo-beta-D-galactopyranosyl-(1 --> 4)-beta-D-glucopyranoside was synthesized via a [2 + 1 + 1] block building mode. In the last coupling step toward the trisaccharide acceptor 8, benzoyl protected galactosyl bromide donor 14 was found to be much more reactive than the acetyl-protected donors.
Asunto(s)
Antígenos de Neoplasias/química , Carcinoma Hepatocelular/inmunología , Oligosacáridos/síntesis química , Conformación de Carbohidratos , Haptenos/química , Humanos , Espectroscopía de Resonancia Magnética , Oligosacáridos/inmunología , SulfatosRESUMEN
Novel compounds, which can be considered as conformationally restricted analogues of MKC-442, have been synthesized and tested as inhibitors of the reverse transcriptase of human immunodeficiency virus type-1 (HIV-1). Reaction of urea with a beta-ketoester furnished 6,7,8,9-tetrahydro-9-phenyl-1H-cyclohepta[d]pyrimidine-2,4-(3H,5H)-dione (6a) and 6,7,8,9-tetrahydro-9-p-tolyl-1H-cyclohepta[d]pyrimidine-2,4-(3H,5H)-dione (6b) which were then alkylated at the N-1 position with chloromethyl ether, allyl bromide and benzyl bromide to afford the target compounds 7a-b, 8a-b, 9 and 10, respectively. The seven-membered, annelated compounds have a relatively rigid structures and can lock the orientation of the aromatic ring. Chemical modification at N-1 of the pyrinidine ring and the 9-phenyl ring was attempted, with the aim of improving the antiretroviral activity. In particular, replacement of the aliphatic group with the phenyl moiety at the terminus of N-1 side chain can enhance the activity. The most active compounds showed activity in the low micromolar range with IC50 values comparable to that of nevirapine. The biological activity results are in accordance with the docking results.