RESUMEN
We report herein an unusual one-pot preparation of α-benzyl-substituted conjugated enals via ZnCl2/LiCl/H2O-mediated transformation of styrenes. On the basis of experimental and computational studies, an underlying mechanism including electrophilic addition and hydride transfer with iminium cations has been proposed. The effect of the LiCl/ZnCl2/H2O combination on the reaction yield has been studied, demonstrating their participation in the activation and the key isomerization of an iminium electrophile.
Asunto(s)
Ácidos de Lewis , Estirenos , Cloruro de LitioRESUMEN
Photodynamic therapy (PDT) is a treatment modality where light-mediated activation of photosensitizers in a patient's body leads to the generation of cytotoxic reactive oxygen species (ROS), eliminating cancer cells. One direction that has been firmly established over past years is the conjugation of photosensitizers with various molecules that demonstrate their own cytotoxic activity. As a result, improved selectivity and treatment outcomes are observed compared to those of unconjugated drugs. The attractiveness of such an approach is due to the variability of cytotoxic warheads and specific linkers available for the construction of conjugates. In this review, we summarize and analyze data concerning these inventions with the ultimate goal to find a promising conjugation partner for a porphyrinoid-based photosensitizer. The current challenges toward successful conjugation are also outlined and discussed. We hope that this review will motivate researchers to pay closer attention to conjugates and possibilities hidden in these molecules for the PDT of cancer.
Asunto(s)
Antineoplásicos/uso terapéutico , Metaloporfirinas/uso terapéutico , Neoplasias/tratamiento farmacológico , Fármacos Fotosensibilizantes/uso terapéutico , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/efectos de la radiación , Línea Celular Tumoral , Humanos , Luz , Metaloporfirinas/química , Metaloporfirinas/farmacología , Metaloporfirinas/efectos de la radiación , Fotoquimioterapia , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/efectos de la radiación , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Two series of heterocyclic colchicinoids bearing ß-methylenedihydrofuran or 2H-pyran-2-one fragments were synthesized by the intramolecular Heck reaction. Methylenedihydrofuran compounds 9a and 9h were found to be the most cytotoxic among currently known colchicinoids, exhibiting outstanding antiproliferative activity on tumor cell lines in picomolar (0.01-2.1 nM) range of concentrations. Compound 9a potently and substoichiometrically inhibits microtubule formation in vitro, being an order of magnitude more active in this assay than colchicine. Derivatives 9a and 9h revealed relatively low acute toxicity in mice (LD50 ≥ 10 mg/kg i.v.). The X-Ray structure of colchicinoid 9a bound to tubulin confirmed interaction of this compound with the colchicine binding site of tubulin.
Asunto(s)
Antimitóticos/química , Antimitóticos/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Colchicina/análogos & derivados , Colchicina/farmacología , Animales , Antimitóticos/toxicidad , Antineoplásicos/toxicidad , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Colchicina/toxicidad , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales , Furanos/química , Furanos/farmacología , Furanos/toxicidad , Humanos , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacología , Moduladores de Tubulina/toxicidadRESUMEN
A new water-soluble conjugate, consisting of a chlorin-e6 photosensitizer part, a 4-arylaminoquinazoline moiety with affinity to epidermal growth factor receptors, and a hydrophilic ß-d-maltose fragment, was synthesized starting from methylpheophorbide-a in seven steps. The prepared conjugate exhibited low levels of dark cytotoxicity and pronounced photoinduced cytotoxicity at submicromolar concentrations in vitro, with an IC50(dark)/IC50(light) ratio of â¼368 and a singlet oxygen quantum yield of about 20%. In tumor-bearing Balb/c nude mice, conjugate 1 preferentially accumulates in the tumor tissue. Irradiation of the nude mice bearing A431 xenograft tumors after intravenous administration of the prepared conjugate with a relatively low light dose (50 J/cm2) produced an excellent therapeutic effect with profound tumor regression and low systemic toxicity.
Asunto(s)
Carcinoma de Células Escamosas/tratamiento farmacológico , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacología , Porfirinas/química , Quinazolinas/química , Animales , Apoptosis , Carcinoma de Células Escamosas/metabolismo , Proliferación Celular , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacocinética , Solubilidad , Distribución Tisular , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A new water-soluble conjugate, consisting of a chlorin-based photosensitizing part, and a 4-arylaminoquinazoline moiety with high potential affinity to an epidermal growth factor receptors (EGFR) and vascular endothelial growth factor receptors (VEGFR), suitable for photodynamic therapy (PDT), was synthesized starting from methylpheophorbide-a in seven steps. An increased accumulation of this compound in A431â¯cells with high level of EGFR expression, in comparison with CHO and HeLa cells with low EGFR expression was observed. The prepared conjugate exhibits dark and photoinduced cytotoxicity at micromolar concentrations with IC50dark/IC50light ratio of 11-18. In tumor-bearing mice, the conjugate preferentially accumulates in the tumor tissue.
Asunto(s)
Sistemas de Liberación de Medicamentos , Fármacos Fotosensibilizantes/farmacología , Porfirinas/farmacología , Quinazolinas/farmacología , Animales , Células CHO , Línea Celular Tumoral , Cricetulus , Relación Dosis-Respuesta a Droga , Células HeLa , Humanos , Ratones , Ratones Endogámicos BALB C , Estructura Molecular , Fotoquimioterapia , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/química , Porfirinas/química , Quinazolinas/química , Solubilidad , Relación Estructura-Actividad , Factor A de Crecimiento Endotelial Vascular/biosíntesis , Agua/químicaRESUMEN
A series of novel antimitotic hybrids were synthesized in good yields by linking of azide-containing colchicine congeners with acetylene-substituted tubulizine-type derivatives using copper-mediated 1,3-dipolar cycloaddition. Obtained compounds exhibit good cytotoxicity against HBL100 epithelial cell lines (IC(50)=0.599-2.93 µÐ). Several newly synthesized compounds are the substoichiometric inhibitors of microtubule assembly (R=0.41-0.78). The results highlight the importance of the length of spacer linking the tubulin binding ligands in heterodimeric molecules.