RESUMEN
Boron-neutron capture therapy (BNCT) is a binary anticancer therapy that requires boron compound for nuclear reaction during which high energy alpha particles and lithium nuclei are formed. Unnatural, boron-containing nucleoside with hydrophobic pinacol moiety was investigated as a potential BNCT boron delivery agent. Biological properties of this compound are presented for the first time and prove that boron nucleoside has low cytotoxicity and that observed apoptotic effects suggest alteration of important functions of cancer cells. Mass spectrometry analysis of DNA from cancer cells proved that boron nucleoside is inserted into nucleic acids as a functional nucleotide derivative. NMR studies present very high degree of similarity of natural dG-dC base pair with dG-boron nucleoside system.
Asunto(s)
Antineoplásicos/química , Boro/química , Desoxicitidina/química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Terapia por Captura de Neutrón de Boro , Línea Celular , Daño del ADN/efectos de los fármacos , ADN de Neoplasias/análisis , ADN de Neoplasias/aislamiento & purificación , Células Hep G2 , Humanos , Espectroscopía de Resonancia Magnética , Espectrometría de Masa por Láser de Matriz Asistida de Ionización DesorciónRESUMEN
By seeking new stable boron-containing nucleoside derivatives, potential BNCT boron delivery agents, a novel synthetic approach was tested, aimed at a boron attachment via a single bond to an aliphatic carbon of sp(3) hybridization. The latter allowed successful modification of deoxycytidine in the reaction with 2-(iodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane of the deoxynucleoside amino group. For new compounds, detailed NMR, LDI HRMS (Laser Desorption/Ionization High-Resolution Mass Spectrometry) analyses along with in vivo phosphorylation studies, toxicity assays and DFT modelling are presented.