RESUMEN
In comparison with pristine sinomenine and carborane precursors, the calculations of molecular docking with matrix metalloproteinases (MMPs) and methylcarboranyl-n-butyl sinomenine showed improved interactions. Accordingly, methylcarboranyl-n-butyl sinomenine shows a high potential in the treatment of rheumatoid arthritis (RA) in the presence of slow neutrons. The reaction of potassium salt of sinomenie, which is generated from the deprotonation of sinomenine (1) using potassium carbonate in a solvent of N,N-dimethyl formamide, with 4-methylcarboranyl-n-butyl iodide, (2) forms methylcarboranyl-n-butyl sinomenine (3) in 54.3% yield as a new product. This new compound was characterized by 1H, 13C, and 11B NMR spectroscopy, FT-IR spectroscopy, and elemental analyses to confirm its molecular composition. In addition to molecular docking interactions with MMPs, the in vitro killing effects of 3, along with its toxicity measurements, exhibited its potential to be the new drug delivery agent for boron neutron capture synovectomy (BNCS) and boron neutron capture therapy (BNCT) for the treatment of rheumatoid arthritis (RA) and cancers in the presence of slow neutrons, respectively.
Asunto(s)
Antineoplásicos/química , Antirreumáticos/química , Antirreumáticos/farmacología , Terapia por Captura de Neutrón de Boro/métodos , Morfinanos/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Antirreumáticos/síntesis química , Boro/farmacocinética , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Espectroscopía de Resonancia Magnética , Metaloproteinasa 1 de la Matriz/química , Metaloproteinasa 1 de la Matriz/metabolismo , Metaloproteinasa 13 de la Matriz/química , Metaloproteinasa 13 de la Matriz/metabolismo , Simulación del Acoplamiento Molecular , Ratas , Espectroscopía Infrarroja por Transformada de Fourier , Sinoviocitos/efectos de los fármacosRESUMEN
PURPOSE: We evaluated the potential of a newly developed (10)B-containing alpha-amino alcohol of p-boronophenylalanine-(10)B (BPA), p-boronophenylalaninol (BPAol), as a boron carrier in boron neutron capture therapy. METHODS: C57BL mice bearing EL4 tumors received 5-bromo-2'-deoxyuridine (BrdU) continuously via implanted mini-osmotic pumps to label all proliferating (P) cells. After oral administration of L-BPA or D-BPA, or intraperitoneal injection of L-BPAol or D-BPAol, the tumors were irradiated with reactor thermal neutron beams. Some of the tumors were heated at 40 degrees C for 30 min (mild temperature hyperthermia (MTH)) right before neutron exposure, and/or tirapazamine (TPZ) was intraperitoneally injected 30 min before irradiation. The tumors were then excised, minced, and trypsinized. The tumor cell suspensions thus obtained were incubated with cytochalasin-B (a cytokinesis blocker), and the micronucleus (MN) frequency in cells without BrdU labeling [ =quiescent (Q) cells] was determined using immunofluorescence staining for BrdU. Meanwhile, 6 h after irradiation, tumor cell suspensions obtained in the same manner were used for determining the apoptosis frequency in Q cells. The apoptosis and MN frequency in total (P+Q) tumor cells were determined from the tumors that were not pretreated with BrdU. RESULTS: Without TPZ or MTH, L- and D-BPAol increased both frequencies markedly, especially for total cells. Although not significantly larger, L-BPA and D-BPAol increased both frequencies slightly more than D-BPA and L-BPAol, respectively. Combination with both MTH and TPZ markedly reduced the sensitivity difference between total and Q cells. CONCLUSION: Both L- and D-BPAol have potential as a (10)B-carrier in neutron capture therapy, especially when combined with both MTH and TPZ.