ABSTRACT
Five boronated DNA-intercalating compounds [5-ortho-carboranyl phenanthridinium (5-o-CP), 5-para-carboranyl phenanthridinium (5-p-CP), 6-para-carboranyl phenanthridinium, water-soluble boronated phenanthridinium and water-soluble boronated acridine (WSA1)], primarily developed for boron neutron capture therapy (BNCT), were analysed regarding their binding in cultured human malignant glioma spheroids. Comparisons were made with the corresponding DNA intercalators ethidium bromide and acridine orange. Octanol/phosphate buffered saline-water coefficients were determined for all compounds, and it was found that the most lipophilic (5-o-CP and 5-p-CP) were most toxic and accumulated high amounts of boron in monolayer cells. These compounds bound primarily in the outermost part of spheroids with poor penetration into the inner region, even after 2 days of continuous exposure. On the other hand, the most hydrophilic compound (WSA1) showed lower toxicity and lower boron accumulation in monolayer cells, and rapid binding in the inner region of spheroids. A reasonable explanation for this observation is that the lipophilic compounds interact mainly with lipophilic parts of the cells, like cellular membranes, and therefore rapidly binds to cells, preventing penetration and binding to cells in the deeper region of the spheroids. The possibility of using these compounds for BNCT are discussed.
Subject(s)
Acridines/metabolism , Boron Compounds/metabolism , Glioma/metabolism , Intercalating Agents/metabolism , Phenanthridines/metabolism , Acridines/chemistry , Acridines/toxicity , Boron Compounds/chemistry , Boron Compounds/toxicity , DNA, Neoplasm/drug effects , DNA, Neoplasm/metabolism , Glioma/drug therapy , Glioma/pathology , Intercalating Agents/chemistry , Intercalating Agents/toxicity , Phenanthridines/chemistry , Phenanthridines/toxicity , Solubility , Spheroids, Cellular/drug effects , Spheroids, Cellular/metabolismSubject(s)
1-Naphthylamine/analogs & derivatives , Boron Compounds , Boron Neutron Capture Therapy/methods , DNA/metabolism , Imides/chemistry , Intercalating Agents/chemical synthesis , Isoquinolines/chemistry , Mesylates/chemistry , Models, Chemical , Naphthalimides , Solubility , Spermidine/chemistry , WaterABSTRACT
Boronated DNA targeting agents are especially attractive candidates for BNCT because they may deliver boron-10 to the nuclei of tumor cells. Numerous boron-containing analogs have been synthesized and some have shown promising results in initial biological tests. One of the most challenging tasks in this special field of research remains the finding of suitable targeting strategies for the selective delivery of boron rich DNA-intercalator/alkylator to tumor cells. Synthetic and biological studies of boron compounds suitable for DNA-binding are reviewed. The amino acid p-boronophenylalanine (BPA) is presently of considerable clinical interest. Other boronated amino acids might also be candidates for BNCT either per se, as part of part of tumor-seeking peptides or conjugated to targeting macromolecules. A large number of boronated L- and D-amino acids with varying liphophicility and sterical requirements are now available for evaluation. Recent synthetic and biological studies of aromatic boronoamino acids, carboranylamino acids and carboranyl amines are also reviewed.