Synthesis and Biological Evaluation of Boron-Containing Polyamines as Potential Agents for Neutron Capture Therapy of Brain Tumors

Abstract

New boron-containing spermidine/spermine (SPD/SPM) analogues have been synthesized: N5-[4-(2-aminoethyl-o-carboranyl)butyl] and N5-{4-[(2,3-dihydroxypropyl)-o-carboranyl]butyl} SPD/SPM derivatives (ASPD-5, ASPM-5, DHSPD-5, and DHSPM-5) as well as N5-{[4-(dihydroxyboryl)phenyl]methyl}spermidine (BBSPD-5). These boronated polyamines retain their ability to displace ethidium bromide from calf thymus DNA and are rapidly taken up in vitro by F98 rat glioma cells. The in vitro toxicities of ASPD-5, ASPM-5, DHSPD-5, and DHSPM-5 are lower than those previously reported for N5-[4-(o-carboranyl)butyl] SPD/SPM derivatives (SPD-5 and SPM-5) but similar to those of native SPD and SPM. Very low toxicity was also observed for BBSPD-5. In vivo studies of ASPD-5 and BBSPD-5 were performed in mice bearing intracerebral implants of the GL261 glioma and subcutaneous implants of the B16 melanoma. The biodistribution data found in both tumor models suggest that the polyamines synthesized to date do not appear to be suitable boron agents for BNCT.

Boron-Containing Nucleosides as Potential Delivery Agents for Neutron Capture Therapy of Brain Tumors

“…In general, the moderate toxicity of all of the nucleosides that were evaluated appears to have been related to their lipophilicity rather than to nucleoside metabolism. In previous studies involving carboranyl polyamines, carborane-dependent lipophilicity has been identified by us as the source of substantial in vitro and in vivo toxicity (59,60). The cause of this toxicity is still unknown, but it could be reduced partially by the attachment of additional hydrophilic groups to the polyamines.…”

Boron Neutron Capture Therapy

“…Some examples are derivatives of aziridines, acridines, phenanthridines (compound 6), trimethoxyindoles, carboranylpolyamines, Pt(II)-amine complexes, di-and tribenzimidazoles (66)(67)(68)(69). A limitation of boron-containing polyamines is their frequently observed in vitro and in vivo toxicity, although promising derivatives with low cytotoxicity have been synthesized (70)(71)(72)(73). Other nuclear-targeting molecules are nido-carboranyl oligomeric phosphate diesters (OPDs).…”

Crystallographic report: Synthesis and biological evaluation of novel azanonaboranes as potential agents for boron neutron capture therapy

“…9,10 Recently o-carborane cages attached to polyamines have been made. 11 In vitro, these compounds bind to DNA and accumulate in tumor cells similarly to borocaptate (BSH) and p-borophenylalanine (BPA), which are in clinical trials. However, the cytotoxicity of carboranes prohibits their use.…”

“…14 It was observed that the toxicity strongly depended upon the number of carbon atoms in the diamine chain. To reduce this toxicity, the hydrophilic properties of the compounds were increased by exchanging the exo-amino ligand with 3-amino-1-propanol and 4-amino-1-butanol to give the desired target compounds (hydroxyalkylamine)-N-(aminoalkyl)azanonaborane (11) derivatives. The study of their structure-activity relationship with respect to their in vitro toxicities was investigated using V79 cells.…”

“…Both amino and hydroxy groups increase the water solubility and stability of these compounds in comparison to azanonaborane containing only free amino groups. The stability of the water-soluble compounds at room temperature was investigated by 11 B-NMR measurements. At different periods of time, the ratio of the compound to boric acid was determined.…”