Promising carboranylquinazolines for boron neutron capture therapy: Synthesis, characterization, and in vitro toxicity evaluation

Abstract

Novel classes of structurally different boronated quinazolines were designed bearing 22–37% boron by weight for potential application in BNCT of tumors. Firstly, the o-carborane cage was linked to quinazoline at C-2 position via thioether linker: 2- S-(1,2-dicarba- closo-dodecaboran(12)-1-ylmethyl)-3-phenylquinazolin-4(3 H)-one. Secondly, the o-carborane cage connected to quinazoline moiety at C-4 position through an ether linkage: 4- O-( o-carboran-1-ylmethyl)-2-methylquinazoline. Finally, carborane moieties were also linked to the C-6 position of quinazoline: 6-[ N-{3-(2-methyl-1,2-dicarba- closo-dodecaboran(12)-1-yl)methyl}benzylidinamino]quinazolin-4(3 H)-one and 6-[ N-{3,5-di(2-methyl-1,2-dicarba- closo-dodecaboran(12)-1-yl)methyl}benzylidinamino]quinazolin-4(3 H)-one. The water solubility was achieved by the degradative conversion of the o-carboranylquinazolines to the corresponding potassium nido-carboranyl quinazolines: 2- S-(1,2-dicarba- nido-undecacarborate-1-ylmethyl)-3-phenylquinazolin-4(3 H)-one, 4- O-(1,2-dicarba- nido-undecacarborate-1-ylmethyl)-2-methylquinazoline, 6-[ N-{3-(2-methyl-1,2-dicarba- nido-undecacarborate-1-yl)methyl}benzylidinamino]quinazolin-4(3 H)-one and 6-[ N-{3,5-di(2-methyl-1,2-dicarba- nido-undecacarborate-1-yl)methyl}benzylidinamino]quinazolin-4(3 H)-one. The products were confirmed by NMR, elemental analysis, IR, and mass spectrometry. In vitro toxicity was performed with B16 melanoma cells and showed that the connection of hydrophilic nido-carborane to quinazoline moiety decreases the compound's toxicity. This cytotoxicity effect was not observed in the nido-carborane containing two cluster units which was relatively nontoxic and did not inhibit colony formation up to concentrations of 300 μg boron ml −1. The compounds described here can be considered as new candidates for BNCT.