著作: [堀 均]/[永澤 秀子]/[宇都 義浩]/平岡 正光/後藤 恵子/中嶌 瞳/[後藤 了]/Masunaga Shin-ichiro/Design, synthesis, and pharmacokinetics of hypoxic tumor-targeting boron carriers/第12回国際ホウ素化学会議
(英) Design, synthesis, and pharmacokinetics of hypoxic tumor-targeting boron carriers
(英) Purpose: The presence of hypoxic tumor cells is also associated with resistance to boron neutron capture therapy (BNCT). To accomplish the effective boron carrier for BNCT, we have recently developed 2-nitroimidazole-sodium borocaptate-10B (BSH) conjugates, TX-2016, 2017, 2018, 2041, 2042, and 2060, that is, hybrids that have both hypoxic tumor cell g-ray-sensitizing unit, 2-nitroimidazoles, and thermal neutron-sensitizing unit, BSH . Furthermore, In this communication, to improve the hypoxia-targating character, we report the design, synthesis, and pharmacokinetics of hypoxic cytotoxin-hybrid boron carriers, TX-2091, 2095, 2097, 2100, 2124 and 2125, having hypoxic cytotoxin moiety, such as 2-quinoxalinecarbonitrile-1,4-di-N-oxide (TX-402) and tirapazamine (TPZ), and BSH via some carbon chain linker as a pharmacokinetic controlling unit. Result: TX-2016, 2017, and 2018: tertamethylammonium salts of alkyl sulfides of BSH. TX-2041, 2042 and 2060: sodium salts of an alkyl sulfide or a dialkyl sulfonium derivatives of BSH. They were synthesized from their corresponding haloacetylcarbamoyl-2-nitroimidazoles and BSH. To synthesize hypoxic cytotoxin conjugate, 3-clorinated hypoxic cytotoxin (TX-402 or TPZ) was condensed with ethyl-, propyl-, or hexyl-alcoholamine to obtain the corresponding hydroxyalkylamino derivatives. They were treated with bromoacetyl isocyanate followed by disodium (2-cyanoethyl)-thio-undecahydro-closo-dodecaborate(2-) to yield cyanoethyl sulfonium compounds, TX-2095, 2100, 2110, 2124, and 2125. Among the 2-nitroimidazole conjugates, TX-2041 has the most favorable pharmacokinetic characteristics with higher tumor affinity of 10B during neutron beam irradiation. In addition, TX-2041 showed a significantly higher radiosensitizating effect with reactor thermal neutron beams than that of BSH. Cyanoethyl sulufonium derivative, TX-2060 showed better tumor affinity of 10B and more cytotoxicity after irradiation with reactor thermal neutron beams than that of TX-2041. Furthermore, TX-2100 achieved significantly higher tumor affinity than 2-nitoroimidazoles, TX-2041 and 2060, and also showed cytotoxicity comparable to TX-2060. In conclusion, these hypoxic tumor trageting cytotoxin-hybrid 10B-carriers , such as TX-2100, with the potential tumor affinty of10B, are expected to have clinical applications as promising boron carriers for use in BNCT.
(英) IMEBORON12 / (日) 第12回国際ホウ素化学会議
|年月日||必須||2005年 9月 15日|