肿瘤的化学治疗——ⅩⅩⅨ.与双(β-氯乙基)氨甲基苯丙氨酸有关化合物的研究 (二)2-双(β-氯乙基)氨甲基-5-硝基-苯丙氨酸的合成

在邻双(β-氯乙基)氨甲基苯丙氨酸(I,AT-581)苯环的5-位上引进一个硝基,合成了化合物IV.作者希望能通过硝基的拉电子作用降低氮芥基上氯原子的活泼性,从而减低AT-581的毒性并增加其抗癌活性.在同样的设想下,作者又在邻甲基苄基氮芥(V)苯环的4-位上引入一个硝基,合成了化合物VI.组织培养结果表明化合物IV和VI对HeLa细胞具有抑制作用.

TUMOUR CHEMOTHERAPY ⅩⅩⅨ. STUDIES ON BIS (β-CHLOROETHYL)AMINOMETHYL-PHENYLALANINE 2. SYNTHESIS OF 2-BIS (β-CHLOROETHYL)-AMINOMETHYL- 5-NITRO-PHENYLALANINE

o-Bis (β-chloroethyl)-aminomethyl-phenylalanine dihydrochloride (I, AT-581) was re- ported to possess significant antitumour activities. Furthermore, in view of the fact that compounds carrying a nitro group in the benzene ring show invariably higher antitumour activity as compared with the corresponding unsubstituted ones and that the electro- negative groups such as nitro can deactivate the chlorine atoms of the mustard grouping, thus decrease its toxicity, the authors synthesized 2-bis-(β-chloroethyl)-aminomethyl-5- nitro-phenylalanine(IV) in which a nitro group was introduced into the benzene ring of AT-581. Besides, 2-bis(β-chloroethyl)-aminomethyl-4-nitrotoluene(IV) was also synthe- sized. 2-Methyl-5-nitrobenzyl chloride (VII) was condensed with diethyl formamido-malo- nate to give diethyl 2-methyl-5-nitrobenzyl formamido-malonate (VIII), and the latter was readily converted to diethyl 2-bromomethyl-5-nitrobenzyl formamido-malonate(X) by N-bromosuccinimide in the presence of a small amount of dibenzoyl peroxide in anhydrous carbon tetrachloride. Treatment of X with diethanolamine afforded diethyl 2-bis(β- hydroxyethyl)-aminomethyl-5-nitrobenzyl formamido-malonate(XI), which was then chlorinated with thionyl chloride in dichloromethane to give the chloride (XII),and the desired product (IV) was obtained by the hydrolysis of XII with concentrated hydro- chloric acid. When compound VII was first treated with diethanolamine and then with thionyl chloride, compound VI was obtained.