Cantrell J E, Green D, Schein P S
Cancer Res. 1986 May;46(5):2340-3.
In previous structure-activity studies, we have demonstrated that attachment of a glucose molecule to the chloroethylnitrosourea cytotoxic group produces a compound with reduced murine bone marrow toxicity and retention of full antitumor activity. To further define this protective role conferred by the glucose moiety in bone marrow cells, we have replaced the nitrosourea cytotoxic group with another class of alkylating agent, a bifunctional nitrogen mustard. In a detailed structure-activity analysis, we have now characterized four analogues, with the mustard cytotoxic group positioned at carbon 2 [1,3,4,6-tetra-O-acetyl-2-(di-2-chloroethyl)amino-2-deoxy-D-glucopyranos e (TGM)], carbon 6, or carbon 1 (D- and L-isomers) of the aminoglucose molecule. On a molar basis, TGM was most toxic to normal BALB/c X DBA/2 F1 mice, with a 10% lethal dose (LD10) of 3.8 mumol/kg. The D- and L-isomers of 2,3,4,6-tetra-O-acetyl-N,N-bis(2-chloroethyl)glucopyranosylamine (C-1) were the least toxic, with an LD10 of 73 mumol/kg for both. Optimal antitumor activity against the murine P388 leukemia (single i.p. administration of the LD10) did not differ significantly among the four analogues, with increased life span ranging from 83-86%. P388 antitumor activity for nitrogen mustard (HN2) was significantly less, 60% increased life span (P = 0.01), while p-di(2-chloroethyl)amino-L-phenylalanine produced an increased life span of greater than 101%. An LD10 of 6-bis-(2-chloroethyl) amino-6-deoxy-D-glucose (C-6) or TGM produced significantly less depression of WBC counts than did an equitoxic dose of the C-1 isomers, HN2, or p-di(2-chloroethyl)amino-L-phenylalanine. The mean nadir WBC count for C-6 equaled 86% of control, and for TGM, 80% of control. Consistent with this sparing effect on the peripheral WBC, C-6 and TGM produced significantly less in vivo murine bone marrow DNA synthesis depression, 77 and 64% of control, respectively, as compared to the depression nadir produced by HN2 (27% of control), the D-isomer of C-1 (17%), the L-isomer of C-1 (18%), and p-di(2-chloroethyl)amino-L-phenylalanine (2%). These structure-activity studies demonstrate that conjugation of the mustard cytotoxic group to carbon 6 or carbon 2 of glucose produces an analogue that retains P388 antitumor activity significantly greater than that of HN2, with a concomitant reduction in murine bone marrow toxicity.
在先前的构效关系研究中，我们已证明将一个葡萄糖分子连接到氯乙基亚硝基脲细胞毒性基团上会产生一种化合物，其对小鼠骨髓的毒性降低且保留了全部抗肿瘤活性。为进一步明确葡萄糖部分在骨髓细胞中赋予的这种保护作用，我们用另一类烷化剂——双功能氮芥取代了亚硝基脲细胞毒性基团。在详细的构效分析中，我们现已对四种类似物进行了表征，其中氮芥细胞毒性基团位于氨基葡萄糖分子的2位碳[1,3,4,6 - 四 - O - 乙酰基 - 2 - (二 - 2 - 氯乙基)氨基 - 2 - 脱氧 - D - 吡喃葡萄糖 (TGM)]、6位碳或1位碳（D - 和L - 异构体）上。按摩尔计算，TGM对正常BALB/c X DBA/2 F1小鼠毒性最大，其10%致死剂量（LD10）为3.8 μmol/kg。2,3,4,6 - 四 - O - 乙酰基 - N,N - 双(2 - 氯乙基)葡萄糖胺 (C - 1) 的D - 和L - 异构体毒性最小，两者的LD10均为73 μmol/kg。四种类似物对小鼠P388白血病的最佳抗肿瘤活性（单次腹腔注射LD10）无显著差异，寿命延长范围为83% - 86%。氮芥（HN2）对P388的抗肿瘤活性明显较低，寿命延长60%（P = 0.01），而对 - 二(2 - 氯乙基)氨基 - L - 苯丙氨酸使寿命延长超过101%。6 - 双(2 - 氯乙基)氨基 - 6 - 脱氧 - D - 葡萄糖（C - 6）或TGM的LD10所产生的白细胞计数降低程度明显低于等毒性剂量的C - 1异构体、HN2或对 - 二(2 - 氯乙基)氨基 - L - 苯丙氨酸。C - 6的平均最低白细胞计数等于对照组的86%，TGM为对照组的80%。与对外周白细胞的这种保护作用一致，与HN2（对照组的27%）、C - 1的D - 异构体（17%）、C - 1的L - 异构体（18%）和对 - 二(2 - 氯乙基)氨基 - L - 苯丙氨酸（2%）所产生的最低抑制相比，C - 6和TGM在体内对小鼠骨髓DNA合成的抑制明显较小，分别为对照组的77%和64%。这些构效关系研究表明，将氮芥细胞毒性基团与葡萄糖的6位碳或2位碳结合会产生一种类似物，其保留的P388抗肿瘤活性明显高于HN2，同时小鼠骨髓毒性降低。
