Anderson W K, Chang C P, McPherson H L
J Med Chem. 1983 Sep;26(9):1333-8. doi: 10.1021/jm00363a023.
2-Hydroxy-5-(3,4-dichlorophenyl)-6,7-bis(hydroxymethyl)-2,3-dihydro-1H- pyrrolizine bis(2-propylcarbamate) (11) was prepared in a multistep synthesis. The 2-hydroxy group was used to prepare ester prodrugs 14 and 15, and the antineoplastic activities of 11, 14, and 15a were compared to 1 (the 2-deoxy analogue of 11) in murine P388 lymphocytic leukemia and B16 melanocarcinoma. The alcohol 11 showed comparable activity to 1, while 14 was less active and 15a showed very low activity. The hydrolytic rates of 1, 11, 14, 15a, and 15b were compared, and it was found that the two carbamate moieties were much more susceptible toward hydrolysis than the C-2 esters. The salts 15a and 15b exhibited good water solubility, 3.0 X 10(-2) and 3.88 X 10(-2) M, respectively.
2-羟基-5-(3,4-二氯苯基)-6,7-双(羟甲基)-2,3-二氢-1H-吡咯嗪双(2-丙基氨基甲酸酯)(11)通过多步合成制备。利用2-羟基制备酯前药14和15，并在小鼠P388淋巴细胞白血病和B16黑色素瘤中比较了11、14和15a与1(11的2-脱氧类似物)的抗肿瘤活性。醇11显示出与1相当的活性，而14活性较低，15a显示出非常低的活性。比较了1、11、14、15a和15b的水解速率，发现两个氨基甲酸酯部分比C-2酯更容易水解。盐15a和15b表现出良好的水溶性，分别为3.0×10(-2)和3.88×10(-2)M。
