Marchini S, Cozzi P, Beria I, Geroni C, Capolongo L, D'Incalci M, Broggini M
Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Anticancer Drug Des. 1998 Apr;13(3):193-205.
Three different groups of analogs of the sequence-specific minor groove alkylator tallimustine (2) have been synthesized and investigated. Within group I, the dibromo nitrogen mustard (3) and the half-mustard (4) are more cytotoxic (IC50 = 0.6 and 40 ng/ml respectively) than tallimustine (IC50 = 50.3 ng/ml) against L1210 cells with high reactivity against the region 5'-TTTTGA. The diol derivative (6) and the difluoro nitrogen mustard (5) were not cytotoxic against L1210 cells and did not show any detectable DNA alkylation. The two compounds modified in the propionamidine terminus (7 and 8, group II), showed lower cytotoxic potency (IC50 = 130 and 94 ng/ml respectively) against L1210 cells than tallimustine (IC50 = 50.3 ng/ml) and a loss of in vitro sequence specificity for DNA alkylation. Considering the compounds in which the pyrrole rings were replaced by one (9) or two (10) pyrazole rings, compound 9 was not significantly cytotoxic against L1210 cell line and was apparently unable to produce alkylation on the DNA fragments tested, while compound 10 showed decreased cytotoxicity (IC50 = 114 ng/ml) and no modification in the pattern and intensity of DNA alkylation. The data obtained in this work suggest that it is possible to increase tallimustine potency by modifying the nitrogen mustard moiety. Moreover, the sequence specificity of DNA alkylation appears to be affected by the modification of the propionamidino moiety but not by the isosteric modification of the pyrrole rings. The correlation between cytotoxicity and alkylation pattern suggests that tallimustine exerts its cytotoxicity through DNA sequence-specific alkylation of the adenine located in the sequence 5'-TTTTGA.
已合成并研究了序列特异性小沟烷化剂他利莫司汀（2）的三组不同类似物。在第一组中，二溴氮芥（3）和半氮芥（4）对L1210细胞的细胞毒性更强（IC50分别为0.6和40 ng/ml），高于他利莫司汀（IC50 = 50.3 ng/ml），且对5'-TTTTGA区域具有高反应性。二醇衍生物（6）和二氟氮芥（5）对L1210细胞无细胞毒性，且未显示任何可检测到的DNA烷基化。在丙脒末端修饰的两种化合物（7和8，第二组）对L1210细胞的细胞毒性效力低于他利莫司汀（IC50分别为130和94 ng/ml，他利莫司汀IC50 = 50.3 ng/ml），且体外DNA烷基化序列特异性丧失。考虑用一个（9）或两个（10）吡唑环取代吡咯环的化合物，化合物9对L1210细胞系无明显细胞毒性，且显然无法在所测试的DNA片段上产生烷基化，而化合物10显示细胞毒性降低（IC50 = 114 ng/ml），且DNA烷基化模式和强度无变化。这项工作获得的数据表明，通过修饰氮芥部分有可能提高他利莫司汀的效力。此外，DNA烷基化的序列特异性似乎受丙脒基部分修饰的影响，但不受吡咯环电子等排体修饰的影响。细胞毒性与烷基化模式之间的相关性表明，他利莫司汀通过对位于5'-TTTTGA序列中的腺嘌呤进行DNA序列特异性烷基化发挥其细胞毒性。
