Institute für Pharmazie, Freie Universität Berlin, Berlin, Germany.
Bioconjug Chem. 2010 Oct 20;21(10):1728-43. doi: 10.1021/bc900453f.
Bendamustine and melphalan are very promising alkylating drugs with applicability in the treatment of various tumoral diseases, e.g., chronic lymphocytic leukemia (CLL) or breast cancer. However, numerous adverse effects limited their use. Therefore, 1,3,5-tris(3-aminopropyl)benzene (G0) and its G1 analogue 3,5-bis(3-aminopropyl)-N-(3-{3,5-bis[3-{3,5-bis(3-aminopropyl)benzoylamino}propyl]phenyl}propyl)benzamide were selected to design cytostatic drug-dendrimer conjugates to achieve tumor cell accumulation by endocytosis as already demonstrated for platinum complexes. The dendrimers act as carriers and an N-(2-hydroxyethyl)maleimide spacer between drug and carrier should guarantee a selective release of the cytostatics in the tumor cells. The resulting cytotoxicity was determined in vitro using the human MCF-7 and MDA-MB-231 breast cancer cell lines. It was demonstrated that melphalan caused cytotoxic effects depending on its free amino group (Boc protection strongly decreased the activity) but independent of a derivation of the carboxylic group (dendrimers and spacer binding). Esterification of bendamustine with the N-(2-hydroxyethyl)maleimide spacer strongly increased the hydrolytic stability of the N-lost moiety, so antiproliferative effects were yet observed in vitro.
苯达莫司汀和马法兰是非常有前途的烷化剂药物，适用于治疗各种肿瘤疾病，例如慢性淋巴细胞白血病（CLL）或乳腺癌。然而，许多不良反应限制了它们的使用。因此，选择 1,3,5-三（3-氨丙基）苯（G0）及其 G1 类似物 3,5-双（3-氨丙基）-N-（3-{3,5-双[3-{3,5-双（3-氨丙基）苯甲酰氨基}丙基]苯基}丙基）苯甲酰胺来设计细胞抑制剂-树枝状大分子缀合物，通过内吞作用实现肿瘤细胞的积累，正如已经证明的铂复合物那样。树枝状大分子作为载体，药物和载体之间的 N-（2-羟乙基）马来酰亚胺间隔物应保证细胞抑制剂在肿瘤细胞中的选择性释放。使用人 MCF-7 和 MDA-MB-231 乳腺癌细胞系在体外测定所得的细胞毒性。结果表明，马法兰通过其游离氨基基团（Boc 保护强烈降低活性）而产生细胞毒性作用，但与羧酸基团的衍生无关（树枝状大分子和间隔物结合）。N-（2-羟乙基）马来酰亚胺间隔物与苯达莫司汀的酯化强烈增加了失去 N 的部分的水解稳定性，因此在体外仍观察到抗增殖作用。
