In an attempt to improve the antitumor activity and reduce the side effects of irinotecan (2), novel prodrugs of SN-38 (3) were prepared by conjugating amino acids or dipeptides to the 10-hydroxyl group of SN-38 via a carbamate linkage. The synthesized compounds completely generated SN-38 in pH 7.4 buffer or in human plasma, while remaining stable under acidic conditions. All prodrug compounds demonstrated much greater in vitro antitumor activities against HeLa cells and SGC-7901 cells than irinotecan. The most active compounds, 5h, 7c, 7d, and 7f, exhibited IC50 values that were 1000 times lower against HeLa cells and 30 times lower against SGC-7901 cells than those of irinotecan, and the inhibitory activities of these prodrugs against acetylcholinesterase (AchE) were significantly reduced, with IC50 values more than 6.8 times greater than that of irinotecan. In addition, compound 5e exhibited the same level of tumor growth inhibitory activity as irinotecan (CPT-11) in a human colon xenograft model in vivo.
为了提高
伊立替康(irinotecan, 2)的抗肿瘤活性并减少其副作用,研究人员通过
羧酸酯链接将
氨基酸或二肽与SN-38(3)的10-羟基结合,制备了新型的SN-38前药。这些合成的化合物在pH 7.4的缓冲液或人血浆中能够完全生成SN-38,同时在酸性条件下保持稳定。所有前药化合物在体外对HeLa细胞和SGC-7901细胞的抗肿瘤活性都明显高于
伊立替康。最活跃的化合物5h、7c、7d和7f,在HeLa细胞中的IC50值比
伊立替康低1000倍,而在SGC-7901细胞中的IC50值低30倍,同时这些前药对
乙酰胆碱酯酶(AchE)的抑制活性显著降低,IC50值比
伊立替康高出6.8倍。此外,化合物5e在体内的人类结肠异种移植模型中表现出与
伊立替康(C
PT-11相同的肿瘤生长抑制活性。