Twenty novel aminophosphonates derivatives (5a-5j and 6a-6j) conjugated irinotecan were synthesized through esterification reaction, and evaluated their anticancer activities using MTT assay. In vitro evaluation revealed that they displayed similar or superior cytotoxicity compared to the positive drug irinotecan against A549, MCF-7, SK-OV-3, MG-63, U2OS and multidrug-resistant (MDR) SK-OV-3/CDDP cancer cell lines. Among them, 9b displayed the most potent activity, with IC50 values of 0.92-3.23 μM against five human cancer cells, which exhibited a 5.4-19.1-fold increase in activity compared to the reference drug irinotecan, respectively. Moreover, cellular mechanism studies suggested that 9b arrested cell cycle at S stage and induced cell apoptosis along with the decrease of mitochondrial membrane potential (MMP). Interestingly, 9b significantly inhibited tumor growth in SK-OV-3 xenograft models in vivo without apparent toxicity, which was better than the positive drug irinotecan. Taken together, 9b possessed potent antitumor activity and may be a promising candidate for the potential treatment of human ovarian cancer cells.

中文翻译：

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作为有效的抗肿瘤剂，在体外和体内，结合了伊立替康的新型氨基膦酸酯衍生物的合成，作用机理和毒性。

通过酯化反应合成了二十种新颖的氨基膦酸酯衍生物（5a-5j和6a-6j）共轭伊立替康，并使用MTT法评估了其抗癌活性。体外评估显示，与阳性药物伊立替康相比，它们对A549，MCF-7，SK-OV-3，MG-63，U2OS和多药耐药（MDR）SK-OV-3 / CDDP癌症表现出相似或更高的细胞毒性细胞系。其中，9b表现出最强的活性，对五个人类癌细胞的IC50值为0.92-3.23μM，与参考药物伊立替康相比，其活性分别提高了5.4-19.1倍。此外，细胞机制研究表明9b阻止了S期的细胞周期，并诱导了细胞凋亡以及线粒体膜电位（MMP）的降低。有趣的是 9b在体内显着抑制SK-OV-3异种移植模型中的肿瘤生长，而没有明显的毒性，这比阳性药物伊立替康更好。两者合计，9b具有有效的抗肿瘤活性，并且可能是潜在治疗人类卵巢癌细胞的候选物。