We describe herein the synthesis of a series of carboplatin derivatives with different functional groups at position 3 of the cyclobutane ring. This pharmacomodulation approach aims at facilitating the vectorisation of these analogues, via their subsequent conjugation to a drug delivery system. Five different derivatives bearing a hydroxy, keto, iodo, azido or amino function at position 3 were synthesised. One of these compounds was coupled to a bifunctional maleimide-containing linker. All compounds were tested in vitro for their cytotoxicity on four different cell lines including two platinum-resistant colorectal cancer cell line (SK-OV-3, HCT116, D3E2, D5B7) using an MTS assay. Overall, the tested compounds were up to six times more potent than carboplatin, especially on D5B7 human colorectal cancer cells. We demonstrated that these modifications led to potent analogues which are compatible with conjugation to a drug delivery system.

我们在本文中描述了在环丁烷环的3位具有不同官能团的一系列卡铂衍生物的合成。这种药物调制方法旨在通过这些类似物随后与药物递送系统的结合来促进这些类似物的向量化。合成了在位置3具有羟基，酮基，碘基，叠氮基或氨基官能团的五个不同的衍生物。这些化合物之一与含双官能马来酰亚胺的连接基偶联。所有化合物均经过体外测试使用MTS分析法对四种不同的细胞系（包括两种铂耐药的结直肠癌细胞系（SK-OV-3，HCT116，D3E2，D5B7））具有细胞毒性。总体而言，被测化合物的效力比卡铂强六倍，尤其是在D5B7人结肠直肠癌细胞上。我们证明了这些修饰导致有效的类似物，其与药物递送系统的缀合相容。