Gao Xiangqian, Liu Shengnan, Shi Yunli, Huang Zhenhua, Mi Yi, Mi Qian, Yang Jinna, Gao Qingzhi
Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, Collaborative Innovation Center of Chemical Science and Engineering, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin 300072, PR China.
School of Life Science, Tianjin University, 92 Weijin Road, Nankai District, Tianjin 300072, PR China.
Eur J Med Chem. 2017 Jan 5;125:372-384. doi: 10.1016/j.ejmech.2016.09.047. Epub 2016 Sep 16.
Novel cis-2-methylmalonato(trans-R,R-cyclohexane-1,2-diamine)platinum(II) glycoconjugates derived from different sugar motifs, namely, glucose (Glu-Me-Pt), mannose (Man-Me-Pt) and galactose (Gal-Me-Pt) were designed and synthesized based on the third generation clinical drug oxaliplatin for potential glucose transporters (GLUTs) mediated tumor targeting. All platinum(II) glycoconjugates were characterized by H NMR, C NMR, IR, HRMS as well as Pt-NMR analysis. Despite their substantial improvement in water solubility, the conjugates exhibited comparable or better in vitro cytotoxicities than oxaliplatin determined in six different human cancer cell lines. Glu-Me-Pt has been shown to be more effective than cisplatin and oxaliplatin with improved therapeutic index in leukemia-bearing DBA/2 mice model. The potential GLUT transportability of the complexes was investigated using cell-based fluorescent competition assay and GLUT inhibitor mediated cell viability analysis in GLUT over-expressing HT29 cell line. Each sugar motif was found to be useful to enable the platinum(II) complexes as substrate for GLUT mediated cell uptake. In vitro DNA adduct formation analysis has been investigated for the first time for this class of compounds to reveal the intrinsic differences in antitumor activity between the malonatoplatinum(II) glycoconjugates and oxaliplatin. The intrinsic DNA reactivity of the platinum(II)-sugar conjugates was found as Gal-Me-Pt > Glu-Me-Pt > Man-Me-Pt ≈ oxaliplatin by kinetic study on the formation of platinum(II) adducts with guanosine-5'-monophosphate (5'-GMP). The results from this study demonstrate the usefulness of glucose, mannose and galactose as alternative sugar motif on glycoconjugation for GLUT mediated drug design and pharmaceutical R&D, and the obtained fundamental results also support the potential of the GLUT targeted platinum(II)-sugar conjugates as lead compounds for further pre-clinical evaluation.
基于第三代临床药物奥沙利铂，设计并合成了源自不同糖基序的新型顺式-2-甲基丙二酸（反式-R，R-环己烷-1,2-二胺）铂（II）糖缀合物，即葡萄糖（Glu-Me-Pt）、甘露糖（Man-Me-Pt）和半乳糖（Gal-Me-Pt），用于潜在的葡萄糖转运蛋白（GLUTs）介导的肿瘤靶向治疗。所有铂（II）糖缀合物均通过1H NMR、13C NMR、IR、HRMS以及Pt-NMR分析进行了表征。尽管它们在水溶性方面有了显著改善，但在六种不同的人类癌细胞系中测定时，这些缀合物表现出与奥沙利铂相当或更好的体外细胞毒性。在携带白血病的DBA/2小鼠模型中，已证明Glu-Me-Pt比顺铂和奥沙利铂更有效，且治疗指数有所提高。使用基于细胞的荧光竞争测定法和GLUT抑制剂介导的细胞活力分析，在GLUT过表达的HT29细胞系中研究了这些复合物的潜在GLUT转运能力。发现每个糖基序都有助于使铂（II）复合物作为GLUT介导的细胞摄取的底物。首次对这类化合物进行了体外DNA加合物形成分析，以揭示丙二酸铂（II）糖缀合物和奥沙利铂之间抗肿瘤活性的内在差异。通过对铂（II）与鸟苷-5'-单磷酸（5'-GMP）形成加合物的动力学研究，发现铂（II）-糖缀合物的内在DNA反应活性为Gal-Me-Pt > Glu-Me-Pt > Man-Me-Pt ≈ 奥沙利铂。这项研究的结果证明了葡萄糖、甘露糖和半乳糖作为糖缀合作用的替代糖基序在GLUT介导的药物设计和药物研发中的有用性，并且所获得的基础结果也支持了GLUT靶向的铂（II）-糖缀合物作为进一步临床前评估的先导化合物的潜力。
