Institute for Glycomics, Griffith University, Gold Coast Campus, Southport, Queensland, 4222, Australia.
Department of Chemistry and The Massey Cancer Center, Virginia Commonwealth University, Richmond, 23284, Virginia, USA.
Chemistry. 2018 May 2;24(25):6606-6616. doi: 10.1002/chem.201706030. Epub 2018 Apr 14.
Cleavage of heparan sulfate proteoglycans (HSPGs) by the enzyme heparanase modulates tumour-related events including angiogenesis, cell invasion, and metastasis. Metalloshielding of heparan sulfate (HS) by positively charged polynuclear platinum complexes (PPCs) effectively inhibits physiologically critical HS functions. Studies using bacterial P. heparinus heparinase II showed that a library of Pt complexes varying in charge and nuclearity and the presence or absence of a dangling amine inhibits the cleavage activity of the enzyme on the synthetic pentasaccharide, Fondaparinux (FPX). Charge-dependent affinity of PPC for FPX was seen in competition assays with methylene blue and ethidium bromide. The dissociation constant (K ) of TriplatinNC for FPX was directly measured by isothermal titration calorimetry (ITC). The trend in DFT calculated interaction energies with heparin fragments is consistent with the spectroscopic studies. Competitive inhibition of TAMRA-R internalization in human carcinoma (HCT116) cells along with studies in HCT116, wildtype CHO and mutant CHO-pgsA745 (lacking HS/CS) cells confirm that HSPG-mediated interactions play an important role in the cellular accumulation of PPCs.
硫酸乙酰肝素蛋白聚糖（HSPGs）的裂解被酶肝素酶所调控，从而影响肿瘤相关事件，包括血管生成、细胞侵袭和转移。带正电荷的多核铂配合物（PPCs）对硫酸乙酰肝素（HS）的金属屏蔽作用可有效抑制生理上关键的 HS 功能。使用细菌 P. heparinus 肝素酶 II 的研究表明，一个带电荷和多核性以及是否存在悬垂胺的 Pt 配合物文库，可抑制该酶对合成五糖， Fondaparinux（FPX）的裂解活性。在与亚甲蓝和溴化乙锭的竞争测定中，观察到 PPC 对 FPX 的电荷依赖性亲和力。通过等温滴定量热法（ITC）直接测量 TriplatinNC 与 FPX 的离解常数（K ）。与肝素片段的计算相互作用能的 DFT 趋势与光谱研究一致。TAMRA-R 内化在人癌细胞（HCT116）中的竞争抑制作用以及在 HCT116、野生型 CHO 和突变型 CHO-pgsA745（缺乏 HS/CS）细胞中的研究证实，HSPG 介导的相互作用在 PPC 的细胞积累中起着重要作用。
