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_d) 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‐R₉ 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.

中文翻译：

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取代惰性多核铂络合物作为硫酸乙酰肝素的金属屏蔽剂

乙酰肝素酶对硫酸乙酰肝素蛋白聚糖 (HSPGs) 的切割可调节肿瘤相关事件，包括血管生成、细胞侵袭和转移。带正电荷的多核铂络合物 (PPC) 对硫酸乙酰肝素 (HS) 的金属屏蔽可有效抑制生理关键的 HS 功能。使用细菌肝素肝素酶 II 的研究表明，Pt 复合物库的电荷和核度以及悬空胺的存在或不存在会抑制酶对合成五糖磺达肝素 (FPX) 的切割活性。PPC 对 FPX 的电荷依赖性亲和力在亚甲蓝和溴化乙锭的竞争试验中可见。解离常数 ( K _d) 用于 FPX 的 TriplatinNC 是通过等温滴定量热法 (ITC) 直接测量的。DFT计算的与肝素片段的相互作用能的趋势与光谱研究一致。竞争性抑制人癌细胞 (HCT116) 中的 TAMRA-R ₉内化以及对 HCT116、野生型 CHO 和突变型 CHO-pgsA745（缺乏 HS/CS）细胞的研究证实 HSPG 介导的相互作用在细胞积累中起重要作用PPC。