Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK.
Dalton Trans. 2020 May 7;49(17):5703-5710. doi: 10.1039/c9dt04862f. Epub 2020 Apr 16.
We report the synthesis of two novel platinum(ii) complexes which incorporate histone deacetylase (HDAC) inhibitors: [Pt(R,R-DACH)(Sub)] (1), [Pt(R,R-DACH)(panobinostat)] (2), where SubH = suberoyl-bis-hydroxamic acid; DACH = (1R,2R)-(-)-1,2-diaminocyclohexane and panobinostat = (E)-N-hydroxy-3-[4-[[2-(2-methyl-1H-indol-3-yl)ethylamino]methyl]phenyl]prop-2-enamide. Complexes 1 and 2 were characterised by H, C, Pt NMR spectroscopy and ESI-MS. Whilst oxaliplatin demonstrated considerable cytotoxicity in two patient-derived low-passage paediatric glioma DIPG cell lines (IC values of 0.333 μM in SU-DIPG-IV, and 0.135 μM in SU-DIPG-XXI), complex 2 showed even greater cytotoxicities, with IC values of 0.021 μM (SU-DIPG-IV), 0.067 μM (BIOMEDE 194) and 0.009 μM (SU-DIPG-XXI). Complex 2 also demonstrated superior aqueous solubility in comparison to panobinostat. Complex 2 released free intact panobinostat under HPLC conditions, as determined by ESI-MS. Incubation of solutions of oxaliplatin (HO) and panobinostat (DMF) resulted in instantaneous reactivity and precipitation of a panobinostat derivative which was not a platinum complex; the same reactivity was not observed between carboplatin and panobinostat.
我们报告了两种新型铂（II）配合物的合成，这些配合物包含组蛋白去乙酰化酶（HDAC）抑制剂：[Pt（R，R-DACH）（Sub）]（1），[Pt（R，R-DACH）（panobinostat）]（2），其中SubH = 琥珀酰双羟肟酸；DACH =（1R，2R）-（-）-1,2-二氨基环己烷和panobinostat =（E）-N-羟基-3-[4-[[2-（2-甲基-1H-吲哚-3-基）乙基氨基]甲基]苯基]丙烯酰胺。配合物 1 和 2 通过 H、C、Pt NMR 光谱和 ESI-MS 进行了表征。虽然奥沙利铂在两种源自患者的低传代小儿弥漫性脑桥胶质瘤 DIPG 细胞系（SU-DIPG-IV 的 IC 值为 0.333 μM，SU-DIPG-XXI 的 IC 值为 0.135 μM）中表现出相当大的细胞毒性，但配合物 2 显示出更高的细胞毒性，IC 值分别为 0.021 μM（SU-DIPG-IV）、0.067 μM（BIOMEDE 194）和 0.009 μM（SU-DIPG-XXI）。与 panobinostat 相比，配合物 2 还显示出优异的水溶性。通过 ESI-MS 确定，在 HPLC 条件下，配合物 2 释放出游离的完整 panobinostat。奥沙利铂（HO）和 panobinostat（DMF）溶液的孵育会导致 panobinostat 衍生物的瞬时反应和沉淀，而该衍生物不是铂配合物；卡铂与 panobinostat 之间没有观察到相同的反应性。
