Oxaliplatin and [Pt(R,R-DACH)(panobinostat-2H)] show nanomolar cytotoxicity towards diffuse intrinsic pontine glioma (DIPG)

Abstract

We report the synthesis of two novel platinum(II) complexes which incorporate histone deacetylase (HDAC) inhibitors: [Pt^II(R,R-DACH)(Sub_-H)] (1), [Pt^II(R,R-DACH)(panobinostat_-2H)] (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 ¹H, ¹³C, ¹⁹⁵Pt NMR spectroscopy and ESI-MS. Whilst oxaliplatin demonstrated considerable cytotoxicity in two patient-derived low-passage paediatric glioma DIPG cell lines (IC₅₀ values of 0.333 μM in SU-DIPG-IV, and 0.135 μM in SU-DIPG-XXI), complex 2 showed even greater cytotoxicities, with IC₅₀ 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 (H₂O) 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.