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: [PtII(R,R-DACH)(Sub-H)] (1), [PtII(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. Complexes1and2were characterised by1H,13C,195Pt NMR spectroscopy and ESI-MS. Whilst oxaliplatin demonstrated considerable cytotoxicity in two patient-derived low-passage paediatric glioma DIPG cell lines (IC50values of 0.333 µM in SU-DIPG-IV, and 0.135 µM in SU-DIPG-XXI), complex2showed even greater cytotoxicities, with IC50values of 0.021 µM (SU-DIPG-IV), 0.067 µM (BIOMEDE 194) and 0.009 µM (SU-DIPG-XXI). Complex2also demonstrated superior aqueous solubility in comparison to panobinostat. Complex2released 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.