Cytotoxicity and reactivity of a redox active 1,4-quinone-pyrazole compound and its Ru(II)-p-cymene complex

Abstract

Quinone based compounds display activation in hypoxia, an environment prevalent in tumours. We have synthesized a bis(pyrazole) based 1,4-quinone compound suitable for metal chelation. The quinone (L2) converted to hydroquinone (H2L1) during the complex synthesis leading to [RuII(η6-p-cym)(H2L1)Cl](PF6) (1). We found from 1H NMR studies that in the methanolic solution L2 stoichiometrically converted to H2L1 while oxidizing the methanol to formaldehyde. L2 crystallized in monoclinic space group I2/a while complex 1 crystallizes in P21/c. Cyclic voltammetry of the redox non-innocent L2 showed quasi-reversible (ΔEp = 67 mV) redox behaviour with E1/2 at 0.12 V w.r.t. NHE. Complex 1 is stable at pH 7.4 in presence of 4 mM chloride and does not hydrolyse even up to 24 h. L2 showed IC50 values of 155 and 123 µM against metastatic breast adenocarcinoma (MDA-MB-231) and pancreatic carcinoma (MIA PaCa-2) respectively. L2 gets activated by ca. 2.7-fold in hypoxia against MIA PaCa-2 cells. The mechanistic studies showed ROS accumulation and oxidation of NADH to NAD+, which may be responsible for the cytotoxicity. The reactivity studies showed that conversion to hydroquinone by reaction with NADH or glutathione is irreversible. Complex 1 is not cytotoxic up to 100 µM in normoxia or hypoxia. Complex 1 displays irreversible redox behavior in cyclic voltammetry displaying two overlapping oxidation peaks at 1.00 and 1.57 V w.r.t. NHE, which may be assigned to the conversion of hydroquinone to quinone and RuII → RuIII respectively.