Design, synthesis and evaluation of diarylidenyl piperidone-ligated platinum (IV) complexes as chemoimmunotherapeutic agents

Abstract

A set of diarylidenyl piperidone-ligated platinum (IV) complexes 8a‒8d with chemoimmunotherapy effects was designed and synthesized based on introduction of classic STAT3 inhibitors, diarylidenyl piperidones, into an oxaliplatin (OXA)-based skeleton. 3-(4,5)-Dimethylthiahiazo (-z-y1)-3, 5-di- phenytetrazoliumromide (MTT) assay indicated that complexes 8a‒8d exhibited obvious inhibition on T24, MDA-MB-231 and SW480 cell lines compared to OXA, with IC₅₀ values in range of 4.96 ± 0.14-21.1 ± 0.35 μM. SW480 xenograft nude mice assay demonstrated that complexes 8a (2 mg/kg and 4 mg/kg), 8b (4 mg/kg) and 8c (4 mg/kg) exhibited effective inhibition on this model with tumor inhibitory rates (TIR) of 46.06 %, 51.18 %, 48.82 % and 42.16 %, respectively, compared with OXA (2 mg/kg, TIR = 31.89 %/34.31 %) during 21-days treatment, while CT-26 xenograft BALB/C mice assay showed that complexes 8a (10 mg/kg), 8b (5 and 10 mg/kg), 8c (5 and 10 mg/kg), and 8d (5 and 10 mg/kg) exhibited effective inhibition of with TIR values of 56.95 %, 56.28 %, 78.02 %, 47.28 %, 63.80 %, 51.90 % and 70.65 %, respectively, compared with OXA (5 mg/kg, TIR = 69.28 %/67.53 %) during 13-days treatment. The pathology results in SW480 and CT-26 xenograft showed that complexes 8a-8d displayed limited toxicity in comparison with OXA. All these results indicated that complexes 8a-8c may be good chemoimmunotherapeutic agents with potent efficacy and safety profiles. Further mechanistic studies revealed that the representative complex 8b might exert its chemoimmunotherapeutic effect by inhibiting the expression and phosphorylation of STAT3, thus evoking CD4⁺ and CD8⁺ T lymphocyte immune responses and inducing ferroptosis and apoptosis.

Keywords: Chemoimmunotherapeutic agent; Ferroptosis; Oxaliplatin; STAT3; T cell.