Antitumor trans-N-Heterocyclic Carbene–Amine–Pt(II) Complexes: Synthesis of Dinuclear Species and Exploratory Investigations of DNA Binding and Cytotoxicity Mechanisms

Abstract

A series of bimetallic [(NHC)PtX2]2(diamine) complexes have been prepared as a new chemotype for potential anticancer agents. These complexes display an uncommon set of structural features as far as they combine two bifunctional, trans-configured platinum centers. They display cytotoxic activities in the micromolar range on many cancerous cell lines and do not cross-react with cisplatin in A2780/DDP cell lines. They bind slowly to double-stranded DNAs, giving monoadducts as the major products. Pathways for cellular toxicity have been investigated for both mono- and bimetallic trans-(NHC)PtX2(amine) complexes. It has been highlighted that, unlike cisplatin, these complexes do not induce cell cycle arrest. They trigger apoptosis in A2780 cells by a pathway involving translocation of apoptosis-inducing factor and caspase 12 to the nucleus. Moreover, bimetallic complexes may induce necrosis.

A novel class of ethacrynic acid derivatives as promising drug-like potent generation of anticancer agents with established mechanism of action

“…It is noteworthy that the two phosphate derivatives 10 and 11 and the dioxaphosphorinane 15 showed good homogeneity related to their IC 50 s and higher activity towards MCF7, HCT116 and PC3 cell lines than towards the ovarian cancer cell lines SK-OV3 and OVCAR8. A different sensibility to cisplatin has been reported in these two ovarian cell lines, SK-OV3 been considered as resistant compared to OVCAR8: a similar behavior can be observed with EA and its derivatives [21]. The next step was the determination of the mechanism of action of EA derivatives and was intended to confirm the modulation of anti-proliferative capacity by structural modifications.…”

“…The next step was the determination of the mechanism of action of EA derivatives and was intended to confirm the modulation of anti-proliferative capacity by structural modifications. Evaluations regarding vital cellular processes have been tested essentially in HL60 cells for relevant comparison with a selection of 13 chemically diverse EA derivatives selected in accordance with their structural design and bearing modification either in the part A alleviating activity (23, 24, 25 and 26) or in the part B within the two series A and B: amide-monosubstituted (5, 6, 7, 8 and 9), ester-monosubstituted (21), N-methyl amidemonosubstituted (22), and disubstituted (18 and 19) showing IC 50 s against KB and HL60 between 0.4 µM and 1.6 µM.…”

“…Control cells received the same volume of DMSO (1% final volume). After 24 or 72h exposure to the drug, inhibition of cell proliferation was determined as previously reported [21]. For IC 50 determinations (50% inhibition of cell proliferation) experiments were performed in duplicate with concentrations ranged 0.5 nm to 100 µm.…”

“…Necrosis was estimated through the release of LDH in the culture medium. 20,000 HL60 cells were incubated for 24 and 48 h in the presence of chemicals in 96-well [21,31]. Flow cytometric detection of apoptosis.…”

“…Flow cytometric detection of apoptosis. Apoptotic and necrotic cells were analysed in flow cytometry using HL60 cells [21,31]. The cellular fluorescence was measured by flow cytometry with a Guava EasyCyte plus cytometer (Millipore).…”