Cyclometallated iridium complexes inducing paraptotic cell death like natural products: synthesis, structure and mechanistic aspects

Abstract

Six mononuclear Ir complexes (1-6) using polypyridyl-pyrazine based ligands (L1 and L2) and {[cp*IrCl(μ-Cl)] and [(ppy)Ir(μ-Cl)]} precursors have been synthesised and characterised. Complexes 1-5 have shown potent anticancer activity against various human cancer cell lines (MCF-7, LNCap, Ishikawa, DU145, PC3 and SKOV3) while complex 6 is found to be inactive. Flow cytometry studies have established that cellular accumulation of the complexes lies in the order 2 > 1 > 5 > 4 > 3 > 6 which is in accordance with their observed cytotoxicity. No changes in the expression of the proteins like PARP, caspase 9 and beclin-1, Atg12 discard apoptosis and autophagy, respectively. Overexpression of CHOP, activation of MAPKs (P38, JNK, and ERK) and massive cytoplasmic vacuolisation collectively suggest a paraptotic mode of cell death induced by proteasomal dysfunction as well as endoplasmic reticulum and mitochondrial stress. An intimate relationship between p53, ROS production and extent of cell death has also been established using p53 wild, null and mutant type cancer cells.

In Vitro Anticancer Activity and in Vivo Biodistribution of Rhenium(I) Tricarbonyl Aqua Complexes

“…Poly­(ADP-ribose) polymerase (PARP), for example, is cleaved by caspases during aptoposis . In addition, the protein LC3 is upregulated during the process of autophagy, and ERK is phosphorylated (p-ERK) in paraptosis. , The expression levels of all of these proteins in HeLa cells were evaluated in the presence of complex 13 by Western blots (Figure S34). This compound did not significantly alter the expression levels of any of these proteins, providing evidence against these mechanisms of cell death.…”

Cyclometalated Iridium(III) Complex–Cationic Peptide Hybrids Trigger Paraptosis in Cancer Cells via an Intracellular Ca2+ Overload from the Endoplasmic Reticulum and a Decrease in Mitochondrial Membrane Potential

“…Paraptosis has recently been recognized as another non-caspase-dependent type of PCD, as evidenced by the development of endoplasmic reticulum (ER) stress, extensive cytoplasmic vacuolization, and swelling or the dysfunction of the ER and/or mitochondria [7][8][9][10][11]. It has been reported that paraptosis in cancer cells can be induced by viruses [12], metal complexes including copper [13][14][15][16], ruthenium [17,18], titanium [19], iridium [20,21], and rhenium [22], organic compounds such as quinone derivatives [23,24], and naturally occurring compounds such as taxol [25,26], celastrol [27,28], hesperidin [29][30][31], curcumin [32][33][34], gypenoside L [35], morusin [36], chalcomoracin [37], cyclosporine A [38], and ophiobolin A [39]. However, the mechanism responsible for the paraptosis in cancer cells that is induced by these molecules appears to be complicated and has not yet been extensively studied.…”

Cyclometallated imidazo-phenanthroline iridium complexes and their anticancer activity

“…[1][2][3] In addition, iridium complexes are known to induce selective kinase inhibition property and often display non-apoptotic mode of cancer cell death which are useful for the treatment of resistant cancer. 1,[4][5][6][7][8][9] Moreover, the exciting luminescence properties of iridium complexes are often used as probes for understanding biological processes. In this aspect, a large number of cyclometallated iridium complexes have been developed and studied using various ligand frameworks.…”

“…In this aspect, a large number of cyclometallated iridium complexes have been developed and studied using various ligand frameworks. 5,7,8,[10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] Among various ancillary ligands, pyridine-based N ∧ N chelating ligands are most promising considering their excellent coordinating ability and stability under physiological condition. 2,4,5,14,18,20,[24][25][26][27][28] Different substituents have been incorporated to N ∧ N donor-based ligands in order to tune the property and activity of the complexes.…”