Combining PARP inhibition with platinum, ruthenium or gold complexes for cancer therapy

Platinum drugs are heavily used first-line chemotherapeutic agents for many solid tumours and have stimulated substantial interest in the biological activity of DNA-binding metal complexes. These complexes generate DNA lesions which trigger the activation of DNA damage response (DDR) pathways that are essential to maintain genomic integrity. Cancer cells exploit this intrinsic DNA repair network to counteract many types of chemotherapies. Now, advances in the molecular biology of cancer has paved the way for the combination of DDR inhibitors such as poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) and agents that induce high levels of DNA replication stress or single-strand break damage for synergistic cancer cell killing. In this review, we summarise early-stage, preclinical and clinical findings exploring platinum and emerging ruthenium anti-cancer complexes alongside PARPi in combination therapy for cancer and also describe emerging work on the ability of ruthenium and gold complexes to directly inhibit PARP activity

Ionothermal synthesis of Zn-based metal organic frameworks in pyridinium ionic liquid

Metal organic frameworks (MOFs) are crystalline porous frameworks which have been investigated as absorbent for removing dye, metal ion, drug contaminant, and organic solvent from water. However, the traditional synthesis of MOF involves the use of organic solvents and also requires high temperature; termed solvothermal reaction. This study aimed to synthesis MOF in a rather mild condition (room temperature) using ionic liquids (ILs) instead of organic solvents. Theoretically, high ionic conductivity of cetyl pyridinium bromide (C16PyBr) ionic liquid can develop novel MOF compounds thus, this study also aimed to investigate the possible effects of using ionic liquid in MOF synthesis. Zinc nitrate hexahydrate (Zn(NO3)2.6H2O) was used as the metal precursor and was reacted with the organic ligands, which is either benzene-1,3,5-tricarboxylic acid (H3BTC) or benzene-1,4-dicarboxylate (H2BDC), at 6:1 ratio in C16PyBr ionic liquid at room temperature. We hope to fabricate Zn-BDC and Zn-BTC MOFs with the same compositions, and thus recognize the effects of ILs. The powder X-ray diffraction (PXRD) and Fourier Transform Infrared Spectroscopy (FTIR) spectra of both newly synthesized MOFs showed that both Zn-BDC and ZnBTC MOFs can be reproduced with these conditions. ILs have also been found to significantly accelerate the formation of MOFs at room temperature as the reaction time is shortened to 6 hours in IL, meanwhile the organic solvent DMF needs at least 120 hours

Ruthenium(II) Polypyridyl Complexes as FRET Donors: Structure- and Sequence-Selective DNA-Binding and Anticancer Properties

Ruthenium(II) polypyridyl complexes (RPCs) that emit from metal-to-ligand charge transfer (MLCT) states have been developed as DNA probes and are being examined as potential anticancer agents. Here, we report that MLCT-emissive RPCs that bind DNA undergo Förster resonance energy transfer (FRET) with Cy5.5-labeled DNA, forming mega-Stokes shift FRET pairs. Based on this discovery, we developed a simple and rapid FRET binding assay to examine DNA-binding interactions of RPCs with diverse photophysical properties, including non-“light switch” complexes [Ru(dppz)2(5,5′dmb)]2+ and [Ru(PIP)2(5,5′dmb)]2+ (dppz = dipyridophenazine, 5,5′dmb = 5,5′-dimethyl-2,2′-bipyridine, PIP = 2-phenyl-imidazo[4,5-f][1,10]phenanthroline). Binding affinities toward duplex, G-quadruplex, three-way junction, and mismatch DNA were determined, and derived FRET donor–acceptor proximities provide information on potential binding sites. Molecules characterized by this method demonstrate encouraging anticancer properties, including synergy with the PARP inhibitor Olaparib, and mechanistic studies indicate that [Ru(PIP)2(5,5′dmb)]2+ acts to block DNA replication fork progression

Combining PARP Inhibition with Platinum, Ruthenium or Gold Complexes for Cancer Therapy

Platinum drugs are heavily used first-line chemotherapeutic agents for many solid tumours and have stimulated substantial interest in the biological activity of DNA-binding metal complexes. These complexes generate DNA lesions which trigger the activation of DNA damage response (DDR) pathways that are essential to maintain genomic integrity. Cancer cells exploit this intrinsic DNA repair network to counteract many types of chemotherapies. Now, advances in the molecular biology of cancer has paved the way for the combination of DDR inhibitors such as poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) and agents that induce high levels of DNA replication stress or single-strand break damage for synergistic cancer cell killing. In this review, we summarise early-stage, preclinical and clinical findings exploring platinum and emerging ruthenium anti-cancer complexes alongside PARPi in combination therapy for cancer and also describe emerging work on the ability of ruthenium and gold complexes to directly inhibit PARP activity