Design, synthesis and biological activity of novel molecules designed to target PARP and DNA

Synthesis, chemical characterization, PARP inhibition, DNA binding and cellular uptake of novel ruthenium(II)-arene complexes bearing benzamide derivatives in human breast cancer cells

“…The highest intracellular uptake of C1, and accompanying accumulation in the DNA fraction of HCC1937 cells, are well in accordance with the higher growth inhibitory activity of this compound. Additionally, notable C1 accumulation in the nuclear fraction of cells may point to the tendency of this type of -combi-molecules‖ [63] to also interact with DNA-associated proteins, such as PARP-1. This is in accordance with the PARP-1 inhibitory potential of C1 observed in the present study, and as well as with the previous reports of cellular uptake of some ruthenium(II)-arene complexes with phenanthridin-based ligands [65].…”

“…Growing tendency in the drug design area is to connect metals with pharmacophoric moieties of bioactive ligand, to achieve different spectra of biological activity and improve the properties of both constituents [29,32,63,64]. Reports up to date showed that different ruthenium(II)-arene complexes entered tumor cells efficiently and bound DNA [24,65].…”

Quantitative Analysis of the Potency of Equimolar Two-Drug Combinations and Combi-Molecules Involving Kinase Inhibitors In Vitro: The Concept of Balanced Targeting

“…Thus, in recent years, strategies designed to overcome resistance mediated by compensatory signaling have involved the use of a multi-targeted approach [4,5]. Within this context, over the past decade, we developed a novel approach termed "combi-targeting" that sought to design agents designated as "combi-molecules" capable of inducing tandem blockade of two divergent biological targets (e.g., EGFR, PARP, MEK, and DNA) [6][7][8][9][10][11][12][13][14][15][16]. Further work on the concept led to the synthesis of molecules rationally designed to target two oncogenic tyrosine kinases involved in adverse signaling [17,18].…”

Design and Synthesis of a Trifunctional Molecular System “Programmed” to Block Epidermal Growth Factor Receptor Tyrosine Kinase, Induce High Levels of DNA Damage, and Inhibit the DNA Repair Enzyme (Poly(ADP-ribose) Polymerase) in Prostate Cancer Cells

“…Despite the overlapping role of receptors, DNA repair enzymes, and other adverse compensatory signaling responses associated with chemotherapy resistance, cancer drug discovery is primarily directed at designing monofunctional molecules. In the past, to circumvent the effect of receptor-mediated signaling on DNA damage, we designed several single molecules, termed “combi-molecules”, capable of damaging DNA and blocking EGFR according to a strategy termed “combi-targeting”. , We categorized these combi-molecules, generalized as I 1 –I 2 in Figure , into three different types according to their mechanism of action. As depicted in Figure , type I combi-molecules are designed to block target T 1 (e.g., EGFR) as an intact molecule and to be hydrolyzed into I 1 (an EGFR inhibitor) + I 2 (a DNA damaging species) capable to target T 1 (EGFR) and T 2 (DNA), respectively.…”