Targeting Parallel Topology of G-Quadruplex Structures by Indole- Fused Quindoline Scaffolds.

Preferential stabilization of G-quadruplex (G4) structures using small-molecule ligands has emerged as an effective approach to develop anticancer drugs. Herein, we report the synthesis of three indole-fused quindoline derivatives with varying lengths of side chains (InqEt1, InqEt2, and InqPr2) as selective ligands for promoter G4 structures. The ligands stabilize the parallel topology of c-MYC and c-KIT1 promoter G4 DNAs over telomeric and duplex DNAs, as evident from the circular dichroism melting and polymerase stop-assay experiments. The lead ligand, InqPr2, downregulates the gene expression of c-MYC and c-KIT in HeLa and HepG2 cells, respectively, leading to apoptotic cell death. Molecular modeling and dynamics studies support the 2:1 binding stoichiometry revealed from the Job plot analysis and show the ligand's structural features that enable the preferential binding to the parallel G4 structures over other topologies. Our studies show that indole-fused quindoline derivatives can be harnessed as new molecular scaffolds for selective targeting of parallel G4 topologies.

Stabilization and fluorescence light-up of G-quadruplex nucleic acids using indolyl-quinolinium based probes.

G-Quadruplexes (G4s) are four-stranded motifs formed by G-rich nucleic acid sequences. These structures harbor significant biological importance as they are involved in telomere maintenance, transcription, and translation. Owing to their dynamic and polymorphic nature, G4 structures relevant for therapeutic applications need to be stabilized by small-molecule ligands. Some of these ligands turn on fluorescence upon binding to G4 structures, which provides a powerful detection platform for G4 structures. Herein, we report the synthesis of fluorescent ligands based on the indolyl-quinolinium moiety to specifically stabilize G4 structures and sense DNA. CD titration and melting experiments have shown that the lead ligand induces the formation of parallel G4 with preferential stabilization of the c-MYC and c-KIT1 promoter G4s over the telomeric, h-RAS1 G4, and duplex DNA. Fluorimetric titration data revealed fluorescence enhancement when these ligands interact with G4 DNA structures. The fluorescence lifetime experiment of the ligand with different DNAs revealed three excited state lifetimes (ns), which indicates more than one binding site. MD studies showed that the ligand exhibits 3 : 1 stoichiometry of binding with c-MYC G4 DNA and revealed the unique structural features, which impart selectivity toward parallel topology. The ligand was found to have low cytotoxicity and exhibited preferential staining of DNA over RNA. Collectively, the results presented here offer avenues to harness indolyl-quinolinium scaffolds for sensing and selective stabilization of G4 structures.

Acetylcholinesterase and Aß Aggregation Inhibition by Heterometallic Ruthenium(II)-Platinum(II) Polypyridyl Complexes.

Two heteronuclear ruthenium(II)-platinum(II) complexes [Ru(bpy)2(BPIMBp)PtCl2]2+ (3) and [Ru(phen)2(BPIMBp)PtCl2]2+ (4), where bpy = 2,2'-bipyridine, phen = 1,10-phenanthroline, and BPIMBp = 1,4'-bis[(2-pyridin-2-yl)-1H-imidazol-1-ylmethyl]-1,1'-biphenyl, have been designed and synthesized from their mononuclear precursors [Ru(bpy)2(BPIMBp)]2+ (1) and [Ru(phen)2(BPIMBp)]2+ (2) as multitarget molecules for Alzheimer's disease (AD). The inclusion of the cis-PtCl2 moiety facilitates the covalent interaction of Ru(II) polypyridyl complexes with amyloid ß (Aß) peptide. These multifunctional complexes act as inhibitors of acetylcholinesterase (AChE), Aß aggregation, and Cu-induced oxidative stress and protect neuronal cells against Aß-toxicity. The study highlights the design of metal based anti-Alzheimer's disease (AD) systems.

Honeycomb-like Ordered Assembly of DNA Induced by Flexible Binuclear Ruthenium(II)-Polypyridyl Complexes.

A series of binuclear ruthenium(II)-polypyridyl complexes of the type [Ru2 (N-N)4 (BPIMBp)]4+ , in which N-N is 2,2'-bipyridine (bpy; 1), 1,10-phenanthroline (phen; 2), dipyrido[3,2-d:2',3-f] quinoxaline (dpq; 3), dipyrido[3,2-a:2',3'-c] phenanzine (dppz; 4), and 1,4'-bis[(2-pyridin-2-yl)-1H-imidazol-1-yl)methyl]-1,1'-biphenyl (BPIMBp) is a bridging ligand, have been synthesized and characterized. These complexes are charged (4+) cations and flexible due to the -CH2 group of the bridging ligand and possess terminal ligands with variable intercalative abilities. The interaction of complexes 1-4 with calf thymus DNA (CT-DNA) was explored by using UV/Vis absorption spectroscopy, steady-state emission, emission quenching with K4 [Fe(CN)6 ], ethidium bromide displacement assay, Hoechst displacement assay, and viscosity measurements and revealed a groove-binding mode for all the complexes through a spacer and an intercalative mode for complexes 3 and 4. A decrease in the viscosity of DNA revealed bending and coiling of DNA, an initial step toward aggregation. Interestingly, a distinctive honeycomb-like ordered assembly of the DNA-complex species was visualized by fluorescence microscopy in the solution state. The use of SEM and AFM confirmed the disordered self-organization of the DNA-complex adduct on evaporation of the solvent. The small orderly nanosized DNA aggregates were confirmed by means of circular dichroism, dynamic light scattering (DLS), and TEM. These complexes are moderately cytotoxic against three different cell lines, namely, MCF-7, HeLa, and HL-60.

An insight into the morphology of DNA compaction induced by homobinuclear Ru(II) polypyridyl complexes.

Binuclear Ru(II) polypyridyl complexes [Ru2(NN)4(BIPMB)]4+ (1-4), where N-N = 2,2'-bipyridine (bpy), 1,10-phenanthroline (phen), dipyrido [3,2-d:2',3'-f] quinoxaline (dpq), and dipyrido[3,2-a:2',3'-c]phenazine (dppz), have been synthesized using suitable precursors and bridging ligand (BIPMB), where BIPMB = 3,3'-bis-{(imidazol-1-yl)-[4,5-f]-1,10-phenanthroline) methyl}-1,1'-biphenyl. The binding mode and affinity of complexes 1-4 with Calf Thymus DNA (CT-DNA) were determined by absorption and steady-state fluorescence spectroscopy. The decrease in viscosity of CT-DNA on sequential addition of these complexes indicated DNA condensation and the result was corroborated by circular dichroism (CD). The nanosized globular aggregates of CT-DNA induced by complexes 1-4 were observed by dynamic light scattering (DLS) and transmission electron microscopy (TEM) measurements. The gel electrophoretic mobility studies revealed the small orderly particles of supercoiled plasmid pBR322 DNA induced by these complexes. Additionally, the morphology and size of compact plasmid DNA condensates were studied by DLS and atomic force microscopy (AFM). The complexes were moderately cytotoxic against MCF-7 cells.

Copper(ii) mixed-ligand polypyridyl complexes with doxycycline - structures and biological evaluation.

Mixed-ligand Cu(ii) complexes of the type [Cu(doxycycline)(L)(H2O)2](NO3)2, where doxycycline = [4-(dimethylamino)-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide] and L = 2,2'-bipyridine (bpy, 1), 1,10-phenanthroline (phen, 2), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq, 3) and dipyrido[3,2-a:2',3'-c]phenazine (dppz, 4) have been synthesised and characterised by structural, analytical, and spectral methods. The single-crystal X-ray structures of 1 and 2 exhibited two different geometries, distorted square-pyramidal and octahedral respectively as well as different coordination modes of doxycycline. Complexes 2-4 exhibit prominent plasmid DNA cleavage at significantly low concentrations probably by an oxidative mechanism. Matrix Metalloproteinase (MMP-2) inhibition studies revealed that all complexes inhibit MMP-2 similar to doxycycline which is a well-known MMP inhibitor with 3 being the most potent. IC50 values of doxycycline and 1-4 against MCF-7 (human breast cancer) and HeLa cell lines were almost equal in which 3 showed the highest efficiency (IC50 = 0.46 ± 0.05 µM), being consistent with its increased MMP inhibition potency. The antimalarial activities of these complexes against the chloroquine-sensitive Plasmodium falciparum NF54 and chloroquine-resistant Plasmodium falciparum Dd2 strains reveal that complex 3 exhibited a higher activity than artesunate drug against the chloroquine-resistant Dd2 strain.