Theoretical Insight into the Library Screening Approach for Binding of Intermolecular G-Quadruplex RNA and Small Molecules through Docking and Molecular Dynamics Simulation Studies.

The interactions of intermolecular G-quadruplex RNA and small molecules have been investigated by computational studies. Various anthraquinone, bisbenzimidazole, and carbazole-benzimidazole based ligands have shown a distinct preference to G-quadruplex structures as opposed to the corresponding duplex forms of DNA that were docked with telomeric G-quadruplex RNA. The comparative binding study of such ligands with G-quadruplex (G4) RNA showed higher binding affinities toward carbazole-benzimidazole ligands than those of the anthraquinone and bisbenzimidazole based ligands.

Single position substitution of hairpin pyrrole-imidazole polyamides imparts distinct DNA-binding profiles across the human genome.

Pyrrole-imidazole (Py-Im) polyamides are synthetic molecules that can be rationally designed to target specific DNA sequences to both disrupt and recruit transcriptional machinery. While in vitro binding has been extensively studied, in vivo effects are often difficult to predict using current models of DNA binding. Determining the impact of genomic architecture and the local chromatin landscape on polyamide-DNA sequence specificity remains an unresolved question that impedes their effective deployment in vivo.

Specific stabilization of promoter G-Quadruplex DNA by 2,6-disubstituted amidoanthracene-9,10-dione based dimeric distamycin analogues and their selective cancer cell cytotoxicity.

We have designed and synthesized anthraquinone containing compounds which have oligopyrrole side chains of varying lengths. These compounds stabilized the G-quadruplex DNA formed in the promoter regions of c-MYC oncogenes selectively over the duplex DNA. These observations were recorded using UV-vis spectroscopic titrations, fluorescence measurements and circular dichroism (CD) spectral titrations.

Simultaneous sensing of ferritin and apoferritin proteins using an iron-responsive dye and evaluation of physiological parameters associated with serum iron estimation.

An iron-responsive optical probe has been developed for simultaneous sensing of both ferritin and apoferritin proteins at pH 7.4 in water. The compound showed an exclusive response (turn-off signal) towards ferritin among a wide range of proteins even at nanomolar concentration.

Noncanonical CTD kinases regulate RNA polymerase II in a gene-class-specific manner.

Phosphorylation of the carboxyl-terminal domain (CTD) of the largest subunit of RNA polymerase II (Pol II) governs stage-specific interactions with different cellular machines. The CTD consists of YSPTSPS heptad repeats and sequential phosphorylations of Ser7, Ser5 and Ser2 occur universally at Pol II-transcribed genes. Phosphorylation of Thr4, however, appears to selectively modulate transcription of specific classes of genes.

Targeting G-quadruplex DNA structures in the telomere and oncogene promoter regions by benzimidazole‒carbazole ligands.

Recent studies support the idea that G-quadruplex structures in the promoter regions of oncogenes and telomere DNA can serve as potential therapeutic targets in the treatment of cancer. Accordingly, several different types of organic small molecules that stabilize G-quadruplex structures and inhibit telomerase activity have been discerned. Here, we describe the binding of benzimidazole-carbazole ligands to G-quadruplex structures formed in G-rich DNA sequences containing the promoter regions of human c-MYC, c-KIT1, c-KIT2, VEGF and BCL2 proto-oncogenes.

Synthetic transcription elongation factors license transcription across repressive chromatin.

The release of paused RNA polymerase II into productive elongation is highly regulated, especially at genes that affect human development and disease. To exert control over this rate-limiting step, we designed sequence-specific synthetic transcription elongation factors (Syn-TEFs). These molecules are composed of programmable DNA-binding ligands flexibly tethered to a small molecule that engages the transcription elongation machinery.

Dual-Mode Optical Sensing of Histamine at Nanomolar Concentrations in Complex Biological Fluids and Living Cells.

An easily synthesized fluorescein-based luminescent dye has been utilized for the dual-mode detection of histamine at nanomolar concentrations at pH 7.0 in water. The specific response to histamine was achieved by imidazole-catalyzed 'imine formation' reaction.

Knockdown of Broad-Complex Gene Expression of Bombyx mori by Oligopyrrole Carboxamides Enhances Silk Production.

Bombyx mori (B. mori) is important due to its major role in the silk production. Though DNA binding ligands often influence gene expression, no attempt has been made to exploit their use in sericulture.

Enhanced G-Quadruplex DNA Stabilization and Telomerase Inhibition by Novel Fluorescein Derived Salen and Salphen Based Ni(II) and Pd(II) Complexes.

Metal based salen complexes have been considered as an important scaffold toward targeting of DNA structures. In the present work, we have synthesized nickel(II) and palladium(II) salen and salphen complexes by using readily available fluorescein as the backbone to provide an extended aromatic surface. The metal complexes exhibit affinity toward the human telomeric G-quadruplex DNA with promising inhibition of telomerase activity.

Novel Oligopyrrole Carboxamide based Nickel(II) and Palladium(II) Salens, Their Targeting of Human G-Quadruplex DNA, and Selective Cancer Cell Toxicity.

DNA targeting by various metal complexes is a key strategy toward the restriction of cancer cell proliferation. Toward this end, we designed and synthesized novel salen-based Ni(II) and Pd(II) metal complexes with positively charged flanking side chains comprising N-methylpyrrole carboxamides of varying lengths. The compounds showed high specificity toward G-quadruplex DNA over duplex DNA.

New Fe(iii) and Co(ii) salen complexes with pendant distamycins: selective targeting of cancer cells by DNA damage and mitochondrial pathways.

Minor groove binding distamycin like moieties were conjugated with core salens and the corresponding Fe(iii) and Co(ii) complexes were synthesized. Herein, we have shown efficient DNA minor groove binding specificities along with excellent DNA cleavage capacities with metallosalen conjugates. The metal complexes showed toxicity toward various cancer cells over normal cells with high specificity.

Ligand 5,10,15,20-tetra(N-methyl-4-pyridyl)porphine (TMPyP4) prefers the parallel propeller-type human telomeric G-quadruplex DNA over its other polymorphs.

The binding of ligand 5,10,15,20-tetra(N-methyl-4-pyridyl)porphine (TMPyP4) with telomeric and genomic G-quadruplex DNA has been extensively studied. However, a comparative study of interactions of TMPyP4 with different conformations of human telomeric G-quadruplex DNA, namely, parallel propeller-type (PP), antiparallel basket-type (AB), and mixed hybrid-type (MH) G-quadruplex DNA, has not been done. We considered all the possible binding sites in each of the G-quadruplex DNA structures and docked TMPyP4 to each one of them.

DNA binders in clinical trials and chemotherapy.

Cancer has always been a dreadful disease and continues to attract extensive research investigations. Various targets have been identified to restrain cancer. Among these DNA happens to be the most explored one.