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Herein, we demonstrate for the first time that noncanonical DNA can direct macrocyclization‐like challenging reactions to synthesize gene modulators. The planar G‐quartets present in DNA G‐quadruplexes (G4s) provide a size complementary reaction platform for the bio‐orthogonal macrocyclization of bifunctional azide and alkyne fragments over oligo‐ and polymerization. G4s immobilized on gold‐coated magnetic nanoparticles have been used as target templates to enable easy identification of a selective peptidomimetic macrocycle. Structurally similar macrocycles have been synthesized to understand their functional role in the modulation of gene function. The innate fluorescence of the in situ formed macrocycle has been utilized to monitor its cellular localization using a G4 antibody and its in cell formation from the corresponding azide and alkyne fragments. The successful execution of in situ macrocyclization in vitro and in cells would open up a new dimension for target‐directed therapeutic applications. [ABSTRACT FROM AUTHOR]

We herein report the synthesis and biophysical evaluation of triazolyl dibenzo[a,c]phenazine derivatives as a novel class of G‐quadruplex ligands. The aromatic core facilitates π‐π interaction and the flexible, protonable side chains interact with the phosphate backbone of DNA via electrostatic interactions. Förster resonance energy transfer (FRET) melting assay and isothermal titration calorimetry (ITC) studies suggest that these ligands show binding preference for the hTELO G‐quadruplex over G‐quadruplexes found in the promoter region of various oncogenes and duplex DNA. The in vitro telomeric repeat amplification protocol (Q‐TRAP) assay reveals that these ligands reduce telomerase activity in cancer cells. [ABSTRACT FROM AUTHOR]

G-quadruplexes (G4s) are guanine rich and i-motifs are cytosine rich non-canonical four-stranded DNA secondary structures present throughout the genome. Their presence in important regulatory regions of the genome marks their significance in biology. This perspective discusses the importance of both G-quadruplex and i-motif structures and highlights their discovery, structural uniqueness, prevalence, and role in the biological system. Herein, we discuss the ligands developed in our laboratory that target G-quadruplexes and i-motifs and modulate gene expression in cancer cells. We also shed light on some recent techniques developed by us to simplify the synthesis and screening of G4 and i-motif specific ligands and their importance in anti-cancer therapeutics. Synopsis: G-quadruplexes and i-motifs are non-canonical DNA secondary structures prevalent in the telomeric region as well as in the regulatory regions of proto-oncogenes. We have described selective targeting of DNA secondary structures by small molecules and their functional role in the regulation of gene expression. [ABSTRACT FROM AUTHOR]

The selective transport of ions across cell membranes, controlled by membrane proteins, is critical for a living organism. DNA-based systems have emerged as promising artificial ion transporters. However, the development of stable and selective artificial ion transporters remains a formidable task. We herein delineate the construction of an artificial ionophore using a telomeric DNA G-quadruplex (h-TELO) and a lipophilic guanosine (MG). MG stabilizes h-TELO by non-covalent interactions and, along with the lipophilic side chain, promotes the insertion of h-TELO within the hydrophobic lipid membrane. Fluorescence assays, electrophysiology measurements and molecular dynamics simulations reveal that MG/h-TELO preferentially transports K+-ions in a stimuli-responsive manner. The preferential K+-ion transport is presumably due to conformational changes of the ionophore in response to different ions. Moreover, the ionophore transports K+-ions across CHO and K-562 cell membranes. This study may serve as a design principle to generate selective DNA-based artificial transporters for therapeutic applications. DNA based ionophores can mediate efficient ion transport and are crucial to understand the biological role of their natural counterparts. Here authors engineer a telomeric DNA G-quadruplex based ionophore which transports K+ in a stimuli responsive manner. [ABSTRACT FROM AUTHOR]

DNA sequences rich in cytosine have the propensity, under acidic pH, to fold into four‐stranded intercalated DNA structures called i‐motifs. Recent studies have provided significant breakthroughs that demonstrate how chemists can manipulate these structures for nanobiotechnology and therapeutics. The first section of this Minireview discusses the development of advanced functional nanostructures by synthetic conjugation of i‐motifs with organic scaffolds and metal nanoparticles and their role in therapeutics. The second section highlights the therapeutic targeting of i‐motifs with chemical scaffolds and their significance in biology. For this, first we shed light on the long‐lasting debate regarding the stability of i‐motifs under physiological conditions. Next, we present a comparative analysis of recently reported small molecules for specifically targeting i‐motifs over other abundant DNA structures and modulating their function in cellular systems. These advances provide new insights into i‐motif‐targeted regulation of gene expression, telomere maintenance, and therapeutic applications. Non‐canonical DNA structures: i‐Motifs are four‐stranded DNA structures formed by the folding of cytosine‐rich sequences present in telomeres and gene promoters. Compared to complementary G‐quadruplexes, i‐motifs are less explored. This Minireview describes significant advances in chemically regulated i‐motif‐based functional nanostructures and small‐molecule targeting of i‐motifs for therapeutics. [ABSTRACT FROM AUTHOR]

The Cu(i)-catalyzed azide and alkyne 1,3-dipolar cycloaddition (CuAAC), commonly known as the “click reaction”, has emerged as a powerful and versatile synthetic tool that finds a broad spectrum of applications in chemistry, biology and materials science. The efficiency, selectivity and versatility of the CuAAC reactions have enabled the preparation of vast arrays of triazole compounds with biological and pharmaceutical applications. In this feature article, we outline the applications and future prospects of click chemistry in the synthesis and development of small molecules that target G-quadruplex nucleic acids and show promising biological activities. Furthermore, this article highlights the template-assisted in situ click chemistry for developing G-quadruplex specific ligands and the use of click chemistry for enhancing drug specificity as well as designing imaging and sensor systems to elucidate the biological functions of G-quadruplex nucleic acids in live cells. [ABSTRACT FROM AUTHOR]

The design and synthesis of water soluble, amino-acid-functionalised naphthalenediimides (NDIs) as potential ligands of native G-quadruplexes is reported. The NDIs were tested on a panel of oncogene promoters, on the human telomeric sequence h-telo, and on double-stranded DNA. Out of the ligands tested, NDI 3 ( N ϵ-Boc- l-lysine NDI) exhibited a highly discriminating nature by only stabilising the oncogene promoter c-kit2, which is up-regulated up to 80 % in ovarian, gastrointestinal, and breast malignancies. [ABSTRACT FROM AUTHOR]

Bis(phenylethynyl)pyridylcarboxamides with amide side chains at the para position of the NH2 group possess strong solvatochromic properties compared with the meta analogues. Fluorescence binding titrations show that these probes exhibit remarkable fluorescence turn-on responses upon interacting with the human telomeric G-quadruplex ( h-TELO). Förster resonance energy transfer melting analysis shows the high selectivity of these probes for h-TELO over duplex DNA. Isothermal titration calorimetry, as well as UV/Vis and fluorescence spectroscopy studies, show that the meta analogue has a twofold binding affinity for h-TELO over the para analogue. The noncovalent interaction of these small-molecule probes with h-TELO has been used to regulate the assembly of novel supramolecular nanoarchitectures. [ABSTRACT FROM AUTHOR]

Like likes like! A novel fluorescent C2‐symmetric guanosine‐based dinucleoside has been engineered by chemical ligation of two guanosine units with a biocompatible dansyl tag. The nucleoside exhibits high selectivity for c‐myc G‐quadruplex DNA through fluorescence enhancement over duplex DNA and other promoter G‐quadruplexes (see scheme). It stains the nucleus preferentially, arrests the cell cycle at the G2/M phase, inhibits cell growth, and induces apoptosis in A375 cancer cells. [ABSTRACT FROM AUTHOR]

A variety of logic operations such as XNOR, NOR, AND, NAND, NOT have been designed with pH as an external modulator by choosing thiazole orange (TO) and a c-kit2 promoter quadruplex as two inputs and fluorescence signals of pyridyl bis-indole amide (PBIA) and TO as two outputs. [ABSTRACT FROM AUTHOR]

A modular synthesis of L-proline derived peptidomimetics has been developed using the CuI catalyzed Huisgen cycloaddition between an azido prolinamide with pyridine and benzene dicarboxamide containing dialkynes. Förster Resonance Energy Transfer (FRET) melting assay provided an initial indication that the pyridyl analogue can stabilize the c-KIT1 quadruplex DNA. A competitive FRET-melting assay and Fluorescent Intercalator Displacement (FID) assay suggest that the pyridyl ligand shows excellent selectivity for c-KIT1 quadruplex over duplex DNA and other investigated G-quadruplexes. Molecular docking studies indicate that the pyridyl ligand can adopt unique conformations upon binding to c-KIT1 quadruplex due to the presence of intramolecular hydrogen bonds. The pyridyl ligand can perturb cell cycle progression and induce necrotic cell death of human hepatocellular liver carcinoma HepG2 cells. [ABSTRACT FROM AUTHOR]

Two novel binaphthyl amines have been designed and synthesized using Buchwald amination and oxidative homocoupling as key steps. The binaphthyl amine containing two triazole rings shows higher affinity for c-MYC G-quadruplex, exhibits fluorescence "turn-on" response with c-MYC, and stains the nucleus in cells. The triazolyl binaphthyl amine shows cytotoxicity for cancer cells by inducing G2/M phase cell cycle arrest and apoptosis. Moreover, both ligands can downregulate c-MYC expression at transcriptional and translational levels. [ABSTRACT FROM AUTHOR]