Supramolecular or molecular gels are attractive for various applications, including diagnostics, tissue scaffolding and targeted drug release. Gelators derived from natural products are of particular interest for biomedical purposes, as they are generally biocompatible and stimuli-responsive. The building blocks of nucleic acids (i.e. nucleobases, nucleosides, and nucleotides) are desirable candidates for supramolecular gelation as they readily engage in reversible, noncovalent interactions. In this review, we describe a number of organo- and hydrogels formed through the assembly of nucleosides, nucleotides, and their derivatives. While natural nucleosides and nucleotides generally require derivatization to induce gelation, guanosine and its corresponding nucleotides are well known gelators. This unique gelating ability is due to propensity of the guanine nucleobase to self-associate into stable higher-order assemblies, such as G-ribbons, G4-quartets, and G-quadruplexes.

Supramolecular gels made from nucleobase, nucleoside and nucleotide analogs

A G-quadruplex (G4) is a well-known nucleic acid secondary structure comprising guanine-rich sequences, and has profound implications for various pharmacological and biological events, including cancers. Therefore, ligands interacting with G4s have attracted great attention as potential anticancer therapies or in molecular probe applications. To date, a large variety of DNA/RNA G4 ligands have been developed by a number of laboratories. As protein-targeting drugs face similar situations, G-quadruplex-interacting drugs displayed low selectivity to the targeted G-quadruplex structure. This low selectivity could cause unexpected effects that are usually reasons to halt the drug development process. In this review, we address the recent research on synthetic G4 DNA-interacting ligands that allow targeting of selected G4s as an approach toward the discovery of highly effective anticancer drugs.

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Recent Progress of Targeted G-Quadruplex-Preferred Ligands Toward Cancer Therapy

We have synthesized three new phenylethynylated carbazole boronic acid sensors, which were predicted to display novel d-PeT fluorescence transduction (PeT, photoinduced electron transfer; fluorophore as the electron donor of the electron transfer, ET) by DFT/TDDFT calculations. The d-PeT effect is characterized by a lower background fluorescence at acidic pH than at neutral pH, which is in stark contrast to the normal a-PeT effect (fluorophore as the electron acceptor of the ET) that shows a strong and undesired background fluorescence at acidic pH. Our experimental results confirmed the theoretical predictions and d-PeT was observed for two of the sensors (with p-dimethylaminophenylethynyl substitution at 6- position of the carbazole core). For the third sensor (with phenylethynyl substitution at 6- position of the carbazole core), however, not d-PeT but rather the normal a-PeT was observed. The discrepancy between the DFT/TDDFT calculations and the experimental observations can be rationalized using free energy changes (Rehm-Weller equations) and the rate constants for the ET (k(ET), Marcus equation). These new d-PeT boronic acid sensors show improved photophysical properties compared to the known d-PeT sensor reported previously by us. In particular, the fluorescence transduction efficiency of the new sensors was improved 8-fold when compared to the known d-PeT boronic acid sensors. Novel fluorescence enhancement/reduction was observed for one of the sensors upon binding with mandelic acid or tartaric acid at pH 5.6. The effect of pH as well as the bonding with analytes on the emission of the sensors were rationalized using DFT/TDDFT calculations. We believe that rational sensor design aided by DFT/TDDFT calculations as well as using free energy changes and electron transfer rate constants to study the emission properties of PeT sensors will become an essential tool in the design of new fluorophores or fluorescent sensors with predetermined photophysical properties.

Rational Design of d-PeT Phenylethynylated-Carbazole Monoboronic Acid Fluorescent Sensors for the Se

The incorporation of biomolecules into nanomaterials generates functional nanosystems with novel and advanced properties, presenting great potential for applications in various fields. Nucleobases, nucleosides and nucleotides, as building blocks of nucleic acids and biological coenzymes, constitute necessary components of the foundation of life. In recent years, as versatile biomolecules for the construction or regulation of functional nanomaterials, they have stimulated interest in researchers, due to their unique properties such as structural diversity, multiplex binding sites, self-assembly ability, stability, biocompatibility, and chirality. In this review, strategies for the synthesis of nanomaterials and the regulation of their morphologies and functions using nucleobases, nucleosides, and nucleotides as building blocks, templates or modulators are summarized alongside selected applications. The diverse applications range from sensing, bioimaging, and drug delivery to mimicking light-harvesting antenna, the construction of logic gates, and beyond. Furthermore, some perspectives and challenges in this emerging field are proposed. This review is directed toward the broader scientific community interested in biomolecule-based functional nanomaterials.

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Nucleobases, nucleosides, and nucleotides: versatile biomolecules for generating functional nanomaterials

G-Quadruplex: A Regulator of Gene Expression and Its Chemical Targeting

Hydrogels are attractive materials for designing sensors, catalysts, scaffolds for tissue engineering, stimuli responsive soft materials, and controlled-release drug delivery systems. In recent years, self-assembly of guanosine and its derivatives has received immense interests for devising programmable supramolecular biomaterials including hydrogels. This perspective highlights some of the history and the recent developments of guanosine-based supramolecular hydrogels and their applications. Future prospects and scope of the guanosine-based hydrogels have also been discussed.

Guanosine-Derived Supramolecular Hydrogels: Recent Developments and Future Opportunities.

The development of small molecules is essential to modulate the cellular functions of biological targets in living system. Target Guided Synthesis (TGS) approaches have been used for the identification of potent small molecules for biological targets. We herein demonstrate an innovative example of TGS using DNA nano-templates that promote Huisgen cycloaddition from an array of azide and alkyne fragments. A G-quadruplex and a control duplex DNA nano-template have been prepared by assembling the DNA structures on gold-coated magnetic nanoparticles. The DNA nano-templates facilitate the regioselective formation of 1,4-substituted triazole products, which are easily isolated by magnetic decantation. The G-quadruplex nano-template can be easily recovered and reused for five reaction cycles. The major triazole product, generated by the G-quadruplex inhibits c-MYC expression by directly targeting the c-MYC promoter G-quadruplex. This work highlights that the nano-TGS approach may serve as a valuable strategy to generate target-selective ligands for drug discovery.

Target guided synthesis using DNA nano-templates for selectively assembling a G-quadruplex binding c-MYC inhibitor.

The application of click chemistry for targeting quadruplex nucleic acids

This paper highlights recent developments in the design and construction of functional materials such as supramolecular hydrogels and ion channels using a guanine motif as a self-assembling building block.

Functional architectures derived from guanine quartets

The four-stranded G-quadruplex present in the c-MYC P1 promoter has been shown to play a pivotal role in the regulation of c-MYC transcription. Small-molecule compounds capable of inhibiting the c-MYC promoter activity by stabilising the c-MYC G-quadruplex could potentially be used as anticancer agents. In this context, here we report the synthesis of dansyl-guanosine conjugates through one-pot modular click reactions. The dansyl-guanosine conjugates can selectively detect c-MYC G-quadruplex over other biologically relevant quadruplexes and duplex DNA and can be useful as staining reagents for selective visualisation of c-MYC G-quadruplex over duplex DNA by gel electrophoresis. NMR spectroscopic titrations revealed the preferential binding sites of these dansyl ligands to the c-MYC G-quadruplex. A dual luciferase assay and qRT-PCR revealed that a dansyl-bisguanosine ligand represses the c-MYC expression, possibly by stabilising the c-MYC G-quadruplex.

Puja Saha

Papers

Guanosine-Derived Supramolecular Hydrogels: Recent Developments and Future Opportunities.

Target guided synthesis using DNA nano-templates for selectively assembling a G-quadruplex binding c-MYC inhibitor.

The application of click chemistry for targeting quadruplex nucleic acids

Functional architectures derived from guanine quartets

Fluorescent Dansyl-Guanosine Conjugates that Bind c-MYC Promoter G-Quadruplex and Downregulate c-MYC Expression