Guanosine (DL-Guanosine)

The potential role of N7-methylguanosine (m7G) in cancer

N7-methylguanosine (m7G), one of the most prevalent RNA modifications, has recently attracted significant attention. The m7G modification actively participates in biological and pathological functions by affecting the metabolism of various RNA molecules, including messenger RNA, ribosomal RNA, microRNA, and transfer RNA. Increasing evidence indicates a critical role for m7G in human disease development, especially cancer, and aberrant m7G levels are closely associated with tumorigenesis and progression via regulation of the expression of multiple oncogenes and tumor suppressor genes. Currently, the underlying molecular mechanisms of m7G modification in cancer are not comprehensively understood. Here, we review the current knowledge regarding the potential function of m7G modifications in cancer and discuss future m7G-related diagnostic and therapeutic strategies.

Manipulating DNA G-Quadruplex Structures by Using Guanosine Analogues

The ability to control the folding topology of DNA G-quadruplexes allows for rational design of quadruplex-based scaffolds for potential use in various therapeutic and technological applications. By exploiting the distinct conformational properties of some base- and sugar-modified guanosine surrogates, conformational transitions can be induced through their judicious incorporation at specific sites in the quadruplex core. Changes may involve tetrad polarity inversions with conservation of the global fold or complete refolding to new topologies. Reliable predictions relating to low-energy conformers formed upon specific chemical perturbations of the system and the rational design of modified sequences suffer from our still limited understanding of the subtle interplay of various favorable and unfavorable interactions within a particular quadruplex scaffold. However, aided by an increasing number of systematic substitution experiments and high-resolution structures of modified quadruplex variants, critical interactions, in addition to glycosidic bond angle propensities, are starting to emerge as important contributors to modification-driven quadruplex refolding.

Excited State Dynamics of Methylated Guanosine Derivatives Revealed by Femtosecond Time-resolved Spectroscopy

Methylated DNA/RNA nucleobases are important epigenetic marks in living species and play an important role for targeted therapies. Moreover, methylation could bring significant changes to the photo-stability of nucleic acid, leading these sites become mutational hotspots for disease such as skin cancer. While a number of studies have demonstrated the relationship between excited state dynamics and the biological function of methylated cytosine in DNA, investigations aimed at unraveling the excited state dynamics of methylated guanosine in RNA have been largely overlooked. In this work, influence of methylation on the excited state dynamics of guanosine is studied by using femtosecond time-resolved spectroscopy. Our results suggest that the effect of methyl substitution on the photophysical properties of guanosine is position sensitive. N1-methylguanosine shows very similar excited state dynamics as that in guanosine, while almost one order of magnitude longer lifetime of the La state is observed in N2, N2-dimethylguanosine. Notably, N7-methylation can lead to a new minimum on the La state and the excited state lifetime is two orders of magnitude longer than that of guanosine. These findings not only help understanding excited state dynamics of methylated guanosines, but also lay the foundation for further studying DNA/RNA strands incorporated with these bases.

Thiophene-expanded guanosine analogues of Gemcitabine

The chemotherapeutic drug Gemcitabine, 2',2'-difluoro-2'-deoxycytidine, has long been the standard of care for a number of cancers. Gemcitabine's chemotherapeutic properties stem from its 2',2'-difluoro-2'-deoxyribose sugar, which mimics the natural nucleoside, but also disrupts nucleic acid synthesis, leading to cell death. As a result, numerous analogues have been prepared to further explore the biological implications for this structural modification. In that regard, a thieno-expanded guanosine analogue was of interest due to biological activity previously observed for the tricyclic heterobase scaffold. Several analogues were prepared, including the McGuigan ProTide, however the parent nucleoside exhibited the best chemotherapeutic activity, specifically against breast cancer cell lines (89.53% growth inhibition).

Subsecond detection of guanosine using fast-scan cyclic voltammetry

Guanosine is an important neuromodulator and neuroprotector in the brain and is involved in many pathological conditions, including ischemia and neuroinflammation. Traditional methods to detect guanosine in the brain, like HPLC, offer low limits of detection and are robust; however, subsecond detection is not possible. Here, we present a method for detecting rapid fluctuations of guanosine concentration in real-time using fast-scan cyclic voltammetry (FSCV) at carbon-fiber microelectrodes. The optimized waveform scanned from -0.4 V to 1.3 V and back at a rate of 400 V s-1 and application frequency of 10 Hz. Potential limits were chosen to increase selectivity of guanosine over the structurally similar interferent adenosine. Two oxidation peaks were detected with the optimized waveform: the primary oxidation reaction occurred at 1.3 V and the secondary oxidation at 0.8 V. Guanosine detection was stable over time with a limit of detection of 30 ± 10 nM, which permits its use to monitor low nanomolar fluctuations in the brain. To demonstrate the feasibility of the method for in-tissue detection, guanosine was exogenously applied and detected within live rat brain slices. This paper demonstrates the first characterization of guanosine using FSCV, and will be a valuable method for measuring signaling dynamics during guanosine neuromodulation and protection.