Chemically modified nucleobases are thought to be important for therapeutic purposes as well as diagnosing genetic diseases and have been widely involved in research fields such as molecular biology and biochemical studies. Many artificially modified nucleobases, such as methyl, halogen, and aryl modifications of purines at the C8 position and pyrimidines at the C5 position, are widely studied for their biological functions. DNA containing these modified nucleobases can form non-canonical helical structures such as Z-DNA, G-quadruplex, i-motif, and triplex. This review summarizes the synthesis of chemically modified nucleotides: (i) methylation, bromination, and arylation of purine at the C8 position and (ii) methylation, bromination, and arylation of pyrimidine at the C5 position. Additionally, we introduce the non-canonical structures of nucleic acids containing these modifications.

An organic catalyst “(R, R)-1,2-diphenylethylenediamine(DPEN) derivative’’ was devel-oped as a chiral bifunctional organocatalyst and applied for asymmetric Michael additions of aromatic ketones to trans-β-nitroalkene compounds under neutral conditions. The isopropyl-subs-tituted thiourea catalyst in neutral condition provides high chemical yield and enantioselectivities (ee) (up to 96% yield, 98% ee).

Although the Michael addition is a very well-known and widely applied reaction, cost-effective, metal-free, and readily prepared organic catalysts remain rare. A chiral, bifunctional, (R,R)-1,2-diphenylethylenediamine-derived thiourea organic catalyst was developed and applied to asymmetric Michael additions of nitroalkenes under neutral conditions. Generally, fluorine-substituted thiourea catalysts exhibited high chemical yields and enantioselectivities under neutral conditions. The mild reactions were tolerant of many functional groups and afforded good-to-excellent yields, as well as high diastereo- and enantioselectivities for the Michael adducts. The utility of the transformation was demonstrated by the synthesis of a bioactive compound, (R)-Phenibut.

Peripheral nerve degeneration (PND) is a preparative process for peripheral nerve regeneration and is regulated by Schwann cells, a unique glial cell in the peripheral nervous system. Dysregulated PND induces irreversible peripheral neurodegenerative diseases (e.g., diabetic peripheral neuropathy). To develop novel synthetic drugs for these diseases, we synthesized a set of new cinnamaldehyde (CAH) derivatives and evaluated their activities in vitro, ex vivo, and in vivo. The 12 CAH derivatives had phenyl or naphthyl groups with different substitution patterns on either side of the α,β-unsaturated ketone. Among them, 3f, which had a naphthaldehyde group, was the most potent at inhibiting PND in vitro, ex vivo, and in vivo. To assess their interactions with transient receptor potential cation channel subfamily A member 1 (TRPA1) as a target of CAH, molecular docking studies were performed. Hydrophobic interactions had the highest binding affinity. To evaluate the underlying pharmacological mechanism, we performed bioinformatics analysis of the effect of 3f on PND based on coding genes and miRNAs regulated by CAH, suggesting that 3f affects oxidative stress in Schwann cells. The results show 3f to be a potential lead compound for the development of novel synthetic drugs for the treatment of peripheral neurodegenerative diseases.

The iodination of pyrimidines is usually carried out by using toxic reagents under acidic conditions, such as with sulfuric acid and nitric acid. To avoid toxic reagents, we developed a simple and eco-friendly approach for the iodination of pyrimidine derivatives under solvent-free conditions using solid iodine and AgNO₃ as an electrophilic iodinating reagent. The advantages of this method are the relatively short reaction time (20–30 min), simple set-up procedure, high yields (70–98%), and environmentally friendly reaction conditions. Our novel approach for the iodination of pyrimidines, as well as a variety of their derivatives, will contribute to the development of nucleobase-related drug candidates.