Artificial nucleic acids—engineered through fine-tuned molecular design based on organic synthetic chemistry and focused on nucleic acid molecular recognition—show significant potential in drug discovery, especially in the development of nucleic acid therapeutics and drugs. This review underscores recent advancements in nucleic acid chemistry achieved by our research group, including the design of novel artificial nucleoside analogs, exploration of their applications, and elucidation of their molecular functions.

This review highlights recent progress in transition metal-free reductive transformations using organic electron donors. According to previous reports, pyridine-derived super electron donors enable the selective reduction of nitrobenzenes to azobenzenes and phenazines, while also promoting the efficient desulfurization of thioacetals and thioethers under mild conditions. These transformations proceeded with a broad substrate scope and good functional group compatibility. Additionally, a sodium hydride (NaH)/1,10-phenanthroline system developed for radical-mediated C–C bond formation promoted the hydroarylation and hydroalkylation of styrenes with high anti-Markovnikov selectivities. Mechanistic studies suggested that the in situ-generated anilide anion acts as both an electron donor and a hydrogen source, supporting a radical-based reaction pathway. These works demonstrate the potential of organic electron donors for use as sustainable and practical alternatives to conventional transition metal-based reductive methods in organic synthesis.

A direct dehydroxylative allylation reaction of benzylic alcohols with allylsilanes catalyzed by Brønsted acids in 1,1,1,3,3,3-hexafluoro-2-propanol was developed. A wide variety of secondary and tertiary benzylic alcohols are applicable to the reaction with various allyltrimethylsilanes, to provide the corresponding coupling products in high yields. Using this catalytic transformation, a concise and short-step synthesis of (±)-crucudiol was achieved.

The chemical analysis of Cladosporium tenuissimum yielded six 12-membered macrolides (1–6), including 2 new ones (1 and 2) and 4 other compounds (7–10). Comprehensive spectroscopic techniques were employed to establish the structures, whereas electronic circular dichroism (ECD) calculations and Mosher’s analysis were performed to confirm the absolute configurations of new compounds. We evaluated the metabolites for their cytotoxic activities, antifungal activity, and α-glucosidase. Notably, compound 1 exhibited moderate antifungal activity against Alternaria solani and Botrytis cinerea with minimum inhibitory concentration (MIC) values of 25 μM, respectively. Compounds 4 and 5 had the best inhibition against A. solani and B. cinerea, better than the positive control, hymexazol. Remarkably, compound 6 inhibited α-glucosidase with IC₅₀ value of 160 μM, outperforming acarbose by 12-fold. Enzyme reaction kinetics and molecular docking were used to investigate potential α-glucosidase inhibition mechanisms. Moreover, compound 7 exhibited moderate cytotoxicity against HeLa cells (IC₅₀ = 15.27 ± 0.72 μM), more active than etoposide. Consequently, the results provide a solid foundation for developing bioactive metabolites of C. tenuissimum.

Acidic-environment targeting peptides (AEPs), which insert into cell membranes under acidic conditions, have been gaining attention as potential targeting ligands for acidic tissues such as tumors. Conventional AEPs have been taken from archaea or designed rationally; therefore, they have a risk of antigenicity. Here, we propose screening for AEPs from the human proteome. AEP candidates were screened from more than 20000 human proteome transmembrane peptides based on 4 conditions AEPs should fulfill. Twenty-seven peptides were found to satisfy the four conditions. The same number of candidate peptides were identified in the mouse membrane proteome, most of which originated from the orthologous membrane proteins identified in the human proteome. Four of the 27 peptides selected from the human proteome were synthesized with a fluorescence label attached or expressed as fusion proteins with green fluorescent protein to examine their acid-responsive accumulation in vitro and in vivo. We found that 1 of the 4 peptides performed similarly to the pH-low insertion peptide, the first reported AEP.

To enhance the efficacy of magnetic resonance imaging (MRI), numerous novel contrast agents have been developed, with peptide modification emerging as a promising strategy. The versatility of peptides renders them particularly useful molecules for the fabrication of new molecule. However, the influence of peptide side chain modification on the imaging performance of contrast agents has not been fully explored in existing studies. Herein, we employed XK (ε-DOTA-Gd) X as a Gd-DOTA-peptide template and the X molecule underwent amino acid block substitution. Six Gd-DOTA-peptide complexes were synthesized and their properties, such as relaxivity, biostability, and biocompatibility, were measured and in vitro MRI assays were carried out. The results demonstrated that the Gd-DOTA-peptides exhibited low hemolysis rates and cytotoxicity. In plasma, the half-lives of the Gd-DOTA-peptide contrast agents exceeded 5 h. Relaxation experiments revealed that the Gd-DOTA-peptide achieved a slightly higher relaxation rate compared with the commercial agent Dotarem. Therefore, the amino acid modularize modification on the gadolinium-based MRI contrast agents were effective and worthy of further investigation.

Targeted protein degradation (TPD) has emerged as an innovative technology in drug development. In this manuscript, we evaluated LJH685 (an RSK2 ligand) and proteolysis targeting chimeras (PROTACs) based on LJH685 as the first degrader targeting ribosomal S6 kinase 2 (RSK2), a serine/threonine kinase associated with cancer progression. LJH685 decreased total RSK2 via the ubiquitin–proteasome system (UPS) in human multiple myeloma cell lines (HMCLs). Four LJH685-based PROTACs, composed of pomalidomide (a cereblon E3 ligase ligand) and different lengths of polyethylene glycol (PEG) linkers, decreased both total RSK2 and phosphorylated RSK2^Ser227 levels in HMCLs. Among these, PROTAC 2, which features 1 PEG unit as a linker, demonstrated the strongest degradation using cereblon (CRBN) and UPS and anti-proliferative activity, which were comparable to those of LJH685. Molecular docking simulations further supported these findings, revealing that PROTACs with PEG linkers formed stable ternary complexes with RSK2 and CRBN, whereas the linkerless PROTAC, which showed lower activity, was unable to form an appropriate complex. These results emphasize the critical role of linker length in optimizing PROTAC efficacy for targeting RSK2. Future exploration of diverse E3 ligases could enable optimization of PROTAC selectivity.

The asymmetric α-regioselective conjugate addition of 2-thienylacetones to nitrostyrenes was achieved using a tertiary amine–thiourea organocatalyst, affording the α-addition products in high yields with excellent stereoselectivities. This study provides the first demonstration of an asymmetric α-regioselective conjugate addition of 2-thienylacetones to nitroalkenes.

Cell-penetrating peptides (CPPs) have been widely applied as carriers in drug delivery systems (DDS) capable of transporting diverse biomolecules, including nucleic acids and highly hydrophilic low-molecular-weight compounds, into cells. Amphipathic CPPs composed of arginine and the α,α-disubstituted amino acid Aib (2-aminoisobutyric acid) have been investigated for their potential application as carrier peptides. In addition, the incorporation of d-amino acids into CPPs has been utilized as a strategy to confer resistance against proteolytic degradation, which is one of the major challenges associated with CPPs. In this study, we evaluated the structure, membrane permeability, and plasmid DNA (pDNA) delivery capability of (Arg–Arg–Aib)_n peptides with different combinations of l/d-Arg residues. Secondary structures were analyzed by circular dichroism (CD) spectroscopy, and their correlation with membrane permeability was examined. Consequently, α-helical peptides exhibited enhanced membrane permeability with increasing peptide chain length. In comparison between the same chain length of α-helical peptides and random-coil peptides, the difference in membrane permeabilities decreased as the peptide chain length increased. Notably, the peptide (l-Arg–d-Arg–Aib)₄ exhibited the highest protease resistance despite containing l-Arg residues and demonstrated pDNA transfection efficiency comparable to that of an α-helical peptide composed entirely of d-Arg residues. Optimization of l/d-Arg combinations for membrane permeability and gene delivery efficiency in (Arg–Arg–Aib)_n is useful for rationally designing amphipathic CPPs with l/d-amino acids.

Artemisinin derivatives (ARTs) induce ferrous iron-dependent cell death (ferroptosis) by generating free radicals. Polymer-ARTs conjugates would be advantageous for cancer therapy. In this paper, we designed and synthesized the three types of ART-conjugated novel methacrylamide derivatives with or without a spacer between the aromatic group and the methacrylamide moiety for mechanochemical solid-state polymerization. The polymer conversion rate of ART-ethyl-MA and ART-methyl-MA for 90 min polymerization was achieved at 78 and 49%, respectively. However, ART-MA, which does not have a spacer, could not polymerize owing to the lowest unoccupied molecular orbital (LUMO) expanding from the methacrylamide moiety to the aromatic sites. The resulting poly(ART-ethyl-MA) produced the thermodynamically stable end-chain radicals through the main-chain scission via mechanical energy, and the generated mechanoradicals would play a role as an initiator of the surrounding monomers. The biocompatible sulfobetaine polymer-ARTs conjugates were fabricated through the mechanochemical solid-state copolymerization of sulfobetaine methacrylate (SBMA) and ART-ethyl-MA. The number average molecular weight and heterogeneity of the resulting water-soluble PSBMA-ARTs conjugates were 8000 g mol^–1 and 1.10, respectively. These results suggest that the design of solid monomers suitable for mechanochemical solid-state polymerization would require a molecular structure susceptible to single solid-state electron transfer (SSET) and the stability of mechanoradicals generated by the main-chain scission of resulting polymer. The mechanochemical solid-state copolymerization of zwitterionic monomer and hydrophobic monomer would be advantageous for the development of biocompatible polymer–drug conjugates.

Highly strained small-ring heterocycles have recently attracted considerable attention as three-dimensional alternatives to planar aromatic motifs in medicinal chemistry. Among these, 1-azabicyclo[1.1.0]butanes (ABBs) represent an exceptionally compact nitrogen-containing scaffold with potential utility as precursors to heterocyclic bioisosteres. Nevertheless, general and modular synthetic approaches to ABBs remain scarce. Herein, we report a concise three-step route to C3-substituted ABBs from readily accessible azetidinones. Central to this strategy is an intramolecular 3-exo-tet cyclization triggered by deprotonation with organolithium reagents, proceeding efficiently at low temperature. The method accommodates a broad range of aryl substituents with diverse electronic properties. In addition, vinyl chloride-containing substrates undergo tandem cyclization and elimination, enabling direct access to previously unreported alkynyl-substituted ABBs. Although ABB formation is highly efficient, the resulting compounds exhibit limited stability, leading to rapid decomposition during purification. To clarify the factors governing this behavior, density functional theory (DFT) calculations were performed. Comparison of strain and protonation energies across a series of ABB derivatives revealed that differences in intrinsic ring strain are minimal and cannot account for the observed instability. Instead, protonation energy calculations suggest that protonation promotes heterolytic cleavage of the central C–N bond, generating a benzylic cation whose stability is strongly influenced by substituent electronics. A pronounced linear correlation between calculated protonation energies and Hammett σ parameters supports a dominant role of resonance stabilization.

The copper-catalyzed azide–alkyne cycloaddition (CuAAC) is a representative click reaction with practical applications in various fields, including medicinal chemistry. Its product, 1,4-disubstituted triazoles, has an elongated, rod-like shape. The continued proliferation of 1,4-disubstituted triazole-based drug candidates is concerning because existing bioactive compounds are heavily biased toward rod-like shapes with limited structural diversity, even though three-dimensional compounds generally possess more favorable druglike properties. Replacing this triazole ring with a 1,5-disubstituted counterpart is expected to bend the molecular shape and address these limitations. Here, to evaluate this possibility, we constructed a new library in which the triazole rings of our previously established 7-azanorbornane-based 1,4-disubstituted triazole library were replaced with 1,5-disubstituted counterparts. We then assessed the effects of this change on molecular shape, aqueous solubility, and membrane permeability. Ruthenium-catalyzed azide–alkyne cycloaddition (RuAAC), the most common synthetic method for 1,5-disubstituted triazoles, failed to produce the designed compounds, likely due to steric hindrance around the bicyclic scaffold. We therefore employed the reaction between acetylides and azides, which is relatively tolerant to steric hindrance, and successfully obtained the target 1,5-disubstituted triazoles, although not all designed compounds were produced. The 1,5-disubstituted triazoles synthesized here exhibited more three-dimensional shapes, greater structural diversity, and improved aqueous solubility than their 1,4-disubstituted counterparts, although no clear difference was observed in membrane permeability. These results suggest that replacing the triazole rings in CuAAC-derived libraries with 1,5-disubstituted counterparts is a promising strategy to construct libraries that exhibit greater three-dimensional structural diversity, and are more soluble in aqueous media.

α-Silyl alcohols serve as versatile building blocks in organic synthesis. Despite their broad utility, efficient methods for their preparation remain limited. Although the nucleophilic addition of silyllithium reagents acting as silyl anion equivalents to carbonyl compounds offers a straightforward route to α-silyl alcohols, detailed investigations on the preparation of highly basic and inherently unstable trialkylsilyllithium reagents, as well as the scope of compatible carbonyl substrates, remain scarce. In this study, we report an efficient and environmentally benign method for the generation of trimethylsilyllithium and demonstrate its application to the synthesis of α-silyl alcohols from a range of carbonyl compounds.