Insights into the selectivity of polar stationary phases based on quantitative retention mechanism assessment in hydrophilic interaction chromatography.

Hydrophilic interaction chromatography (HILIC) offers different selectivity than reversed-phase liquid chromatography (RPLC). However, our knowledge of the driving force for selectivity is limited and there is a need for a better understanding of the selectivity in HILIC. Quantitative assessment of retention mechanisms makes it possible to investigate selectivity based on understanding the underlying retention mechanisms. In this study, selected model compounds from the Ikegami selectivity tests were evaluated on different polar stationary phases. The study results revealed significant insights into the selectivity in HILIC. First, hydroxy and methylene selectivity is driven by hydrophilic partitioning; but surface adsorption for 2-deoxyuridine or 5-methyluridine reduces the selectivity factor. Furthermore, the retention of 2-deoxyuridine or 5-methyluridine by surface adsorption in combination with the phase ratio explain the difference in hydroxy or methylene selectivity observed among different stationary phases. Investigations on xanthine positional isomers (1-methylxanthine/3-methylxanthine, theophylline/theobromine) indicate that isomeric selectivity is controlled by surface adsorption; however, hydrophilic partitioning may contribute to resolution by enhancing overall retention. In addition, two pairs of nucleoside isomers (adenosine/vidarabine, 2'-deoxy and 3'-deoxyguanosine) provide an example that isomeric selectivity can also be controlled by hydrophilic partitioning if their partitioning coefficients are significantly different in HILIC. Although more data is needed, the current study provides a mechanistic based understanding of the selectivity in HILIC and potentially a new way to design selectivity tests.

Unraveling the structure-chirality sensing relationship between achiral anthracene-based tetracationic nanotubes and nucleosides in aqueous host-guest complexation.

In biological systems, nucleosides play crucial roles in various physiological processes. In this study, we designed and synthesized four achiral anthracene-based tetracationic nanotubes (1-4) as artificial hosts and chiroptical sensors for nucleosides in aqueous media. Notably, different nanotubes exhibit varied chirality sensing on circular dichroism (CD)/circularly polarized luminescence (CPL) spectra through the host-guest complexation, which prompted us to explore the factors influencing their chiroptical responses. Through systematic host-guest experiments, the structure-chirality sensing relationship between achiral anthracene-based tetracationic nanotubes and nucleosides in the host-guest complexation was unraveled. Firstly, the CD response originates from the anthracene rings situated at the side-wall position, resulting from the right-handed (P)- or left-handed (M)-twisted conformation of the macrocyclic structure. Secondly, the CPL signal is influenced by the presence of anthracene rings at the linking-wall position, which results from intermolecular chiral twisted stacking between these anthracene rings. Therefore, these nanotubes can serve as chiroptical sensor arrays to enhance the accuracy of nucleotide recognition through principal component analysis (PCA) analysis based on the diversified CD spectra. This study provides insights for the construction of adaptive chirality from achiral nanotubes with dynamic conformational nature and might facilitate further design of chiral functional materials for several applications.

Friedel-Crafts reactions for biomolecular chemistry.

Chemical tools and principles have become central to biological and medical research/applications by leveraging a range of classical organic chemistry reactions. Friedel-Crafts alkylation and acylation are arguably some of the most well-known and used synthetic methods for the preparation of small molecules but their use in biological and medical fields is relatively less frequent than the other reactions, possibly owing to the notion of their plausible incompatibility with biological systems. This review demonstrates advances in Friedel-Crafts alkylation and acylation reactions in a variety of biomolecular chemistry fields. With the discoveries and applications of numerous biomolecule-catalyzed or -assisted processes, these reactions have garnered considerable interest in biochemistry, enzymology, and biocatalysis. Despite the challenges of reactivity and selectivity of biomolecular reactions, the alkylation and acylation reactions demonstrated their utility for the construction and functionalization of all the four major biomolecules (i.e., nucleosides, carbohydrates/saccharides, lipids/fatty acids, and amino acids/peptides/proteins), and their diverse applications in biological, medical, and material fields are discussed. As the alkylation and acylation reactions are often fundamental educational components of organic chemistry courses, this review is intended for both experts and nonexperts by discussing their basic reaction patterns (with the depiction of each reaction mechanism in the ESI) and relevant real-world impacts in order to enrich chemical research and education. The significant growth of biomolecular Friedel-Crafts reactions described here is a testament to their broad importance and utility, and further development and investigations of the reactions will surely be the focus in the organic biomolecular chemistry fields.

Discovery of C-Linked Nucleoside Analogues with Antiviral Activity against SARS-CoV-2.

The recent COVID-19 pandemic underscored the limitations of currently available direct-acting antiviral treatments against acute respiratory RNA-viral infections and stimulated major research initiatives targeting anticoronavirus agents. Two novel nsp5 protease (MPro) inhibitors have been approved, nirmatrelvir and ensitrelvir, along with two existing nucleos(t)ide analogues repurposed as nsp12 polymerase inhibitors, remdesivir and molnupiravir, but a need still exists for therapies with improved potency and systemic exposure with oral dosing, better metabolic stability, and reduced resistance and toxicity risks. Herein, we summarize our research toward identifying nsp12 inhibitors that led to nucleoside analogues 10e and 10n, which showed favorable pan-coronavirus activity in cell-infection screens, were metabolized to active triphosphate nucleotides in cell-incubation studies, and demonstrated target (nsp12) engagement in biochemical assays.

Access to Reverse Glycosyl Azides and Rare Sugar-Based Glycosyl Azides via Radical Decarboxylative Azidation: Divergent Synthesis of 4'-C-Azidonucleosides as Potential Antiviral Agents.

The radical decarboxylative azidation of structurally diverse uronic acids has been established as an efficient approach to reverse glycosyl azides and rare sugar-derived glycosyl azides under the action of Ag2CO3, 3-pyridinesulfonyl azide, and K2S2O8. The power of this method has been highlighted by the divergent synthesis of 4'-C-azidonucleosides using Vorbrüggen glycosylation of nucleobases with 4-C-azidofuranosyl acetates. The antiviral assessment of the resulting nucleosides revealed one compound as a potential inhibitor of covalently closed circular DNA.

Isomorphic Fluorescent Nucleosides.

ConspectusIn 1960, Weber prophesied that "There are many ways in which the properties of the excited state can be utilized to study points of ignorance of the structure and function of proteins". This has been realized, illustrating that an intrinsic and highly responsive fluorophore such as tryptophan can alter the course of an entire scientific discipline. But what about RNA and DNA? Adapting Weber's protein photophysics prophecy to nucleic acids requires the development of intrinsically emissive nucleoside surrogates as, unlike Trp, the canonical nucleobases display unusually low emission quantum yields, which render nucleosides, nucleotides, and oligonucleotides practically dark for most fluorescence-based applications.Over the past decades, we have developed emissive nucleoside surrogates that facilitate the monitoring of nucleoside-, nucleotide-, and nucleic acid-based transformations at a nucleobase resolution in real time. The premise underlying our approach is the identification of minimal atomic/structural perturbations that endow the synthetic analogs with favorable photophysical features while maintaining native conformations and pairing. As illuminating probes, the photophysical parameters of such isomorphic nucleosides display sensitivity to microenvironmental factors. Responsive isomorphic analogs that function similarly to their native counterparts in biochemical contexts are defined as isofunctional.Early analogs included pyrimidines substituted with five-membered aromatic heterocycles at their 5 position and have been used to assess the polarity of the major groove in duplexes. Polarized quinazolines have proven useful in assembling FRET pairs with established fluorophores and have been used to study RNA-protein and RNA-small-molecule binding. Completing a fluorescent ribonucleoside alphabet, composed of visibly emissive purine (thA, thG) and pyrimidine (thU, thC) analogs, all derived from thieno[3,4-d]pyrimidine as the heterocyclic nucleus, was a major breakthrough. To further augment functionality, a second-generation emissive RNA alphabet based on an isothiazolo[4,3-d]pyrimidine core (thA, tzG, tzU, and tzC) was fabricated. This single-atom "mutagenesis" restored the basic/coordinating nitrogen corresponding to N7 in the purine skeleton and elevated biological recognition.The isomorphic emissive nucleosides and nucleotides, particularly the purine analogs, serve as substrates for diverse enzymes. Beyond polymerases, we have challenged the emissive analogs with metabolic and catabolic enzymes, opening optical windows into the biochemistry of nucleosides and nucleotides as metabolites as well as coenzymes and second messengers. Real-time fluorescence-based assays for adenosine deaminase, guanine deaminase, and cytidine deaminase have been fabricated and used for inhibitor discovery. Emissive cofactors (e.g., SthAM), coenzymes (e.g., NtzAD+), and second messengers (e.g., c-di-tzGMP) have been enzymatically synthesized, using xyNTPs and native enzymes. Both their biosynthesis and their transformations can be fluorescently monitored in real time.Highly isomorphic and isofunctional emissive surrogates can therefore be fabricated and judiciously implemented. Beyond their utility, side-by-side comparison to established analogs, particularly to 2-aminopurine, the workhorse of nucleic acid biophysics over 5 decades, has proven prudent as they refined the scope and limitations of both the new analogs and their predecessors. Challenges, however, remain. Associated with such small heterocycles are relatively short emission wavelengths and limited brightness. Recent advances in multiphoton spectroscopy and further structural modifications have shown promise for overcoming such barriers.

Reaction sites of pyrimidine bases and nucleosides during chlorination: A computational study.

As important components of soluble microbial products in water, nucleobases have attracted much attention due to the high toxicity of their direct aromatic halogenated disinfection by-products (AH-DBPs) during chlorination. However, multiple halogenation sites of AH-DBPs pose challenges to identify them. In this study, reaction sites of pyrimidine bases and nucleosides during chlorination were investigated by quantum chemical computational method. The results indicate that the anion salt forms play key roles in chlorination of uracil, thymine, and their nucleosides, while neutral forms make predominant contributions to cytosine and cytidine. In view of both kinetics and thermodynamics, C5 is the most reactive site for uracil and thymine, N3/C5 and N3 for respective uridine and thymidine, N1/C5/N4 and N4 for respective cytosine and cytidine, whose estimated apparent rate constants kobs-est of ∼103, 103/102, 106/102/104, and 103 M-1 s-1, respectively, in consistent with the known experimental results. C6 in all pyrimidine compounds is hardly attacked by Cl+ in HOCl ascribed to its positive charge, but readily attacked by OH‾ in hydrolysis and the N1=C6 bond was found to possess the highest reactivity in hydrolysis among all double bonds. In addition, the structure-kinetic reactivity relationship study reveals a relatively strong correlation between lgkobs-est and APT charge in all pyrimidine compounds rather than FED2 (HOMO). The results are helpful to further understand the reactivity of various reaction sites in aromatic compounds during chlorination.

Identification of reaction sites and chlorinated products of purine bases and nucleosides during chlorination: a computational study.

Hypochlorous acid (HOCl) released from activated leukocytes plays a significant role in the human immune system, but is also implicated in numerous diseases due to its inappropriate production. Chlorinated nucleobases induce genetic changes that potentially enable and stimulate carcinogenesis, and thus have attracted considerable attention. However, their multiple halogenation sites pose challenges to identify them. As a good complement to experiments, quantum chemical computation was used to uncover chlorination sites and chlorinated products in this study. The results indicate that anion salt forms of all purine compounds play significant roles in chlorination except for adenosine. The kinetic reactivity order of all reaction sites in terms of the estimated apparent rate constant kobs-est (in M-1 s-1) is heterocyclic NH/N (102-107) > exocyclic NH2 (10-2-10) > heterocyclic C8 (10-5-10-1), but the order is reversed for thermodynamics. Combining kinetics and thermodynamics, the numerical simulation results show that N9 is the most reactive site for purine bases to form the main initial chlorinated product, while for purine nucleosides N1 and exocyclic N2/N6 are the most reactive sites to produce the main products controlled by kinetics and thermodynamics, respectively, and C8 is a possible site to generate the minor product. The formation mechanisms of biomarker 8-Cl- and 8-oxo-purine derivatives were also investigated. Additionally, the structure-kinetic reactivity relationship study reveals a good correlation between lg kobs-est and APT charge in all purine compounds compared to FED2 (HOMO), which proves again that the electrostatic interaction plays a key role. The results are helpful to further understand the reactivity of various reaction sites in aromatic compounds during chlorination.

Halo-1,2,3-triazoles: Valuable Compounds to Access Biologically Relevant Molecules.

1,2,3-triazole is an important building block in organic chemistry. It is now well known as a bioisostere for various functions, such as the amide or the ester bond, positioning it as a key pharmacophore in medicinal chemistry and it has found applications in various fields including life sciences. Attention was first focused on the synthesis of 1,4-disubstituted 1,2,3-triazole molecules however 1,4,5-trisubstituted 1,2,3-triazoles have now emerged as valuable molecules due to the possibility to expand the structural modularity. In the last decade, methods mainly derived from the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction have been developed to access halo-triazole compounds and have been applied to nucleosides, carbohydrates, peptides and proteins. In addition, late-stage modification of halo-triazole derivatives by metal-mediated cross-coupling or halo-exchange reactions offer the possibility to access highly functionalized molecules that can be used as tools for chemical biology. This review summarizes the synthesis, the functionalization, and the applications of 1,4,5-trisubstituted halo-1,2,3-triazoles in biologically relevant molecules.

Design, synthesis and biological evaluation of aryloxy thiophosphoramidate triesters of anticancer nucleoside analogues.

Aryloxy phosphoroamidate triesters, known as ProTides, are a class of prodrugs developed to enhance the physicochemical and pharmacological properties of therapeutic nucleosides. This approach has been extensively investigated in the antiviral and anticancer areas leading to three prodrugs on the market and several others in clinical stage. In this article we have prepared the PS analogues of three ProTides that have reached the clinic as anticancer agents. These novel PS ProTides were tested for their capacity in enzymatic activation and for their cytotoxic properties against a panel of solid and liquid tumor cell lines. As expected, the replacement of the PO with a PS bond led to increased metabolic stability albeit concomitant to a decrease in potency. Surprisingly, the intermediate formed after the first activation step of a thiophosphoramidate with carboxypeptidase Y is not the expected PS aminoacyl product but the corresponding PO aminoacyl compound.

Tissue distribution of metabolites in Cordyceps cicadae determined by DESI-MSI analysis.

In this paper, we establish an in situ visualization analysis method to image the spatial distribution of metabolites in different parts (sclerotium, coremium) and different microregions of Cordyceps cicadae (C. cicadae) to achieve the in situ visual characterization of tissues for a variety of metabolites such as nucleosides, amino acids, polysaccharides, organic acids, fatty acids, and so on. The study included LC-MS chemical composition identification, preparation of C. cicadae tissue sections, DEDI-MSI analysis, DESI combined with Q-TOF/MS to obtain high-resolution imaging of mass-to-charge ratio and space, imaging of C. cicadae in positive-negative ion mode with a spatial resolution of 100 µm, and localizing and identifying its chemical compositions based on its precise mass. A total of 62 compounds were identified; nucleosides were mainly distributed in the coremium, L-threonine and DL-isoleucine, and other essential amino acids; peptides were mainly distributed in the sclerotium of C. cicadae; and the rest of the amino acids did not have a clear pattern; sugars and sugar alcohols were mainly distributed in the coremium of C. cicadae; organic acids and fatty acids were distributed in the nucleus of C. cicadae more than in the sclerotium, and the mass spectrometry imaging method is established in the research. The mass spectrometry imaging method established in this study is simple and fast and can visualize and analyse the spatial distribution of metabolites of C. cicadae, which is of great significance in characterizing the metabolic network of C. cicadae, and provides support for the quality evaluation of C. cicadae and the study of the temporal and spatial metabolic network of chemical compounds.

Properties and synergistic effects of a nonionic backbone and aminoalkyl modified nucleosides in RNAs.

In this study, we report the synthesis of two formacetal (FA)-linked dimer building blocks, namely 2'-O-methyluridyl-2'-O-methyluridine and 2'-O-methyluridyl-2'-O-aminoethyluridine. We utilize the former dimer in combination with (S)-5'-C-aminopropyl-2'-O-methylnucleosides (5'-APs) as a neutral trimer unit, and the latter dimer as a cationic unit. Double-stranded RNA containing the neutral trimer unit exhibits greater stability compared to the cationic unit and maintains nuclease stability in a serum-containing buffer. Furthermore, this unit appears to establish additional hydrogen bonds with complementary bases, as supported by modeling simulations and mismatch melting temperature assays. Importantly, siRNAs modified with this unit enhance RNA interference activity in cultured cells. These findings suggest that the trimer unit holds promise for therapeutic siRNAs.

1H-1,2,3-triazolyl-1,6-naphthyridin-7(6H)-ones as Potential Fluorescent Nucleoside Analogues: Synthesis and Optical Properties.

In this article, we present the synthesis and the optical properties of three original molecules as potential fluorescent ribonucleoside analogues incorporating a 1,6-naphthyridin-7(6H)-one scaffold as a fluorescent nucleobase and a 1,2,3-triazole as a linkage. The nucleosides were prepared via a Cu alkyne-azide cycloaddition (CuAAC) reaction between a ribofuranosyl azide and a 4-ethynylpyridine partner. Construction of substituted 1,6-naphthyridin-7(6H)-ones was achieved through two additional steps. Optical property studies were investigated on nucleoside analogues. Powerful fluorescence properties have been evidenced with a remarkable change of emissivity depending on the polarity of the solvent, making these molecules suitable as a new class of artificial fluorescent nucleosides for investigating enzyme binding sites as well as probing nucleic acids. In addition, we are convinced that such analogues could be of great interest in the search for new antiviral or antitumoral drugs based on nucleosides.

Synthesis and Enzymatic Incorporation of a Dual-App Nucleotide Probe That Reports Antibiotics-Induced Conformational Change in the Bacterial Ribosomal Decoding Site RNA.

Natural nucleosides are nonfluorescent and do not have intrinsic labels that can be readily utilized for analyzing nucleic acid structure and recognition. In this regard, researchers typically use the so-called "one-label, one-technique" approach to study nucleic acids. However, we envisioned that a responsive dual-app nucleoside system that harnesses the power of two complementing biophysical techniques namely, fluorescence and 19F NMR, will allow the investigation of nucleic acid conformations more comprehensively than before. We recently introduced a nucleoside analogue by tagging trifluoromethyl-benzofuran at the C5 position of 2'-deoxyuridine, which serves as an excellent fluorescent and 19F NMR probe to study G-quadruplex and i-motif structures. Taking forward, here, we report the development of a ribonucleotide version of the dual-app probe to monitor antibiotics-induced conformational changes in RNA. The ribonucleotide analog is derived by conjugating trifluoromethyl-benzofuran at the C5 position of uridine (TFBF-UTP). The analog is efficiently incorporated by T7 RNA polymerase to produce functionalized RNA transcripts. Detailed photophysical and 19F NMR of the nucleoside and nucleotide incorporated into RNA oligonucleotides revealed that the analog is structurally minimally invasive and can be used for probing RNA conformations by fluorescence and 19F NMR techniques. Using the probe, we monitored and estimated aminoglycoside antibiotics binding to the bacterial ribosomal decoding site RNA (A-site, a very important RNA target). While 2-aminopurine, a famous fluorescent nucleic acid probe, fails to detect structurally similar aminoglycoside antibiotics binding to the A-site, our probe reports the binding of different aminoglycosides to the A-site. Taken together, our results demonstrate that TFBF-UTP is a very useful addition to the nucleic acid analysis toolbox and could be used to devise discovery platforms to identify new RNA binders of therapeutic potential.

Antiviral Activity of Lipophilic Nucleoside Tetraphosphate Compounds.

We report on the synthesis and characterization of three types of nucleoside tetraphosphate derivatives 4-9 acting as potential prodrugs of d4T nucleotides: (i) the δ-phosph(on)ate is modified by two hydrolytically stable alkyl residues 4 and 5; (ii) the δ-phosph(on)ate is esterified covalently by one biodegradable acyloxybenzyl moiety and a nonbioreversible moiety 6 and 7; or (iii) the δ-phosphate of nucleoside tetraphosphate is masked by two biodegradable prodrug groups 8 and 9. We were able to prove the efficient release of d4T triphosphate (d4TTP, (i)), δ-monoalkylated d4T tetraphosphates (20 and 24, (ii)), and d4T tetraphosphate (d4T4P, (iii)), respectively, by chemical or enzymatic processes. Surprisingly, δ-dialkylated d4T tetraphosphates, δ-monoalkylated d4T tetraphosphates, and d4T4P were substrates for HIV-RT. Remarkably, the antiviral activity of TetraPPPPro-prodrug 7 was improved by 7700-fold (SI 5700) as compared to the parent d4T in CEM/TK- cells, denoting a successful cell membrane passage of these lipophilic prodrugs and an intracellular delivery of the nucleotide metabolites.

Synthesis of Boron-Containing Nucleoside Analogs.

Over the last century, nucleoside-based therapeutics have demonstrated remarkable effectiveness in the treatment of a wide variety of diseases from cancer to HIV. In addition, boron-containing drugs have recently emerged as an exciting and fruitful avenue for medicinal therapies. However, borononucleosides have largely been unexplored in the context of medicinal applications. Herein, we report the synthesis, isolation, and characterization of two novel boron-containing nucleoside compound libraries which may find utility as therapeutic agents. Our synthetic strategy employs efficient one-step substitution reactions between a diverse variety of nucleoside scaffolds and an assortment of n-alkyl potassium trifluoroborate-containing electrophiles. We demonstrated that these alkylation reactions are compatible with cyclic and acyclic nucleoside substrates, as well as increasing alkyl chain lengths. Furthermore, regioselective control of product formation can be readily achieved through manipulation of base identity and reaction temperature conditions.

Stereocontrolled access to thioisosteres of nucleoside di- and triphosphates.

Nucleoside diphosphates and triphosphates impact nearly every aspect of biochemistry; however, the use of such compounds as tools or medicinal leads for nucleotide-dependent enzymes and receptors is hampered by their rapid in vivo metabolism. Although a successful strategy to address the instability of the monophosphate moiety in oligonucleotide therapeutics has been accomplished by their isosteric replacement with phosphorothioates, no practical methods exist to rapidly and controllably access stereopure di- and triphosphate thioisosteres of both natural and unnatural nucleosides. Here we show how a modular, reagent-based platform can enable the stereocontrolled and scalable synthesis of a library of such molecules. This operationally simple approach provides access to pure stereoisomers of nucleoside α-thiodiphosphates and α-thiotriphosphates, as well as symmetrical or unsymmetrical dinucleoside thiodiphosphates and thiotriphosphates (including RNA cap reagents). We demonstrate that ligand-receptor interactions can be dramatically influenced by P-stereochemistry, showing that such thioisosteric replacements can have profound effects on the potency and stability of lead candidates.

Stabilizing Pseudouridimycin: Synthesis, RNA Polymerase Inhibitory Activity, and Antibacterial Activity of Dipeptide-Modified Analogues.

Pseudouridimycin (PUM) is a microbially produced C-nucleoside dipeptide that selectively targets the nucleotide addition site of bacterial RNA polymerase (RNAP) and that has a lower rate of spontaneous resistance emergence relative to current drugs that target RNAP. Despite its promising biological profile, PUM undergoes relatively rapid decomposition in buffered aqueous solutions. Here, we describe the synthesis, RNAP-inhibitory activity, and antibacterial activity of chemically stabilized analogues of PUM. These analogues feature targeted modifications that mitigate guanidine-mediated hydroxamate bond scission. A subset of analogues in which the central hydroxamate is replaced with amide or hydrazide isosteres retain the antibacterial activity of the natural product.

Research Progress on hCNT3 Structure/Function and Nucleoside Anticancer Drugs.

Membrane protein human concentrative nucleoside transporter 3 (hCNT3) can not only transport extracellular nucleosides into the cell but also transport various nucleoside-derived anticancer drugs to the focus of infection for therapeutic effects. Typical nucleoside anticancer drugs, including fludarabine, cladabine, decitabine, and clofarabine, are recognized by hCNT3 and then delivered to the lesion site for their therapeutic effects. hCNT3 is highly conserved during the evolution from lower to higher vertebrates, which contains scaffold and transport domains in structure and delivers substrates by coupling with Na+ and H+ ions in function. In the process of substrate delivery, the transport domain rises from the lower side of transmembrane 9 (TM9) in the inward conformation to the upper side of the outward conformation, accompanied by the collaborative motion of TM7b/ TM4b and hairpin 1b (HP1b)/ HP2b. With the report of a series of three-dimensional structures of homologous CNTs, the structural characteristics and biological functions of hCNT3 have attracted increasing attention from pharmacists and biologists. Our research group has also recently designed an anticancer lead compound with high hCNT3 transport potential based on the structure of 5-fluorouracil. In this work, the sequence evolution, conservation, molecular structure, cationic chelation, substrate recognition, elevator motion pattern and nucleoside derivative drugs of hCNT3 were reviewed, and the differences in hCNT3 transport mode and nucleoside anticancer drug modification were summarized, aiming to provide theoretical guidance for the subsequent molecular design of novel anticancer drugs targeting hCNT3.

Is it still worth renewing nucleoside anticancer drugs nowadays?

Nucleoside has situated the convergence point in the discovery of novel drugs for decades, and a large number of nucleoside derivatives have been constructed for screening novel pharmacological properties at various experimental platforms. Notably, nearly 20 nucleosides are approved to be used in the clinic treatment of various cancers. Nevertheless, the blossom of synthetic nucleoside analogs in comparison with the scarcity of nucleoside anticancer drugs leads to a question: Is it still worth insisting on the screening of novel anticancer drugs from nucleoside derivatives? Hence, this review attempts to emphasize the importance of nucleoside analogs in the discovery of novel anticancer drugs. Firstly, we introduce the metabolic procedures of nucleoside anticancer drug (such as 5-fluorouracil) and summarize the designing of novel nucleoside anticancer candidates based on clinically used nucleoside anticancer drugs (such as gemcitabine). Furthermore, we collect anticancer properties of some recently synthesized nucleoside analogs, aiming at emphasizing the availability of nucleoside analogs in the discovery of anticancer drugs. Finally, a variety of synthetic strategies including the linkage of sugar moiety with nucleobase scaffold, modifications on the sugar moiety, and variations on the nucleobase structure are collected to exhibit the abundant protocols in the achievement of nucleoside analogs. Taken the above discussions collectively, nucleoside still advantages for the finding of novel anticancer drugs because of the clearly metabolic procedures, successfully clinic applications, and abundantly synthetic routines.