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Molecules (Basel, Switzerland) Apr 2020Nucleoside analogues have proven to be highly successful chemotherapeutic agents in the treatment of a wide variety of cancers. Several such compounds, including... (Review)
Review
Nucleoside analogues have proven to be highly successful chemotherapeutic agents in the treatment of a wide variety of cancers. Several such compounds, including gemcitabine and cytarabine, are the go-to option in first-line treatments. However, these materials do have limitations and the development of next generation compounds remains a topic of significant interest and necessity. Herein, we discuss recent advances in the chemical synthesis and biological evaluation of nucleoside analogues as potential anticancer agents. Focus is paid to 4'-heteroatom substitution of the furanose oxygen, 2'-, 3'-, 4'- and 5'-position ring modifications and the development of new prodrug strategies for these materials.
Topics: Adenosine; Animals; Antineoplastic Agents; Cell Line, Tumor; Drug Design; Drug Screening Assays, Antitumor; Furans; Humans; K562 Cells; Mice; Molecular Structure; Nucleosides; Oxygen; Prodrugs; Purine Nucleosides; Pyrimidinones; Thionucleosides; Vitamin E
PubMed: 32354007
DOI: 10.3390/molecules25092050 -
Nature Communications Jun 2021Methylation is a prevalent post-transcriptional modification encountered in coding and non-coding RNA. For RNA methylation, cells use methyltransferases and small...
Methylation is a prevalent post-transcriptional modification encountered in coding and non-coding RNA. For RNA methylation, cells use methyltransferases and small organic substances as methyl-group donors, such as S-adenosylmethionine (SAM). SAM and other nucleotide-derived cofactors are viewed as evolutionary leftovers from an RNA world, in which riboswitches have regulated, and ribozymes have catalyzed essential metabolic reactions. Here, we disclose the thus far unrecognized direct link between a present-day riboswitch and its inherent reactivity for site-specific methylation. The key is O-methyl pre-queuosine (mpreQ), a potentially prebiotic nucleobase which is recognized by the native aptamer of a preQ class I riboswitch. Upon binding, the transfer of the ligand's methyl group to a specific cytidine occurs, installing 3-methylcytidine (mC) in the RNA pocket under release of pre-queuosine (preQ). Our finding suggests that nucleic acid-mediated methylation is an ancient mechanism that has offered an early path for RNA epigenetics prior to the evolution of protein methyltransferases. Furthermore, our findings may pave the way for the development of riboswitch-descending methylation tools based on rational design as a powerful alternative to in vitro selection approaches.
Topics: Aptamers, Nucleotide; Base Sequence; Kinetics; Methylation; Molecular Structure; Nucleic Acid Conformation; Nucleoside Q; RNA; Riboswitch; S-Adenosylmethionine
PubMed: 34162884
DOI: 10.1038/s41467-021-24193-7 -
Cells Jan 2022Inosine triphosphate pyrophosphatase (ITPase) is an enzyme encoded by the gene and functions to prevent the incorporation of noncanonical purine nucleotides into DNA... (Review)
Review
Inosine triphosphate pyrophosphatase (ITPase) is an enzyme encoded by the gene and functions to prevent the incorporation of noncanonical purine nucleotides into DNA and RNA. Specifically, the ITPase catalyzed the hydrolysis of (deoxy) nucleoside triphosphates ((d) NTPs) into the corresponding nucleoside monophosphate with the concomitant release of pyrophosphate. Recently, thiopurine drug metabolites such as azathioprine have been included in the lists of ITPase substrates. Interestingly, inosine or xanthosine triphosphate (ITP/XTP) and their deoxy analogs, deoxy inosine or xanthosine triphosphate (dITP/dXTP), are products of important biological reactions such as deamination that take place within the cellular compartments. However, the incorporation of ITP/XTP, dITP/dXTP, or the genetic deficiency or polymorphism of the gene have been implicated in many human diseases, including infantile epileptic encephalopathy, early onset of tuberculosis, and the responsiveness of patients to cancer therapy. This review provides an up-to-date report on the ITPase enzyme, including information regarding its discovery, analysis, and cellular localization, its implication in human diseases including cancer, and its therapeutic potential, amongst others.
Topics: Humans; Inosine; Inosine Triphosphate; Mutation; Neoplasms; Nucleosides; Nucleotides; Pyrophosphatases; Inosine Triphosphatase
PubMed: 35159194
DOI: 10.3390/cells11030384 -
Frontiers in Endocrinology 2023
Topics: Humans; Adenosine; Endocrine System Diseases
PubMed: 38089607
DOI: 10.3389/fendo.2023.1330202 -
Molecules (Basel, Switzerland) Sep 2020An efficient route to acylated acyclic nucleosides containing a branched hemiaminal ether moiety is reported via three-component alkylation of -heterocycle (purine...
An efficient route to acylated acyclic nucleosides containing a branched hemiaminal ether moiety is reported via three-component alkylation of -heterocycle (purine nucleobase) with acetal (cyclic or acyclic, variously branched) and anhydride (preferentially acetic anhydride). The procedure employs cheap and easily available acetals, acetic anhydride, and trimethylsilyl trifluoromethanesulfonate (TMSOTf). The multi-component reaction is carried out in acetonitrile at room temperature for 15 min and provides moderate to high yields (up to 88%) of diverse acyclonucleosides branched at the aliphatic side chain. The procedure exhibits a broad substrate scope of -heterocycles and acetals, and, in the case of purine derivatives, also excellent regioselectivity, giving almost exclusively -9 isomers.
Topics: Acetals; Acetic Anhydrides; Alkylation; Lewis Acids; Mesylates; Purine Nucleosides; Solvents; Stereoisomerism
PubMed: 32961820
DOI: 10.3390/molecules25184307 -
International Journal of Molecular... Dec 2023Adenosine-to-inosine (A-to-I) RNA editing is the most prevalent RNA modification in the nervous systems of metazoans. To study the biological significance of RNA... (Review)
Review
Adenosine-to-inosine (A-to-I) RNA editing is the most prevalent RNA modification in the nervous systems of metazoans. To study the biological significance of RNA editing, we first have to accurately identify these editing events from the transcriptome. The genome-wide identification of RNA editing sites remains a challenging task. In this review, we will first introduce the occurrence, regulation, and importance of A-to-I RNA editing and then describe the established bioinformatic procedures and difficulties in the accurate identification of these sit esespecially in small sized non-model insects. In brief, (1) to obtain an accurate profile of RNA editing sites, a transcriptome coupled with the DNA resequencing of a matched sample is favorable; (2) the single-cell sequencing technique is ready to be applied to RNA editing studies, but there are a few limitations to overcome; (3) during mapping and variant calling steps, various issues, like mapping and base quality, soft-clipping, and the positions of mismatches on reads, should be carefully considered; (4) Sanger sequencing of both RNA and the matched DNA is the best verification of RNA editing sites, but other auxiliary evidence, like the nonsynonymous-to-synonymous ratio or the linkage information, is also helpful for judging the reliability of editing sites. We have systematically reviewed the understanding of the biological significance of RNA editing and summarized the methodology for identifying such editing events. We also raised several promising aspects and challenges in this field. With insightful perspectives on both scientific and technical issues, our review will benefit the researchers in the broader RNA editing community.
Topics: Transcriptome; RNA; RNA Editing; Reproducibility of Results; Adenosine; DNA; Inosine
PubMed: 38138955
DOI: 10.3390/ijms242417126 -
Archives of Cardiovascular Diseases 2016
Review
Topics: Acute Coronary Syndrome; Adenosine; Humans; Purinergic P2Y Receptor Antagonists; Ticagrelor; Treatment Outcome
PubMed: 27342807
DOI: 10.1016/j.acvd.2016.04.001 -
Archives of Pharmacal Research May 2017Nucleoside analogues play an important role in antiviral, antibacterial and antineoplastic chemotherapy. Herein we report the synthesis, structural characterization and...
Nucleoside analogues play an important role in antiviral, antibacterial and antineoplastic chemotherapy. Herein we report the synthesis, structural characterization and biological activity of some 4'-C -methyl- and -phenyl dioxolane-based nucleosides. In particular, α and β anomers of all natural nucleosides were obtained and characterized by NMR, HR-MS and X-ray crystallography. The compounds were tested for antimicrobial activity against some representative human pathogenic fungi, bacteria and viruses. Antitumor activity was evaluated in a large variety of human cancer cell-lines. Although most of the compounds showed non-significant activity, 23α weakly inhibited HIV-1 multiplication. Moreover, 22α and 32α demonstrated a residual antineoplastic activity, interestingly linked to the unnatural α configuration. These results may provide structural insights for the design of active antiviral and antitumor agents.
Topics: Anti-HIV Agents; Antineoplastic Agents; Cell Line; Cell Proliferation; Crystallography, X-Ray; Dioxolanes; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; HIV-1; Humans; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; Purine Nucleosides; Pyrimidine Nucleosides; Structure-Activity Relationship
PubMed: 27615010
DOI: 10.1007/s12272-016-0825-6 -
Theranostics 2020More than a hundred chemical modifications in coding and non-coding RNAs have been identified so far. Many of the RNA modifications are dynamic and reversible, playing... (Review)
Review
More than a hundred chemical modifications in coding and non-coding RNAs have been identified so far. Many of the RNA modifications are dynamic and reversible, playing critical roles in gene regulation at the posttranscriptional level. The abundance and functions of RNA modifications are controlled mainly by the modification regulatory proteins: writers, erasers and readers. Modified RNA bases and their regulators form intricate networks which are associated with a vast array of diverse biological functions. RNA modifications are not only essential for maintaining the stability and structural integrity of the RNA molecules themselves, they are also associated with the functional outcomes and phenotypic attributes of cells. In addition to their normal biological roles, many of the RNA modifications also play important roles in various diseases particularly in cancer as evidenced that the modified RNA transcripts and their regulatory proteins are aberrantly expressed in many cancer types. This review will first summarize the most commonly reported RNA modifications and their regulations, followed by discussing recent studies on the roles of RNA modifications in cancer, cancer stemness as wells as functional RNA modification machinery as potential cancer therapeutic targets. It is concluded that, while advanced technologies have uncovered the contributions of many of RNA modifications in cancer, the underlying mechanisms are still poorly understood. Moreover, whether and how environmental pollutants, important cancer etiological factors, trigger abnormal RNA modifications and their roles in environmental carcinogenesis remain largely unknown. Further studies are needed to elucidate the mechanism of how RNA modifications promote cell malignant transformation and generation of cancer stem cells, which will lead to the development of new strategies for cancer prevention and treatment.
Topics: Antineoplastic Agents; Drug Design; Forecasting; Gene Expression Regulation, Neoplastic; Humans; Methyltransferases; Molecular Targeted Therapy; Neoplasm Proteins; Neoplasms; Neoplastic Stem Cells; Oxidoreductases, N-Demethylating; Pseudouridine; Purine Nucleosides; RNA Processing, Post-Transcriptional; RNA, Neoplasm
PubMed: 32194861
DOI: 10.7150/thno.41687 -
Molecules (Basel, Switzerland) Nov 2022spp. (belonging to the group) are entomopathogenic mushrooms that have traditionally been used in ethnomedicine in Asian countries such as China, Japan, Korea, and... (Review)
Review
spp. (belonging to the group) are entomopathogenic mushrooms that have traditionally been used in ethnomedicine in Asian countries such as China, Japan, Korea, and India. They are unique parasites of larvae of selected species of moths. is one of the best sources of cordycepin. Worldwide, osteoporosis is one of the most common bone diseases, whose pharmacotherapy includes various medical interventions; however, the research and development of new molecules and new drugs is required. The impact of adenosine receptors (ARs) on the purinergic signaling pathway may regulate proliferation, differentiate dental pulp stem cells and bone marrow, and modulate osteogenesis and bone repair. The aim of the review was to collect and analyze the available data on the effects of spp. or cordycepin on bone function and related processes. To the best of our knowledge, this is the first systematic review in this perspective, not necessarily using mushroom raw material or even the isolated parent compound cordycepin, but new molecules that are analogs of nucleosides, such as those from This review found that spp. or isolated cordycepin interacts via the AR, 5' adenosine monophosphate-activated protein kinase (AMPK), and adenosine-5'-triphosphate (ATP) signaling pathway and evaluated their impact on bones, teeth, and dental pulp. spp. was found to have the potential to develop regenerative medicines, thus providing an opportunity to expand the treatment or intervention methods in the recovery after traumatic injuries, convalescence, and terminal-stage or devastating diseases.
Topics: Cordyceps; Deoxyadenosines; Signal Transduction; Osteoporosis; China; Asia
PubMed: 36500262
DOI: 10.3390/molecules27238170