Beyond silver sulfadiazine: A dive into more than 50 years of research and development on metal complexes of sulfonamides in medicinal inorganic chemistry

Sulfonamides revolutionized the treatment and management of bacterial infections. Prontosil was the very first synthetic antibacterial agent ever used in the clinics and its metabolite, sulfanilamide, led to the development of a diverse range of sulfonamides with a diverse spectrum of action. Although being developed as antibacterial agents, sulfonamides have also shown to present antitumor, antifungal, and antiviral activities. While for antibacterial applications the focus is on the dihydropteroate synthase enzyme, for antitumor compounds a lot of attention has been given to carbonic anhydrases. For antiviral applications some studies focus on inhibiting HIV replication, and with the COVID-19 pandemic in the last years, attention has been given to inhibit SARS-CoV-2 replication as well. For antifungal applications it seems there is a lack of target focus, but with some compounds presenting relevant activities. Silver sulfadiazine was the first metal complex of a sulfonamide to be used in the clinics as a topical agent for prevention and treatment of infections in burn patients and is vastly used to this day. Here, we covered the history of silver sulfadiazine development, its chemical properties, antibacterial activity and clinical data. Controversial results on the true efficacy of silver sulfadiazine as a topical treatment for burn wounds gave rise to ongoing debate on the advantages of using this compound when compared to other dressings loaded or not with silver-containing agents. Nonetheless, the 50-year history of silver sulfadiazine's successful use in the clinics has motivated the development of other metal complexes of sulfonamides, which are reviewed here. The biological endpoints for these novel metal complexes were not limited to antibacterial use, but expanded to antitumor, antifungal, and antiviral applications as well. Altogether, this review presents the developments in the applications of metal complexes of sulfonamides in medicinal inorganic chemistry in the past years.

Association of SARS-CoV-2 Infection and Triple Negative Breast Cancer (TNBC) A Computational Illustrative Study

Background: Anticipating the correlation between SARS-CoV-2 infection and ‘triplenegative breast cancer (TNBC)' remains challenging. It has been reported that people currently diagnosed with cancer have a higher risk of severe complications if they are affected by the viral infection. Cancer treatments, including chemotherapy, targeted therapies, and immunotherapy, may weaken the immune system and possibly cause critical lung damage and breathing problems. Special attention must be paid to the ‘comorbidity condition' while estimating the risk of severe SARSCoV- 2 infection in TNBC patients. Hence the work aims to study the correlation between triplenegative breast cancer (TNBC) and SARS-CoV-2 using biomolecular networking.Methods: The genes associated with SARS CoV-2 have been collected from curated data in Bio- GRID. TNBC-related genes have been collected from expression profiles. Molecular networking has generated a Protein-Protein Interaction (PPI) network and a Protein-Drug Interaction (PDI) network. The network results were further evaluated through molecular docking studies followed by molecular dynamic simulation.Results: The genetic correlation of TNBC and SARS-Cov-2 has been observed from the combined PPI of their proteins. The drugs interacting with the disease's closely associated genes have been identified. The docking and simulation study showed that anti-TNBC and anti-viral drugs interact with these associated targets, suggesting their influence in inhibiting both the disease mutations.Conclusion: The study suggests a slight influence of SARS-CoV-2 viral infection on Triple Negative Breast Cancer. Few anticancer drugs such as Lapatinib, Docetaxel and Paclitaxel are found to inhibit both TNBC and viral mutations. The computational studies suggest these molecules are also useful for TNBC patients to control SARS-CoV-2 infection.

Molecular Docking and Simulation Analysis of Cyclopeptides as Anticancer Agents

Background: Cancer is a leading cause of death for people worldwide, in addition to the rise in mortality rates attributed to the Covid epidemic. This allows scientists to do additional research. Here, we have selected Integerrimide A, cordy heptapeptide, and Oligotetrapeptide as the three cyclic proteins that will be further studied and investigated in this context.Methods: Docking research was carried out using the protein complexes 1FKB and 1YET, downloaded from the PDB database and used in the docking investigations. Cyclopeptides have been reported to bind molecularly to human HSP90 (Heat shock protein) and FK506. It was possible to locate HSP90 in Protein Data Banks 1YET and 1FKB. HSP90 was retrieved from Protein Data Bank 1YET and 1FKB. Based on these findings, it is possible that the anticancer effects of Int A, Cordy, and Oligo substances could be due to their ability to inhibit the mTOR rapamycin binding domain and the HSP90 Geldanamycin binding domain via the mTOR and mTOR chaperone pathways. During the calculation, there were three stages: system development, energy reduction, and molecular dynamics (also known as molecular dynamics). Each of the three compounds demonstrated a binding affinity for mTOR's Rapamycin binding site that ranged from -6.80 to -9.20 Kcal/mol (FKB12).Results: An inhibition constant Ki of 181.05 nM characterized Cordy A with the highest binding affinity (-9.20 Kcal/mol). Among the three tested compounds, Cordy A was selected for MD simulation. HCT116 and B16F10 cell lines were used to test each compound's anticancer efficacy. Doxorubicin was used as a standard drug. The cytotoxic activity of substances Int A, Cordy A, and Oligo on HCT116 cell lines was found to be 77.65 μM, 145.36 μM, and 175.54 μM when compared to Doxorubicin 48.63 μM, similarly utilizing B16F10 cell lines was found to be 68.63 μM, 127.63 μM, and 139.11 μM to Doxorubicin 45.25 μM.Conclusion: Compound Cordy A was more effective than any other cyclic peptides tested in this investigation.

COVID-19 and systemic anti-cancer therapy.

The corona virus disease 2019 (COVID-19) pandemic continues to severely impact healthcare systems around the world, and patients with cancer are even worse affected owing to compromised immune status and greater exposure risk. In the present review, we retrieved the relevant literature including guidelines and consensuses directly related to the purpose of this study from the PubMed database, and then summarized the research data on cancer and COVID-19, aiming to discuss the personal protection, systemic anti-cancer therapy, outcome of co-infection, and the clinical management strategy in this population. We found that patients with malignant tumors had a higher chance of suffering COVID-19, co-infection of whom had an even worse clinical prognosis, especially for those with lung cancer or hematologic cancers. Systemic chemotherapy may delay the clearance of severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) virus of human body, and thus have a negative impact on the clinical outcomes of COVID-19, while certain endocrine therapy and targeted drugs having limited or no impact. There has been no sufficient evidence for the impact of immune checkpoint therapy on the outcomes of COVID-19 till now. It is of great value to strengthen the personal protection of patients, adjust the anti-tumor treatments rationally and optimize the clinical management processes.Copyright © 2022, Editorial Office of China Oncology. All rights reserved.

Biological Activities of Ruthenium NHC Complexes: An Update.

Ruthenium N-heterocyclic carbene (NHC) complexes have unique physico-chemical properties as catalysts and a huge potential in medicinal chemistry and pharmacology, exhibiting a variety of notable biological activities. In this review, the most recent studies on ruthenium NHC complexes are summarized, focusing specifically on antimicrobial and antiproliferative activities. Ruthenium NHC complexes are generally active against Gram-positive bacteria, such as Bacillus subtilis, Staphylococcus aureus, Micrococcus luteus, Listeria monocytogenes and are seldom active against Gram-negative bacteria, including Salmonella typhimurium, Pseudomonas aeruginosa and Escherichia coli and fungal strains of Candida albicans. The antiproliferative activity was tested against cancer cell lines of human colon, breast, cervix, epidermis, liver and rat glioblastoma cell lines. Ruthenium NHC complexes generally demonstrated cytotoxicity higher than standard anticancer drugs. Further studies are needed to explore the mechanism of action of these interesting compounds.

A review of the immune activity of chitooligosaccharides

Under the influence of the COVID-19, people's awareness of physical health and immunity has increased significantly. Chitooligosaccharide is an oligomer of β-(1, 4)-linked D-glucosamine, furthermore, is one of the most widely studied immunomodulators. Chitooligosaccharide can be prepared from the chitin or chitosan polymers through enzymatically, chemically or physically processes. Chitooligosaccharide and its derivatives have been proven to have a wide range of biological activities including intestinal flora regulation, immunostimulant, anti-tumor, anti-obesity and anti-oxidation effects. This review summarizes the latest research of the preparation methods, biological activities in immunity and safety profiles of Chitooligosaccharide and its derivatives. We recapped the effect mechanisms of Chitooligosaccharide basing on overall immunity. Comparing the effects of Chitooligosaccharide with different molecular weights and degree of aggregation, a reference range for usage has been provided. This may provide a support for the application of Chitooligosaccharide in immune supplements and food. In addition, future research directions are also discussed. © 2023, Sociedade Brasileira de Ciencia e Tecnologia de Alimentos, SBCTA. All rights reserved.

Functionalized starch for formulation of graphitic carbon nanodots as viricidal/anticancer laborers

Biocompatibility of carbon nanodots (CNDs) ingrained from biopolymers are considered as prerequisite characters for their successive exploitation in different biomedical purposes. CNDs are known to be categorized to carbogenic nanodots (CgNDs) and graphitic nanodots (GNDs). The point of novelty in the current approach is to study the effect of chemical medication for starch before and after its functionalization with glucose, to ingrain carbon nanodots, that were sequentially applicable as viricidal and anticancer laborers. The represented data revealed that, CgNDs were nucleated from alkali-hydrolyzed starch exhibited with particle size of 4.8 ± 1.8 nm, whereas, glucose-functionalized starch was successfully exploited for ingraining of GNDs with particle size of 3.1 ± 1.3 nm. The viricidal action of the prepared CgNDs and GNDs against Low Pathogenic Coronavirus (229E) was estimated via CPE-inhibition Assay and the obtained IC50 was 61.2 and 29.6 mg/mL for CgNDs and GNDs, respectively. The synthesized CgNDs and GNDs were tested against human non-small cell lung cancer cell line (NSCLC, A549) via Sulforhodamine B (SRB) assay and the estimated IC50 was 356.5 and 220.3 μg/mL in case of CgNDs and GNDs, respectively. The obtained data approved the seniority of GNDs over CgNDs to be applicable as antiviral and antitumor laborers. © 2022 Elsevier Ltd

Dressing Bacteria With a Hybrid Immunoactive Nanosurface to Elicit Dual Anticancer and Antiviral Immunity.

Approaches capable of simultaneously treating cancer and protecting susceptible patients from lethal infections such as coronavirus disease 2019, are highly desirable but prove to be difficult. Here, dressing bacteria with a hybrid immunoactive nanosurface is reported to elicit dual anticancer and antiviral immunity. A combination of a checkpoint blocking antibody and a virus-specific antigen is covalently conjugated to polydopamine nanoparticles, which can be anchored onto bacterial surface, by a one-step in situ polymerization of dopamine under a cell-friendly condition. By virtue of the ability to colonize and penetrate deep tumor tissue, dressed bacteria enable sustained release and expanded exposure of carried immunoactivators to stimulate immune cells. In addition to a carrier role, bacteria are able to further provoke innate immunity due to the native immunogenicity of the pathogen-associated molecular patterns. Immunization with dressed bacteria promotes the maturation, and activation of antigen-presenting cells, which induces robust humoral and cellular immune responses in tumor-bearing mice. As evidenced by efficient production of viral-antigen-specific immunoglobulin G antibody in serum and significantly suppressed tumor growth in different models, dressing bacteria with a hybrid immunoactive nanosurface paves an avenue to prepare next-generation therapeutics for synergistic treatment and prevention.

Response to COVID-19 vaccine is reduced in patients with inflammatory bowel disease, but improved with additional dose.

BACKGROUND: Coronavirus disease 2019 (COVID-19) vaccination is recommended for patients with inflammatory bowel disease (IBD); however, suppressed immune responses have been reported for fully vaccinated patients under immunosuppressive therapy, mainly from Western countries. We prospectively analyzed antibody titers of IBD patients in Asia induced by two-dose and additional dose of messengerRNA COVID-19 vaccine. METHODS: After measuring high-affinity antibody titers, factors associated with antibody titers were identified by multiple regression analyses using the following covariates: sex, age (≥60 or <60 years), disease type (Crohn's disease or ulcerative colitis), vaccine type (BNT162b2 or mRNA-1273), time from second/third vaccination, molecular-targeted agent (anti-tumor necrosis factor [TNF] agents, ustekinumab, vedolizumab, tofacitinib, or no molecular-targeted agents), thiopurine, steroid, and 5-aminosalicylic acid. RESULTS: Among 409 patients analyzed, mean titer was 1316.7 U/mL (SD, 1799.3); 403 (98.5%) were judged to be seropositive (≥0.8 U/mL), and 389 (95.1%) had neutralizing antibodies (≥15 U/mL). After the third vaccination, mean titer raised up to 21 123.8 U/mL (SD, 23 474.5); all 179 were seropositive, and 178 (99.4%) had neutralizing antibodies. In 248 patients with genetic data, there was no difference in mean titer after two/third doses between carriers and non-carriers of HLA-A24 associated with severe disease during COVID-19 infection. A multiple regression analyses using covariates revealed that older age, vaccine type (BNT162b2), time from second/third dose, anti-TNF agent, tofacitinib, and thiopurine were independently associated with lower antibody titers. CONCLUSIONS: Our findings further support the recommendation for COVID-19 vaccination in patients under immunosuppressive therapy, especially additional third dose for patients receiving anti-TNF agents and/or thiopurine or tofacitinib.

Induction of potent antitumor immunity by intradermal DNA injection using a novel needle-free pyro-drive jet injector.

The current success of mRNA vaccines against COVID-19 has highlighted the effectiveness of mRNA and DNA vaccinations. Recently, we demonstrated that a novel needle-free pyro-drive jet injector (PJI) effectively delivers plasmid DNA into the skin, resulting in protein expression higher than that achieved with a needle syringe. Here, we used ovalbumin (OVA) as a model antigen to investigate the potential of the PJI for vaccination against cancers. Intradermal injection of OVA-expression plasmid DNA into mice using the PJI, but not a needle syringe, rapidly and greatly augmented OVA-specific CD8+ T-cell expansion in lymph node cells. Increased mRNA expression of both interferon-γ and interleukin-4 and an enhanced proliferative response of OVA-specific CD8+ T cells, with fewer CD4+ T cells, were also observed. OVA-specific in vivo killing of the target cells and OVA-specific antibody production of both the IgG2a and IgG1 antibody subclasses were greatly augmented. Intradermal injection of OVA-expression plasmid DNA using the PJI showed stronger prophylactic and therapeutic effects against the progression of transplantable OVA-expressing E.G7-OVA tumor cells. Even compared with the most frequently used adjuvants, complete Freund's adjuvant and aluminum hydroxide with OVA protein, intradermal injection of OVA-expression plasmid DNA using the PJI showed a stronger CTL-dependent prophylactic effect. These results suggest that the novel needle-free PJI is a promising tool for DNA vaccination, inducing both a prophylactic and a therapeutic effect against cancers, because of prompt and strong generation of OVA-specific CTLs and subsequently enhanced production of both the IgG2a and IgG1 antibody subclasses.

Chemistry and Biological Activities of Naturally Occurring and Structurally Modified Podophyllotoxins.

Plants containing podophyllotoxin and its analogues have been used as folk medicines for centuries. The characteristic chemical structures and strong biological activities of this class of compounds attracted attention worldwide. Currently, more than ninety natural podophyllotoxins were isolated, and structure modifications of these molecules were performed to afford a variety of derivatives, which offered optimized anti-tumor activity. This review summarized up to date reports on natural occurring podophyllotoxins and their sources, structural modification and biological activities. Special attention was paid to both structural modification and optimized antitumor activity. It was noteworthy that etoposide, a derivative of podophyllotoxin, could prevent cytokine storm caused by the recent SARS-CoV-2 viral infection.

The Synthesis of Urolithins and Their Derivatives and the Modes of Antitumor Action.

Urolithins are microbial metabolites derived from berries and pomegranate fruits, which display anti-inflammatory, anti-oxidative, and anti-aging activities. There are eight natural urolithins (urolithin A-E, M5, M6 and M7) isolated by now. Structurally, urolithins are phenolic compounds and belong to 6H-dibenzo[b,d]pyran-6-one. They have drawn considerable attention because of their vast range of biological activities and health benefits. Recent studies also suggest that they possess anti-SARS-CoV-2 and anticancer effects. In this article, the recent advances on the synthesis of urolithins and their derivatives from 2015 to 2021 are reviewed. To improve or overcome the solubility and metabolism stability issues, the modifications of urolithins are mainly centered on the hydroxy group and lactone group, and some compounds are showing promising results and potential for further study. The possible modes of antitumor action of urolithin are also discussed. Several signaling pathways, including PI3K-Akt, Wnt/ß-catenin pathways, and multiple receptors (aryl hydrocarbon receptor, estrogen and androgen receptors) and enzymes (tyrosinase and lactate dehydrogenase) are involved in the antitumor activity of urolithins.

Correlation between COVID-19 and cancer comorbidity: COVID-19 biomarkers in cancer patients

Due to the COVID-19 pandemic, many cancer patients around the globe exhibit difficulties to maintain the treatment they needed. However today, it is well known that the mortality rate of cancer patients is higher when they get COVID-19 infection. For these patients with both COVID-19 and cancer, biomarkers can help prognosis. For some biomarkers, gender differences can be observed which affects the disease severity. Additionally, the review focuses on ACE2 as a biomarker for cancer patients, the receptor SARS-COV-2 uses to enter the host cell. Additionally, the usage of flavonoids can be an alternative treatment method due to their various promising therapeutic properties such as anti-inflammatory, antioxidant, antiproliferative, anti-inflammatory, and anticancer activity. When used for cancer therapy, Flavonoids can play a key role in different mechanisms such as inactivation of carcinogens, cell cycle arrest, antiproliferation, and angiogenesis inhibition. Due to the ability of both ACE2 inhibition and anticancer property, flavonoids can be used as a new treatment strategy for cancer patients with COVID-19. Therefore, it is crucial to understand the relation between COVID-19 and cancer to design new specific treatments.

Immunologic Mechanisms and Advances in Clinical Research for The mRNA Cancer Vaccine

Messenger RNA (mRNA) therapy is a novel anticancer treatment strategy based on in vitro transcription (IVT) mRNA, with promising potential for the treatment of malignant tumors. The outbreak of the COVID-19 pandemic in the early 21st century has greatly promoted the application of mRNA technologies in SARS-CoV-2 vaccines. Meanwhile, the research and development of the mRNA cancer vaccine has become a priority. A nwnber of key technologies, including mRNA production strategies, delivery systems, anti-tumor immune strategies, etc., have made dramatic improvements and modifications. These technologies accelerated the research progress and clinical applications of mRNA therapy, thereby greatly overcoming the bottleneck problem, such as the instability, inefficient deliveries, and weak immunogenicity of the mRNA vaccines in the past. This review provides a detailed overview of the production, delivery systems, immunological mechanisms, and antitumor immune response strategies for mRNA cancer vaccines. We list some mRNA cancer vaccines that have been used as candidates for cancer treatment and the clinical trials in the field of tumor immunotherapy. In addition, we discuss about the immunological mechanism of the mRNA vaccines to destroy tumors, as well as the challenges and prospects for the future.

A review of the immune activity of chitooligosaccharides

Under the influence of the COVID-19, people's awareness of physical health and immunity has increased significantly. Chitooligosaccharide is an oligomer of β-(1, 4)-linked D-glucosamine, furthermore, is one of the most widely studied immunomodulators. Chitooligosaccharide can be prepared from the chitin or chitosan polymers through enzymatically, chemically or physically processes. Chitooligosaccharide and its derivatives have been proven to have a wide range of biological activities including intestinal flora regulation, immunostimulant, anti-tumor, anti-obesity and anti-oxidation effects. This review summarizes the latest research of the preparation methods, biological activities in immunity and safety profiles of Chitooligosaccharide and its derivatives. We recapped the effect mechanisms of Chitooligosaccharide basing on overall immunity. Comparing the effects of Chitooligosaccharide with different molecular weights and degree of aggregation, a reference range for usage has been provided. This may provide a support for the application of Chitooligosaccharide in immune supplements and food. In addition, future research directions are also discussed. © 2023, Sociedade Brasileira de Ciencia e Tecnologia de Alimentos, SBCTA. All rights reserved.

Cucurbitacin B: A review of its pharmacology, toxicity, and pharmacokinetics.

Cucurbitacin B (CuB, C32H46O8), the most abundant and active member of cucurbitacins, which are highly oxidized tetracyclic triterpenoids. Cucurbitacins are widely distributed in a variety of plants and mainly isolated from plants in the Cucurbitaceae family. CuB is mostly obtained from the pedicel of Cucumis melo L. Modern pharmacological studies have confirmed that CuB has a broad range of pharmacological activities, with significant therapeutic effects on a variety of diseases including inflammatory diseases, neurodegenerative diseases, diabetes mellitus, and cancers. In this study the PubMed, Web of Science, Science Direct, and China National Knowledge Infrastructure (CNKI) databases were searched from 1986 to 2022. After inclusion and exclusion criteria were applied, 98 out of 2484 articles were selected for a systematic review to comprehensively summarize the pharmacological activity, toxicity, and pharmacokinetic properties of CuB. The results showed that CuB exhibits potent anti-inflammatory, antioxidant, antiviral, hypoglycemic, hepatoprotective, neuroprotective, and anti-cancer activities mainly via regulating various signaling pathways, such as the Janus kinase/signal transducer and activator of transcription-3 (JAK/STAT3), nuclear factor erythroid 2-related factor-2/antioxidant responsive element (Nrf2/ARE), nuclear factor (NF)-κB, AMP-activated protein kinase (AMPK), mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K)/Akt, cancerous inhibitor of protein phosphatase-2A/protein phosphatase-2A (CIP2A/PP2A), Wnt, focal adhesion kinase (FAK), Notch, and Hippo-Yes-associated protein (YAP) pathways. Studies of its toxicity and pharmacokinetic properties showed that CuB has non-specific toxicity and low bioavailability. In addition, derivatives and clinical applications of CuB are discussed in this paper.

Functionalized starch for formulation of graphitic carbon nanodots as viricidal/anticancer laborers

Biocompatibility of carbon nanodots (CNDs) ingrained from biopolymers are considered as prerequisite characters for their successive exploitation in different biomedical purposes. CNDs are known to be categorized to carbogenic nanodots (CgNDs) and graphitic nanodots (GNDs). The point of novelty in the current approach is to study the effect of chemical medication for starch before and after its functionalization with glucose, to ingrain carbon nanodots, that were sequentially applicable as viricidal and anticancer laborers. The represented data revealed that, CgNDs were nucleated from alkali-hydrolyzed starch exhibited with particle size of 4.8 ± 1.8 nm, whereas, glucose-functionalized starch was successfully exploited for ingraining of GNDs with particle size of 3.1 ± 1.3 nm. The viricidal action of the prepared CgNDs and GNDs against Low Pathogenic Coronavirus (229E) was estimated via CPE-inhibition Assay and the obtained IC50 was 61.2 and 29.6 mg/mL for CgNDs and GNDs, respectively. The synthesized CgNDs and GNDs were tested against human non-small cell lung cancer cell line (NSCLC, A549) via Sulforhodamine B (SRB) assay and the estimated IC50 was 356.5 and 220.3 μg/mL in case of CgNDs and GNDs, respectively. The obtained data approved the seniority of GNDs over CgNDs to be applicable as antiviral and antitumor laborers.

The lncRNAs involved in regulating the RIG-I signaling pathway.

Understanding the targets and interactions of long non-coding RNAs (lncRNAs) related to the retinoic acid-inducible gene-I (RIG-I) signaling pathway is essential for developing interventions, which would enable directing the host inflammatory response regulation toward protective immunity. In the RIG-I signaling pathway, lncRNAs are involved in the important processes of ubiquitination, phosphorylation, and glycolysis, thus promoting the transport of the interferon regulatory factors 3 and 7 (IRF3 and IRF7) and the nuclear factor kappa B (NF-κB) into the nucleus, and activating recruitment of type I interferons (IFN-I) and inflammatory factors to the antiviral action site. In addition, the RIG-I signaling pathway has recently been reported to contain the targets of coronavirus disease-19 (COVID-19)-related lncRNAs. The molecules in the RIG-I signaling pathway are directly regulated by the lncRNA-microRNAs (miRNAs)-messenger RNA (mRNA) axis. Therefore, targeting this axis has become a novel strategy for the diagnosis and treatment of cancer. In this paper, the studies on the regulation of the RIG-I signaling pathway by lncRNAs during viral infections and cancer are comprehensively analyzed. The aim is to provide a solid foundation of information for conducting further detailed studies on lncRNAs and RIG-I in the future and also contribute to clinical drug development.

Potential Benefits of Black Chokeberry (Aronia melanocarpa) Fruits and Their Constituents in Improving Human Health.

Aronia berry (black chokeberry) is a shrub native to North America, of which the fresh fruits are used in the food industry to produce different types of dietary products. The fruits of Aronia melanocarpa (Aronia berries) have been found to show multiple bioactivities potentially beneficial to human health, including antidiabetic, anti-infective, antineoplastic, antiobesity, and antioxidant activities, as well as heart-, liver-, and neuroprotective effects. Thus far, phenolic compounds, such as anthocyanins, cyanidins, phenolic acids, proanthocyanidins, triterpenoids, and their analogues have been identified as the major active components of Aronia berries. These natural products possess potent antioxidant activity, which contributes to the majority of the other bioactivities observed for Aronia berries. The chemical components and the potential pharmaceutical or health-promoting effects of Aronia berries have been summarized previously. The present review article focuses on the molecular targets of extracts of Aronia berries and the examples of promising lead compounds isolated from these berries, including cyanidin-3-O-galactoside, chlorogenic acid, quercetin, and ursolic acid. In addition, presented herein are clinical trial investigations for Aronia berries and their major components, including cancer clinical trials for chlorogenic acid and COVID-19 trial studies for quercetin. Additionally, the possible development of Aronia berries and their secondary metabolites as potential therapeutic agents is discussed. It is hoped that this contribution will help stimulate future investigations on Aronia berries for the continual improvement of human health.

Synthesis and Anticancer and Antiviral Activities of C-2'-Branched Arabinonucleosides.

d-Arabinofuranosyl-pyrimidine and -purine nucleoside analogues containing alkylthio-, acetylthio- or 1-thiosugar substituents at the C2' position were prepared from the corresponding 3',5'-O-silylene acetal-protected nucleoside 2'-exomethylenes by photoinitiated, radical-mediated hydrothiolation reactions. Although the stereochemical outcome of the hydrothiolation depended on the structure of both the thiol and the furanoside aglycone, in general, high d-arabino selectivity was obtained. The cytotoxic effect of the arabinonucleosides was studied on tumorous SCC (mouse squamous cell) and immortalized control HaCaT (human keratinocyte) cell lines by MTT assay. Three pyrimidine nucleosides containing C2'-butylsulfanylmethyl or -acetylthiomethyl groups showed promising cytotoxicity at low micromolar concentrations with good selectivity towards tumor cells. SAR analysis using a methyl ß-d-arabinofuranoside reference compound showed that the silyl-protecting group, the nucleobase and the corresponding C2' substituent are crucial for the cell growth inhibitory activity. The effects of the three most active nucleoside analogues on parameters indicative of cytotoxicity, such as cell size, division time and cell generation time, were investigated by near-infrared live cell imaging, which showed that the 2'-acetylthiomethyluridine derivative induced the most significant functional and morphological changes. Some nucleoside analogues also exerted anti-SARS-CoV-2 and/or anti-HCoV-229E activity with low micromolar EC50 values; however, the antiviral activity was always accompanied by significant cytotoxicity.