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1.
Angew Chem Int Ed Engl ; 61(11): e202114619, 2022 03 07.
Article in English | MEDLINE | ID: covidwho-1544209

ABSTRACT

Since early 2020, scientists have strived to find an effective solution to fight SARS-CoV-2, in particular by developing reliable vaccines that inhibit the spread of the disease and repurposing drugs for combatting its effects on the human body. The antiviral prodrug Remdesivir is still the most widely used therapeutic during the early stages of the infection. However, the current synthetic routes rely on the use of protecting groups, air-sensitive reagents, and cryogenic conditions, thus impeding a cost-efficient supply to patients. We have, therefore, focused on the development of a straightforward, direct addition of (hetero)arenes to unprotected sugars. Here we report a silylium-catalyzed and completely stereoselective C-glycosylation that initially yields the open-chain polyols, which can be selectively cyclized to provide either the kinetic α-furanose or the thermodynamically favored ß-anomer. The method significantly expedites the synthesis of Remdesivir precursor GS-441524 after a subsequent Mn-catalyzed C-H oxidation and deoxycyanation.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Adenosine/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/chemical synthesis , Nucleosides/chemical synthesis , Adenosine/chemical synthesis , Adenosine/chemistry , Adenosine Monophosphate/chemical synthesis , Adenosine Monophosphate/chemistry , Alanine/chemical synthesis , Alanine/chemistry , Antiviral Agents/chemistry , COVID-19/drug therapy , Catalysis , Chemistry Techniques, Synthetic/economics , Chemistry Techniques, Synthetic/methods , Cyclization , Glycosylation , Humans , Models, Molecular , Nucleosides/chemistry , Stereoisomerism , Time Factors
2.
Molecules ; 26(21)2021 Oct 27.
Article in English | MEDLINE | ID: covidwho-1512508

ABSTRACT

As cancer remains one of the major health burdens worldwide, novel agents, due to the development of resistance, are needed. In this work, we designed and synthesized harmirins, which are hybrid compounds comprising harmine and coumarin scaffolds, evaluated their antiproliferative activity, and conducted cell localization and cell cycle analysis experiments. Harmirins were prepared from the corresponding alkynes and azides under mild reaction conditions using Cu(I) catalyzed azide-alkyne cycloaddition, leading to the formation of the 1H-1,2,3-triazole ring. Antiproliferative activity of harmirins was evaluated in vitro against four human cancer cell lines (MCF-7, HCT116, SW620, and HepG2) and one human non-cancer cell line (HEK293T). The most pronounced activities were exerted against MCF-7 and HCT116 cell lines (IC50 in the single-digit micromolar range), while the most selective harmirins were 5b and 12b, substituted at C-3 and O-7 of the ß-carboline core and bearing methyl substituent at position 6 of the coumarin ring (SIs > 7.2). Further experiments demonstrated that harmirin 12b is localized exclusively in the cytoplasm. In addition, it induced a strong G1 arrest and reduced the percentage of cells in the S phase, suggesting that it might exert its antiproliferative activity through inhibition of DNA synthesis, rather than DNA damage. In conclusion, harmirin 12b is a novel harmine and coumarin hybrid with significant antiproliferative activity and warrants further evaluation as a potential anticancer agent.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Coumarins/chemistry , Harmine/chemical synthesis , Harmine/pharmacology , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Chemistry Techniques, Synthetic , Dose-Response Relationship, Drug , Harmine/analogs & derivatives , Humans , Molecular Structure
3.
Molecules ; 26(21)2021 Oct 20.
Article in English | MEDLINE | ID: covidwho-1512506

ABSTRACT

Three silver(I) dipeptide complexes [Ag(GlyGly)]n(NO3)n (AgGlyGly), [Ag2(GlyAla)(NO3)2]n (AgGlyAla) and [Ag2(HGlyAsp)(NO3)]n (AgGlyAsp) were prepared, investigated and characterized by vibrational spectroscopy (mid-IR), elemental and thermogravimetric analysis and mass spectrometry. For AgGlyGly, X-ray crystallography was also performed. Their stability in biological testing media was verified by time-dependent NMR measurements. Their in vitro antimicrobial activity was evaluated against selected pathogenic microorganisms. Moreover, the influence of silver(I) dipeptide complexes on microbial film formation was described. Further, the cytotoxicity of the complexes against selected cancer cells (BLM, MDA-MB-231, HeLa, HCT116, MCF-7 and Jurkat) and fibroblasts (BJ-5ta) using a colorimetric MTS assay was tested, and the selectivity index (SI) was identified. The mechanism of action of Ag(I) dipeptide complexes was elucidated and discussed by the study in terms of their binding affinity toward the CT DNA, the ability to cleave the DNA and the ability to influence numbers of cells within each cell cycle phase. The new silver(I) dipeptide complexes are able to bind into DNA by noncovalent interaction, and the topoisomerase I inhibition study showed that the studied complexes inhibit its activity at a concentration of 15 µM.


Subject(s)
Anti-Infective Agents/chemistry , Anti-Infective Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Dipeptides/chemistry , Silver/chemistry , Anti-Infective Agents/chemical synthesis , Antineoplastic Agents/chemical synthesis , Cell Cycle/drug effects , Cell Line, Tumor , Chemical Phenomena , Chemistry Techniques, Synthetic , Coordination Complexes/chemical synthesis , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Stability , Humans , Molecular Conformation , Molecular Dynamics Simulation , Spectrum Analysis , Structure-Activity Relationship , Thermogravimetry
4.
Molecules ; 26(19)2021 Oct 04.
Article in English | MEDLINE | ID: covidwho-1463767

ABSTRACT

Antimicrobial resistance was one of the top priorities for global public health before the start of the 2019 coronavirus pandemic (COVID-19). Moreover, in this changing medical landscape due to COVID-19, finding new organic structures with antimicrobial and antiviral properties is a priority in current research. The Biginelli synthesis that mediates the production of pyrimidine compounds has been intensively studied in recent decades, especially due to the therapeutic properties of the resulting compounds, such as calcium channel blockers, anticancer, antiviral, antimicrobial, anti-inflammatory or antioxidant compounds. In this review we aim to review the Biginelli syntheses reported recently in the literature that mediates the synthesis of antimicrobial compounds, the spectrum of their medicinal properties, and the structure-activity relationship in the studied compounds.


Subject(s)
Anti-Infective Agents/chemical synthesis , Pyrimidines/chemical synthesis , Animals , Anti-Infective Agents/chemistry , Anti-Infective Agents/pharmacology , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , COVID-19/drug therapy , Chemistry Techniques, Synthetic/methods , Drug Discovery , Drug Resistance, Microbial , Humans , Models, Molecular , Pyrimidines/chemistry , Pyrimidines/pharmacology , SARS-CoV-2/drug effects
5.
Nat Commun ; 12(1): 4396, 2021 07 20.
Article in English | MEDLINE | ID: covidwho-1387353

ABSTRACT

Rapid development of antisense therapies can enable on-demand responses to new viral pathogens and make personalized medicine for genetic diseases practical. Antisense phosphorodiamidate morpholino oligomers (PMOs) are promising candidates to fill such a role, but their challenging synthesis limits their widespread application. To rapidly prototype potential PMO drug candidates, we report a fully automated flow-based oligonucleotide synthesizer. Our optimized synthesis platform reduces coupling times by up to 22-fold compared to previously reported methods. We demonstrate the power of our automated technology with the synthesis of milligram quantities of three candidate therapeutic PMO sequences for an unserved class of Duchenne muscular dystrophy (DMD). To further test our platform, we synthesize a PMO that targets the genomic mRNA of SARS-CoV-2 and demonstrate its antiviral effects. This platform could find broad application not only in designing new SARS-CoV-2 and DMD antisense therapeutics, but also for rapid development of PMO candidates to treat new and emerging diseases.


Subject(s)
Chemistry Techniques, Synthetic/instrumentation , Chemistry, Pharmaceutical/instrumentation , High-Throughput Screening Assays/instrumentation , Morpholinos/chemical synthesis , Oligonucleotides, Antisense/chemical synthesis , Animals , COVID-19/drug therapy , COVID-19/virology , Chlorocebus aethiops , Communicable Diseases, Emerging/drug therapy , Communicable Diseases, Emerging/microbiology , Disease Models, Animal , High-Throughput Screening Assays/methods , Humans , Morpholinos/pharmacology , Morpholinos/therapeutic use , Muscular Dystrophy, Duchenne/drug therapy , Muscular Dystrophy, Duchenne/genetics , Oligonucleotides, Antisense/pharmacology , Oligonucleotides, Antisense/therapeutic use , Precision Medicine/methods , RNA, Messenger/antagonists & inhibitors , RNA, Viral/antagonists & inhibitors , SARS-CoV-2/genetics , Time Factors , Vero Cells
6.
Chem Commun (Camb) ; 57(55): 6804-6807, 2021 Jul 08.
Article in English | MEDLINE | ID: covidwho-1284708

ABSTRACT

Glycosylation plays important roles in SARS-CoV-2 infection. We describe here a facile chemoenzymatic synthesis of core-fucosylated N-glycopeptides derived from the SARS-CoV-2 Spike protein and their binding with glycan-dependent neutralizing antibody S309 and human lectin CLEC4G. The synthetic glycopeptides provide tools for further functional characterization of viral glycosylation.


Subject(s)
Glycopeptides/chemical synthesis , Glycopeptides/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Antibodies, Neutralizing/immunology , Chemistry Techniques, Synthetic , Glycopeptides/chemistry , Glycopeptides/immunology , Glycosylation , Polysaccharides/metabolism
7.
Int J Mol Sci ; 22(12)2021 Jun 17.
Article in English | MEDLINE | ID: covidwho-1282513

ABSTRACT

Novel antiviral nanotherapeutics, which may inactivate the virus and block it from entering host cells, represent an important challenge to face viral global health emergencies around the world. Using a combination of bioorthogonal copper-catalyzed 1,3-dipolar alkyne/azide cycloaddition (CuAAC) and photoinitiated thiol-ene coupling, monofunctional and bifunctional peptidodendrimer conjugates were obtained. The conjugates are biocompatible and demonstrate no toxicity to cells at biologically relevant concentrations. Furthermore, the orthogonal addition of multiple copies of two different antiviral peptides on the surface of a single dendrimer allowed the resulting bioconjugates to inhibit Herpes simplex virus type 1 at both the early and the late stages of the infection process. The presented work builds on further improving this attractive design to obtain a new class of therapeutics.


Subject(s)
Antiviral Agents/pharmacology , Dendrimers/pharmacology , Glycoproteins , Herpesvirus 1, Human , Peptides/pharmacology , Viral Proteins , Amino Acid Sequence , Animals , Antiviral Agents/chemistry , CHO Cells , Cell Line , Cell Survival/drug effects , Chemical Phenomena , Chemistry Techniques, Synthetic , Chromatography, High Pressure Liquid , Cricetulus , Dendrimers/chemistry , Glycoproteins/chemistry , Herpesvirus 1, Human/metabolism , Microbial Sensitivity Tests , Molecular Structure , Peptides/chemistry , Spectrum Analysis , Viral Proteins/chemistry
8.
Molecules ; 26(9)2021 Apr 29.
Article in English | MEDLINE | ID: covidwho-1217103

ABSTRACT

The outbreak of SARS-CoV-2 has drastically changed our everyday life and the life of scientists from all over the world. In the last year, the scientific community has faced this worldwide threat using any tool available in order to find an effective response. The recent formulation, production, and ongoing administration of vaccines represent a starting point in the battle against SARS-CoV-2, but they cannot be the only aid available. In this regard, the use of drugs capable to mitigate and fight the virus is a crucial aspect of the pharmacological strategy. Among the plethora of approved drugs, a consistent element is a heterocyclic framework inside its skeleton. Heterocycles have played a pivotal role for decades in the pharmaceutical industry due to their high bioactivity derived from anticancer, antiviral, and anti-inflammatory capabilities. In this context, the development of new performing and sustainable synthetic strategies to obtain heterocyclic molecules has become a key focus of scientists. In this review, we present the recent trends in metal-promoted heterocyclization, and we focus our attention on the construction of heterocycles associated with the skeleton of drugs targeting SARS-CoV-2 coronavirus.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Chemistry Techniques, Synthetic/methods , Heterocyclic Compounds/pharmacology , SARS-CoV-2/drug effects , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , COVID-19/virology , Catalysis , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/metabolism , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/chemistry , Humans , Metals/chemistry , Protease Inhibitors/chemical synthesis , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , SARS-CoV-2/metabolism
9.
Int J Mol Sci ; 22(1)2020 Dec 29.
Article in English | MEDLINE | ID: covidwho-1067750

ABSTRACT

Recently, there has been a growing interest in the medical applications of Cannabis plants. They owe their unique properties to a group of secondary metabolites known as phytocannabinoids, which are specific for this genus. Phytocannabinoids, and cannabinoids generally, can interact with cannabinoid receptors being part of the endocannabinoid system present in animals. Over the years a growing body of scientific evidence has been gathered, suggesting that these compounds have therapeutic potential. In this article, we review the classification of cannabinoids, the molecular mechanisms of their interaction with animal cells as well as their potential application in the treatment of human diseases. Specifically, we focus on the research concerning the anticancer potential of cannabinoids in preclinical studies, their possible use in cancer treatment and palliative medicine, as well as their influence on the immune system. We also discuss their potential as therapeutic agents in infectious, autoimmune, and gastrointestinal inflammatory diseases. We postulate that the currently ongoing and future clinical trials should be accompanied by research focused on the cellular and molecular response to cannabinoids and Cannabis extracts, which will ultimately allow us to fully understand the mechanism, potency, and safety profile of cannabinoids as single agents and as complementary drugs.


Subject(s)
Cannabinoids/pharmacology , Cannabinoids/therapeutic use , Animals , Anti-Infective Agents/pharmacology , Anti-Infective Agents/therapeutic use , Antineoplastic Agents, Phytogenic/pharmacology , Antineoplastic Agents, Phytogenic/therapeutic use , Apoptosis/drug effects , Cannabinoids/chemistry , Cannabis/chemistry , Chemistry Techniques, Synthetic , Communicable Diseases/drug therapy , Communicable Diseases/microbiology , Communicable Diseases/virology , Humans , Immune System/drug effects , Immune System/immunology , Immune System/metabolism , Immunologic Factors/pharmacology , Immunologic Factors/therapeutic use , Neoplasms/drug therapy , Receptors, Cannabinoid/metabolism
10.
Mini Rev Med Chem ; 21(6): 704-723, 2021.
Article in English | MEDLINE | ID: covidwho-922755

ABSTRACT

The current pandemic of COVID-19 caused by SARS-Cov-2 has posed a severe threat to the whole world with its highly infectious, progressive nature with up to 10% mortality rates. The severity of the situation faced by the whole world and the lack of efficient therapeutics to treat this viral disease have led the WHO to depend on the drug-repurposing approach to tackle this major global health problem. This review aims at highlighting the various synthetic approaches employed for the synthesis of these FDA approved drugs that have been presently used for COVID-19 treatment. Additionally, a brief overview of several therapeutic strategies is also presented. This review will encourage the scientific community across the globe to come up with better and efficient synthetic protocols and also novel chemical entities along with this core with more potent activity.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Drug Repositioning/methods , SARS-CoV-2/drug effects , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , Azetidines/chemical synthesis , Azetidines/chemistry , Azetidines/pharmacology , Azetidines/therapeutic use , Chemistry Techniques, Synthetic/methods , Humans , Nitriles , Purines/chemical synthesis , Purines/chemistry , Purines/pharmacology , Purines/therapeutic use , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyrazoles/therapeutic use , Pyrimidines , SARS-CoV-2/physiology , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Sulfonamides/pharmacology , Sulfonamides/therapeutic use , Virus Internalization/drug effects
11.
Org Lett ; 22(21): 8430-8435, 2020 11 06.
Article in English | MEDLINE | ID: covidwho-882861

ABSTRACT

We report an alternative approach to the unnatural nucleobase fragment seen in remdesivir (Veklury). Remdesivir displays broad-spectrum antiviral activity and is currently being evaluated in Phase III clinical trials to treat patients with COVID-19. Our route relies on the formation of a cyanoamidine intermediate, which undergoes Lewis acid-mediated cyclization to yield the desired nucleobase. The approach is strategically distinct from prior routes and could further enable the synthesis of remdesivir and other small-molecule therapeutics.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Amidines/chemistry , Antiviral Agents/chemistry , Antiviral Agents/chemical synthesis , Adenosine Monophosphate/chemical synthesis , Adenosine Monophosphate/chemistry , Adenosine Monophosphate/therapeutic use , Alanine/chemical synthesis , Alanine/chemistry , Alanine/therapeutic use , Antiviral Agents/therapeutic use , COVID-19 , Chemistry Techniques, Synthetic , Coronavirus Infections/drug therapy , Cyclization , Pandemics , Pneumonia, Viral/drug therapy
12.
Med Chem ; 16(3): 368-384, 2020.
Article in English | MEDLINE | ID: covidwho-71681

ABSTRACT

BACKGROUND: Nucleoside analogues are well-known antitumor, antiviral, and chemotherapeutic agents. Alterations on both their sugar and the heterocyclic parts may lead to significant changes in the spectrum of their biological activity and the degree of selective toxicity, as well as in their physicochemical properties. METHODS: C5-arylalkynyl-ß-D-ribofuranonucleosides 3-6, 3΄-deoxy 12-15, 3΄-deoxy-3΄-C-methyl- ß-D-ribofurananucleosides 18-21 and 2΄-deoxy-ß-D-ribofuranonucleosides 23-26 of uracil, were synthesized using a one-step Sonogashira reaction under microwave irradiation and subsequent deprotection. RESULTS: All newly synthesized nucleosides were tested for their antitumor or antiviral activity. Moderate cytostatic activity against cervix carcinoma (HeLa), murine leukemia (L1210) and human lymphocyte (CEM) tumor cell lines was displayed by the protected 3΄-deoxy derivatives 12b,12c,12d, and the 3΄-deoxy-3΄-methyl 18a,18b,18c. The antiviral evaluation revealed appreciable activity against Coxsackie virus B4, Respiratory syncytial virus, Yellow Fever Virus and Human Coronavirus (229E) for the 3΄-deoxy compounds 12b,14, and the 3΄-deoxy-3΄-methyl 18a,18c,18d, accompanied by low cytotoxicity. CONCLUSION: This report describes the total and facile synthesis of modified furanononucleosides of uracil, with alterations on both the sugar and the heterocyclic portions. Compounds 12b,14 and 18a,c,d showed noticeable antiviral activity against a series of RNA viruses and merit further biological and structural optimization investigations.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Drug Design , Pyrimidine Nucleosides/chemical synthesis , Pyrimidine Nucleosides/pharmacology , Animals , Antineoplastic Agents/chemistry , Antiviral Agents/chemistry , Cell Proliferation/drug effects , Chemistry Techniques, Synthetic , HeLa Cells , Humans , Mice , Pyrimidine Nucleosides/chemistry
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