Preparation of C-5 Substituted Cidofovir Derivatives

2006 ◽  
Vol 71 (4) ◽  
pp. 579-594 ◽  
Author(s):  
Marcela Krečmerová ◽  
Milena Masojídková ◽  
Antonín Holý
Keyword(s):  
Antiviral Activity ◽  
Primary Amines ◽  
Sonogashira Coupling ◽  
Phosphonic Acids ◽  
Phosphonate Esters ◽  
Base Moiety

1-[(S)-3-Hydroxy-2-(phosphonomethoxy)propyl]cytosine (HPMPC, cidofovir) was modified by substitution on the base moiety in positions C-5 and N4. Key intermediates of these syntheses, diisopropyl esters of (S)-1-[2-(phosphonomethoxy)-3-(triphenylmethoxy)propyl]-5-alkylcytosines (6 and 7) prepared from 5-alkyl-4-methoxypyrimidin-2(1H)-ones were transformed to the corresponding 5-substituted cytosine or N4-alkylcytosine derivatives by the action of ammonia or primary amines, respectively. These fully protected phosphonate esters gave by treatment with bromotrimethylsilane followed by hydrolysis free phosphonic acids: 1-[(S)-3-hydroxy-2-(phosphonomethoxy)propyl]-5-methylcytosine (5-methyl-HPMPC, 10), 5-ethyl-1-[(S)-3-hydroxy-2-(phosphonomethoxy)propyl]cytosine (5-ethyl-HPMPC, 11) and a series of 5-ethyl-HPMPC analogues 17-21 bearing various substituents in N4 position (cyclopropyl, cyclopentyl, 2-hydroxyethyl, allyl, 2-(dimethylamino)ethyl). 5-Ethynyl-1-[(S)-3-hydroxy-2-(phosphonomethoxy)propyl]cytosine (5-ethynyl-HPMPC, 26) was prepared from 5-iodocytosine derivative 23 using Sonogashira coupling with (trimethylsilyl)acetylene, CuI and [PdCl2(Ph3P)2]. None of the prepared compounds exhibited antiviral activity in vitro.

Pyrimidine Acyclic Nucleotide Analogues with Aromatic Substituents in C-5 Position

2007 ◽  
Vol 72 (7) ◽  
pp. 927-951 ◽  
Author(s):  
Marcela Krečmerová ◽  
Antonín Holý ◽  
Milena Masojídková
Keyword(s):  
Antiviral Activity ◽  
Cell Cultures ◽  
Inhibitory Activity ◽  
Thymidine Phosphorylase ◽  
Sodium Hydride ◽  
Phosphonic Acids ◽  
Nucleotide Analogues ◽  
Varicella Zoster ◽  
Subsequent Hydrolysis ◽  
Phosphonate Esters

NH2-protected 5-phenylcytosine and its derivatives 2a-2d were treated with (2S)-2-[(trityloxy)methyl]oxirane (3) followed by etherification with diisopropyl [(tosyloxy)methyl]phosphonate (5) in the presence of sodium hydride. The intermediary phosphonate esters 6 were debenzoylated and subsequently transformed to free phosphonic acids, i.e. (S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-phenylcytosine (5-phenyl-HPMPC) derivatives (8a-8d) by the action of bromotrimethylsilane and subsequent hydrolysis. Deamination of these compounds with 3-methylbutyl nitrite afforded corresponding (S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-phenyluracil (5-phenyl-HPMPU) derivatives (9a-9d). R-Enantiomers 14 and 15 were prepared analogously starting from (2R)-2-[(trityloxy)methyl]oxirane. 5-Benzyl-, 5-[(1-naphthyl)methyl]- and 5-[(2-naphthyl)methyl]HPMPU (24a-24c) and -HPMPC (25a-25c) were synthesized from appropriate 5-arylmethyl-4-methoxypyrimidin-2(1H)-ones similarly as described for 5-phenyl derivatives. Antiviral activity was found for (S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-phenyluracil (9a) (HSV-1 and HSV-2) and (R)-1-[3-hydroxy2-(phosphonomethoxy)propyl]-5-phenylcytosine (14) (cytomegalovirus and varicella-zoster virus), both tested in cell cultures. Some of the 5-phenyluracil derivatives possessed inhibitory activity against thymidine phosphorylase from SD-lymphoma.

In Vitro Evaluation of the Antiviral Activity of Some Mushrooms from Turkey

2018 ◽  
Vol 20 (3) ◽  
pp. 201-212 ◽  
Author(s):  
Hasan Hüseyin Doğan ◽  
Sami Karagöz ◽  
Rüstem Duman
Keyword(s):  
Antiviral Activity ◽  
In Vitro Evaluation

Preliminary Anti-Coxsackie Activity of Novel 1-[4-(5,6-dimethyl(H)- 1H(2H)-benzotriazol-1(2)-yl)phenyl]-3-alkyl(aryl)ureas

2020 ◽  
Vol 16 (5) ◽  
pp. 677-688 ◽  
Author(s):  
Sandra Piras ◽  
Paola Corona ◽  
Roberta Ibba ◽  
Federico Riu ◽  
Gabriele Murineddu ◽  
...  
Keyword(s):  
Chronic Disease ◽  
Antiviral Activity ◽  
Wide Spectrum ◽  
Immunocompromised Patients ◽  
Human Pathogen ◽  
Alkyl Aryl ◽  
Dna Viruses ◽  
Coxsackievirus B ◽  
Selective Activity

Background: Coxsackievirus infections are associated with cases of aseptic meningitis, encephalitis, myocarditis, and some chronic disease. Methods: A series of benzo[d][1,2,3]triazol-1(2)-yl derivatives (here named benzotriazol-1(2)-yl) (4a-i, 5a-h, 6a-e, g, i, j and 7a-f, h-j) were designed, synthesized and in vitro evaluated for cytotoxicity and antiviral activity against two important human enteroviruses (HEVs) members of the Picornaviridae family [Coxsackievirus B 5 (CVB-5) and Poliovirus 1 (Sb-1)]. Results: Compounds 4c (CC50 >100 μM; EC50 = 9 μM), 5g (CC50 >100 μM; EC50 = 8 μM), and 6a (CC50 >100 μM; EC50 = 10 μM) were found active against CVB-5. With the aim of evaluating the selectivity of action of this class of compounds, a wide spectrum of RNA (positive- and negativesense), double-stranded (dsRNA) or DNA viruses were also assayed. For none of them, significant antiviral activity was determined. Conclusion: These results point towards a selective activity against CVB-5, an important human pathogen that causes both acute and chronic diseases in infants, young children, and immunocompromised patients.

scholarly journals Development of a Mucus Gland Bioreactor in Loach Paramisgurnus dabryanus

2021 ◽  
Vol 22 (2) ◽  
pp. 687
Author(s):  
Tong Zhou ◽  
Bolan Zhou ◽  
Yasong Zhao ◽  
Qing Li ◽  
Guili Song ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Grass Carp ◽  
Single Copy ◽  
Type I ◽  
Western Blots ◽  
Paramisgurnus Dabryanus ◽  
Expression Activity ◽  
Transgenic Construct ◽  
Mucus Gland

Most currently available bioreactors have some defects in the expression, activity, or purification of target protein and peptide molecules, whereas the mucus gland of fish can overcome these defects to become a novel bioreactor for the biopharmaceutical industry. In this study, we have evaluated the practicability of developing a mucus gland bioreactor in loach (Paramisgurnus dabryanus). A transgenic construct pT2-krt8-IFN1 was obtained by subcloning the promoter of zebrafish keratin 8 gene and the type I interferon (IFN1) cDNA of grass carp into the SB transposon. The IFN1 expressed in CIK cells exhibited an antiviral activity against the replication of GCRV873 and activated two genes downstream of JAK-STAT signaling pathway. A transgenic loach line was then generated by microinjection of the pT2-krt8-IFN1 plasmids and in vitro synthesized capped SB11 mRNA. Southern blots indicated that a single copy of IFN1 gene was stably integrated into the genome of transgenic loach. The expression of grass carp IFN1 in transgenic loaches was detected with RT-PCR and Western blots. About 0.0825 µg of grass carp IFN1 was detected in 20 µL mucus from transgenic loaches. At a viral titer of 1 × 103 PFU/mL, plaque numbers on plates containing mucus from transgenic loaches reduced by 18% in comparison with those of the control, indicating that mucus of IFN1-transgenic loaches exhibited an antiviral activity. Thus, we have successfully created a mucus gland bioreactor that has great potential for the production of various proteins and peptides.

scholarly journals A Sustainable Improvement of ω-Bromoalkylphosphonates Synthesis to Access Novel KuQuinones

Organics ◽  
2021 ◽  
Vol 2 (2) ◽  
pp. 107-117
Author(s):  
Mattia Forchetta ◽  
Valeria Conte ◽  
Giulia Fiorani ◽  
Pierluca Galloni ◽  
Federica Sabuzi
Keyword(s):  
Metal Oxides ◽  
Phosphonic Acid ◽  
Organic Molecules ◽  
Building Blocks ◽  
Reaction Conditions ◽  
Phosphonic Acids ◽  
Sustainable Improvement ◽  
Phosphonate Esters ◽  
First Time ◽  
Complex Organic

Owing to the attractiveness of organic phosphonic acids and esters in the pharmacological field and in the functionalization of conductive metal-oxides, the research of effective synthetic protocols is pivotal. Among the others, ω-bromoalkylphosphonates are gaining particular attention because they are useful building blocks for the tailored functionalization of complex organic molecules. Hence, in this work, the optimization of Michaelis–Arbuzov reaction conditions for ω-bromoalkylphosphonates has been performed, to improve process sustainability while maintaining good yields. Synthesized ω-bromoalkylphosphonates have been successfully adopted for the synthesis of new KuQuinone phosphonate esters and, by hydrolysis, phosphonic acid KuQuinone derivatives have been obtained for the first time. Considering the high affinity with metal-oxides, KuQuinones bearing phosphonic acid terminal groups are promising candidates for biomedical and photo(electro)chemical applications.

scholarly journals The Design and Preclinical Evaluation of a Single-Label Bimodal Nanobody Tracer for Image-Guided Surgery

Biomolecules ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 360
Author(s):  
Pieterjan Debie ◽  
Noemi B. Declerck ◽  
Danny van Willigen ◽  
Celine M. Huygen ◽  
Bieke De Sloovere ◽  
...  
Keyword(s):  
Single Molecule ◽  
Gamma Ray ◽  
Nuclear Imaging ◽  
Primary Amines ◽  
Resection Margins ◽  
Fluorescent Light ◽  
Single Structure ◽  
Fluorescence Images

Intraoperative guidance using targeted fluorescent tracers can potentially provide surgeons with real-time feedback on the presence of tumor tissue in resection margins. To overcome the limited depth penetration of fluorescent light, combining fluorescence with SPECT/CT imaging and/or gamma-ray tracing has been proposed. Here, we describe the design and preclinical validation of a novel bimodal nanobody-tracer, labeled using a “multifunctional single attachment point” (MSAP) label, integrating a Cy5 fluorophore and a diethylenetriaminepentaacetic acid (DTPA) chelator into a single structure. After conjugation of the bimodal MSAP to primary amines of the anti-HER2 nanobody 2Rs15d and 111In-labeling of DTPA, the tracer’s characteristics were evaluated in vitro. Subsequently, its biodistribution and tumor targeting were assessed by SPECT/CT and fluorescence imaging over 24 h. Finally, the tracer’s ability to identify small, disseminated tumor lesions was investigated in mice bearing HER2-overexpressing SKOV3.IP1 peritoneal lesions. [111In]In-MSAP.2Rs15d retained its affinity following conjugation and remained stable for 24 h. In vivo SPECT/CT and fluorescence images showed specific uptake in HER2-overexpressing tumors with low background. High tumor-to-muscle ratios were obtained at 1h p.i. and remained 19-fold on SPECT/CT and 3-fold on fluorescence images over 24 h. In the intraperitoneally disseminated model, the tracer allowed detection of larger lesions via nuclear imaging, while fluorescence enabled accurate removal of submillimeter lesions. Bimodal nuclear/fluorescent nanobody-tracers can thus be conveniently designed by conjugation of a single-molecule MSAP-reagent carrying a fluorophore and chelator for radioactive labeling. Such tracers hold promise for clinical applications.

scholarly journals Chloroquine and Sulfadoxine Derivatives Inhibit ZIKV Replication in Cervical Cells

Viruses ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 36
Author(s):  
Audrien Alves Andrade de Souza ◽  
Lauana Ribas Torres ◽  
Lyana Rodrigues Pinto Lima Capobianco ◽  
Vanessa Salete de Paula ◽  
Cynthia Machado Cascabulho ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Specific Treatment ◽  
Vero Cells ◽  
Vehicle Control ◽  
Therapeutic Window ◽  
Chemical Structures ◽  
Hybrid Compounds ◽  
Cervical Cells ◽  
Zika Fever

Despite the severe morbidity caused by Zika fever, its specific treatment is still a challenge for public health. Several research groups have investigated the drug repurposing of chloroquine. However, the highly toxic side effect induced by chloroquine paves the way for the improvement of this drug for use in Zika fever clinics. Our aim is to evaluate the anti-Zika virus (ZIKV) effect of hybrid compounds derived from chloroquine and sulfadoxine antimalarial drugs. The antiviral activity of hybrid compounds (C-Sd1 to C-Sd7) was assessed in an in-vitro model of human cervical and Vero cell lines infected with a Brazilian (BR) ZIKV strain. First, we evaluated the cytotoxic effect on cultures treated with up to 200 µM of C-Sds and observed CC50 values that ranged from 112.0 ± 1.8 to >200 µM in cervical cells and 43.2 ± 0.4 to 143.0 ± 1.3 µM in Vero cells. Then, the cultures were ZIKV-infected and treated with up to 25 µM of C-Sds for 48 h. The treatment of cervical cells with C-Sds at 12 µM induced a reduction of 79.8% ± 4.2% to 90.7% ± 1.5% of ZIKV–envelope glycoprotein expression in infected cells as compared to 36.8% ± 2.9% of infection in vehicle control. The viral load was also investigated and revealed a reduction of 2- to 3-logs of ZIKV genome copies/mL in culture supernatants compared to 6.7 ± 0.7 × 108 copies/mL in vehicle control. The dose–response curve by plaque-forming reduction (PFR) in cervical cells revealed a potent dose-dependent activity of C-Sds in inhibiting ZIKV replication, with PFR above 50% and 90% at 6 and 12 µM, respectively, while 25 µM inhibited 100% of viral progeny. The treatment of Vero cells at 12 µM led to 100% PFR, confirming the C-Sds activity in another cell type. Regarding effective concentration in cervical cells, the EC50 values ranged from 3.2 ± 0.1 to 5.0 ± 0.2 µM, and the EC90 values ranged from 7.2 ± 0.1 to 11.6 ± 0.1 µM, with selectivity index above 40 for most C-Sds, showing a good therapeutic window. Here, our aim is to investigate the anti-ZIKV activity of new hybrid compounds that show highly potent efficacy as inhibitors of ZIKV in-vitro infection. However, further studies will be needed to investigate whether these new chemical structures can lead to the improvement of chloroquine antiviral activity.

scholarly journals Antiviral Activity of the G-Quadruplex Ligand TMPyP4 against Herpes Simplex Virus-1

Viruses ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 196
Author(s):  
Sara Artusi ◽  
Emanuela Ruggiero ◽  
Matteo Nadai ◽  
Beatrice Tosoni ◽  
Rosalba Perrone ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Dna Replication ◽  
Herpes Simplex ◽  
Antiviral Activity ◽  
Herpes Simplex Virus 1 ◽  
Tem Analysis ◽  
Infected Cells ◽  
Simplex Virus ◽  
Hsv 1

The herpes simplex virus 1 (HSV-1) genome is extremely rich in guanine tracts that fold into G-quadruplexes (G4s), nucleic acid secondary structures implicated in key biological functions. Viral G4s were visualized in HSV-1 infected cells, with massive virus cycle-dependent G4-formation peaking during viral DNA replication. Small molecules that specifically interact with G4s have been shown to inhibit HSV-1 DNA replication. We here investigated the antiviral activity of TMPyP4, a porphyrin known to interact with G4s. The analogue TMPyP2, with lower G4 affinity, was used as control. We showed by biophysical analysis that TMPyP4 interacts with HSV-1 G4s, and inhibits polymerase progression in vitro; in infected cells, it displayed good antiviral activity which, however, was independent of inhibition of virus DNA replication or entry. At low TMPyP4 concentration, the virus released by the cells was almost null, while inside the cell virus amounts were at control levels. TEM analysis showed that virus particles were trapped inside cytoplasmatic vesicles, which could not be ascribed to autophagy, as proven by RT-qPCR, western blot, and immunofluorescence analysis. Our data indicate a unique mechanism of action of TMPyP4 against HSV-1, and suggest the unprecedented involvement of currently unknown G4s in viral or antiviral cellular defense pathways.

Antiviral activity of Mulberroside C against enterovirus A71 in vitro and in vivo

2021 ◽  
pp. 174204
Author(s):  
Yiming Cao ◽  
En Lei ◽  
Lei Li ◽  
Jin Ren ◽  
Xiaoyang He ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Enterovirus A71
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