Synthesis and Properties of Artificial Oligonucleotides Containing Novel Nucleoside Analogs with Cationic Alkyl Sidechains

BACKGROUND COVID-19 pandemic prompts the study of coronavirus biology and search of putative therapeutic strategies. OBJECTIVE To compare SARS-CoV-2 genome-wide structure and proteins with other coronaviruses, focusing on putative coronavirus-specific or SARS-CoV-2 specific therapeutic designs. METHODS The genome-wide structure of SARS-CoV-2 was compared to that of SARS and other coronaviruses in order to gain insights, doing a literature review through Google searches. RESULTS There are promising therapeutic alternatives. Host cell targets could be modulated to hamper viral replication, but targeting viral proteins directly would be a better therapeutic design, since fewer adverse side effects would be expected. CONCLUSIONS Therapeutic strategies (Figure 1) could include the modulation of host targets (PARPs, kinases) , competition with G-quadruplexes or nucleoside analogs to hamper RDRP. The nicest anti-CoV options include inhibitors of the conserved essential viral proteases and drugs that interfere ribosome slippage at the -1 PRF site.

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Modified Nucleosides, Nucleotides and Nucleic Acids via Click Azide-Alkyne Cycloaddition for Pharmacological Applications

Molecules ◽

10.3390/molecules26113100 ◽

2021 ◽

Vol 26 (11) ◽

pp. 3100

Author(s):

Daniela Perrone ◽

Elena Marchesi ◽

Lorenzo Preti ◽

Maria Luisa Navacchia

Keyword(s):

Cancer Therapy ◽

Nucleic Acids ◽

Click Chemistry ◽

Nucleoside Analogs ◽

Modified Nucleosides ◽

Biological Molecules ◽

Dipolar Cycloaddition ◽

Virus Diseases ◽

Reaction Conditions ◽

Hybrid Compounds

The click azide = alkyne 1,3-dipolar cycloaddition (click chemistry) has become the approach of choice for bioconjugations in medicinal chemistry, providing facile reaction conditions amenable to both small and biological molecules. Many nucleoside analogs are known for their marked impact in cancer therapy and for the treatment of virus diseases and new targeted oligonucleotides have been developed for different purposes. The click chemistry allowing the tolerated union between units with a wide diversity of functional groups represents a robust means of designing new hybrid compounds with an extraordinary diversity of applications. This review provides an overview of the most recent works related to the use of click chemistry methodology in the field of nucleosides, nucleotides and nucleic acids for pharmacological applications.

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Synthesis and Antiviral Evaluation of Nucleoside Analogues Bearing One Pyrimidine Moiety and Two D-Ribofuranosyl Residues

Molecules ◽

10.3390/molecules26123678 ◽

2021 ◽

Vol 26 (12) ◽

pp. 3678

Author(s):

Olga V. Andreeva ◽

Bulat F. Garifullin ◽

Vladimir V. Zarubaev ◽

Alexander V. Slita ◽

Iana L. Yesaulkova ◽

...

Keyword(s):

Influenza Virus ◽

Antiviral Activity ◽

Theoretical Calculations ◽

Nucleoside Analogs ◽

Coxsackievirus B3 ◽

Nucleoside Analogues ◽

Moderate Activity ◽

Coat Proteins ◽

Influenza Virus A ◽

Ic50 Values

A series of 1,2,3-triazolyl nucleoside analogues in which 1,2,3-triazol-4-yl-β-d-ribofuranosyl fragments are attached via polymethylene linkers to both nitrogen atoms of the heterocycle moiety (uracil, 6-methyluracil, thymine, quinazoline-2,4-dione, alloxazine) or to the C-5 and N-3 atoms of the 6-methyluracil moiety was synthesized. All compounds synthesized were evaluated for antiviral activity against influenza virus A/PR/8/34/(H1N1) and coxsackievirus B3. Antiviral assays revealed three compounds, 2i, 5i, 11c, which showed moderate activity against influenza virus A H1N1 with IC50 values of 57.5 µM, 24.3 µM, and 29.2 µM, respectively. In the first two nucleoside analogues, 1,2,3-triazol-4-yl-β-d-ribofuranosyl fragments are attached via butylene linkers to N-1 and N-3 atoms of the heterocycle moiety (6-methyluracil and alloxazine, respectively). In nucleoside analogue 11c, two 1,2,3-triazol-4-yl-2′,3′,5′-tri-O-acetyl-β-d-ribofuranose fragments are attached via propylene linkers to the C-5 and N-3 atoms of the 6-methyluracil moiety. Almost all synthesized 1,2,3-triazolyl nucleoside analogues showed no antiviral activity against the coxsackie B3 virus. Two exceptions are 1,2,3-triazolyl nucleoside analogs 2f and 5f, in which 1,2,3-triazol-4-yl-2′,3′,5′-tri-O-acetyl-β-d-ribofuranose fragments are attached to the C-5 and N-3 atoms of the heterocycle moiety (6-methyluracil and alloxazine respectively). These compounds exhibited high antiviral potency against the coxsackie B3 virus with IC50 values of 12.4 and 11.3 µM, respectively, although both were inactive against influenza virus A H1N1. According to theoretical calculations, the antiviral activity of the 1,2,3-triazolyl nucleoside analogues 2i, 5i, and 11c against the H1N1 (A/PR/8/34) influenza virus can be explained by their influence on the functioning of the polymerase acidic protein (PA) of RNA-dependent RNA polymerase (RdRp). As to the antiviral activity of nucleoside analogs 2f and 5f against coxsackievirus B3, it can be explained by their interaction with the coat proteins VP1 and VP2.

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Moxetumomab pasudotox in heavily pre-treated patients with relapsed/refractory hairy cell leukemia (HCL): long-term follow-up from the pivotal trial

Journal of Hematology & Oncology ◽

10.1186/s13045-020-01004-y ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Robert J. Kreitman ◽

◽

Claire Dearden ◽

Pier Luigi Zinzani ◽

Julio Delgado ◽

...

Keyword(s):

Hairy Cell Leukemia ◽

Residual Disease ◽

Braf Inhibitor ◽

Nucleoside Analogs ◽

High Rate ◽

Hairy Cell ◽

Cell Leukemia ◽

Long Term Follow Up

Abstract Background Moxetumomab pasudotox is a recombinant CD22-targeting immunotoxin. Here, we present the long-term follow-up analysis of the pivotal, multicenter, open-label trial (NCT01829711) of moxetumomab pasudotox in patients with relapsed/refractory (R/R) hairy cell leukemia (HCL). Methods Eligible patients had received ≥ 2 prior systemic therapies, including ≥ 2 purine nucleoside analogs (PNAs), or ≥ 1 PNA followed by rituximab or a BRAF inhibitor. Patients received 40 µg/kg moxetumomab pasudotox intravenously on Days 1, 3, and 5 of each 28-day cycle for up to six cycles. Disease response and minimal residual disease (MRD) status were determined by blinded independent central review. The primary endpoint was durable complete response (CR), defined as achieving CR with hematologic remission (HR, blood counts for CR) lasting > 180 days. Results Eighty adult patients were treated with moxetumomab pasudotox and 63% completed six cycles. Patients had received a median of three lines of prior systemic therapy; 49% were PNA-refractory, and 38% were unfit for PNA retreatment. At a median follow-up of 24.6 months, the durable CR rate (CR with HR > 180 days) was 36% (29 patients; 95% confidence interval: 26–48%); CR with HR ≥ 360 days was 33%, and overall CR was 41%. Twenty-seven complete responders (82%) were MRD-negative (34% of all patients). CR lasting ≥ 60 months was 61%, and the median progression-free survival without the loss of HR was 71.7 months. Hemolytic uremic and capillary leak syndromes were each reported in ≤ 10% of patients, and ≤ 5% had grade 3–4 events; these events were generally reversible. No treatment-related deaths were reported. Conclusions Moxetumomab pasudotox resulted in a high rate of durable responses and MRD negativity in heavily pre-treated patients with HCL, with a manageable safety profile. Thus, it represents a new and viable treatment option for patients with R/R HCL, who currently lack adequate therapy. Trial registration ClinicalTrials.gov identifier: NCT01829711; first submitted: April 9, 2013. https://clinicaltrials.gov/ct2/show/NCT01829711

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Synthesis and Cytotoxic Activity of New 1,4-Dithiazolyl-5-oxopyrrole Derivatives, Their 1,2,4-Triazoles and Nucleoside Analogs

Russian Journal of General Chemistry ◽

10.1134/s1070363220080241 ◽

2020 ◽

Vol 90 (8) ◽

pp. 1544-1552

Author(s):

H. E. M. Tolan ◽

M. A. A. Radwan ◽

H. S. Khalaf ◽

M. N. El-Bayaa ◽

H. M. Awad ◽

...

Keyword(s):

Cytotoxic Activity ◽

Nucleoside Analogs

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ChemInform Abstract: NUCLEIC ACID RELATED COMPOUNDS. 37. CONVENIENT AND HIGH-YIELD SYNTHESES OF N-((2-HYDROXYETHOXY)METHYL)HETEROCYCLES AS “ACYCLIC NUCLEOSIDE” ANALOGS

Chemischer Informationsdienst ◽

10.1002/chin.198229302 ◽

1982 ◽

Vol 13 (29) ◽

Author(s):

M. J. ROBINS ◽

P. W. HATFIELD

Keyword(s):

Nucleic Acid ◽

Nucleoside Analogs ◽

High Yield ◽

Acyclic Nucleoside ◽

Related Compounds

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Antitrypanosomal activity of purine nucleosides can be enhanced by their conversion to O-acetylated derivatives.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.40.11.2567 ◽

1996 ◽

Vol 40 (11) ◽

pp. 2567-2572 ◽

Cited By ~ 11

Author(s):

J R Sufrin ◽

D Rattendi ◽

A J Spiess ◽

S Lane ◽

C J Marasco ◽

...

Keyword(s):

Trypanosoma Brucei ◽

Parent Compound ◽

Nucleoside Analogs ◽

Significant Activity ◽

Structural Class ◽

Antitrypanosomal Activity ◽

Salvage Pathways ◽

Purine Salvage Pathways

Fifteen purine nucleosides and their O-acetylated ester derivatives were examined for in vitro antitrypanosomal activity against the LAB 110 EATRO isolate of Trypanosoma brucei brucei and two clinical isolates of Trypanosoma brucei rhodesiense. Initial comparisons of activity were made for the LAB 110 EATRO isolate. Three nucleoside analogs exhibited no significant activity (50% inhibitory concentrations [IC50s] of > 100 microM), whether they were O acetylated or unacetylated; three nucleosides showed almost equal activity (IC50s of < 5 microM) for the parent compound and the O-acetylated derivative; nine nucleosides showed significantly improved activity (> or = 3-fold) upon O acetylation; of these nine analogs, six displayed activity at least 10-fold greater than that of their parent nucleosides. The most significant results were those for four apparently inactive compounds which, upon O acetylation, displayed IC50s of < or = 25 microM. When the series of compounds was tested against T. brucei rhodesiense isolates (KETRI 243 and KETRI 269), their antitrypanosomal effects were comparable to those observed for the EATRO 110 strain. Thus, our studies of purine nucleosides have determined that O acetylation consistently improved their in vitro antitrypanosomal activity. This observed phenomenon was independent of their cellular enzyme targets (i.e., S-adenosylmethionine, polyamine, or purine salvage pathways). On the basis of our results, the routine preparation of O-acetylated purine nucleosides for in vitro screening of antitrypanosomal activity is recommended, since O acetylation transformed several inactive nucleosides into compounds with significant activity, presumably by improving uptake characteristics. O-acetylated purine nucleosides may offer in vivo therapeutic advantages compared with their parent nucleosides, and this possibility should be considered in future evaluations of this structural class of trypanocides.

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