Synthesis of Pyrimidine-Annulated Five-Membered Heterocycles: An Overview

“… 1) , 2) , 3) , 4) , 5) , 6) , 7) , 8) Among the most active analogues, furopyrimidine nucleosides stand out as potent and selective antiviral agents with a high specific activity against varicella-zoster virus (VZV). 10) , 11) , 9) p -Alkylphenyl, particularly p -pentylphenyl, substituents attached to C-6 give rise to the most effective structures ( 1a , b ; Figure 1 ). 12) , 13) , 14) In parallel, significant biological activity can be imposed by appending an alkyne, an example includes 5-alkynyluridines.…”

Section: Introductionmentioning

confidence: 99%

Extension of furopyrimidine nucleosides with 5-alkynyl substituent: Synthesis, high fluorescence, and antiviral effect in the absence of free ribose hydroxyl groups

Kaczmarek

Twardy

Olson

et al. 2021

European Journal of Medicinal Chemistry

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A novel methodology to access alkynyl nucleoside analogs was elaborated. Highly fluorescent 5-alkynylfuropyrimidines were synthesized (97-46%) and their antiviral properties investigated in vitro . Regiochemistry of the functionalization was achieved with the aid of 5- endo - dig electrophilic halocyclization of acetyl 5- p -tolyl- or 5- p -pentylphenyl-2'-deoxyuridine. Structure of one of the resulting nucleosides, 6- p -tolyl-5-iodo-2'-deoxyribofuranosyl-furo[2,3- d ]pyrimidin-2-one, was confirmed by X-ray crystallography, and its conformation was compared to related nucleosides. Diverse alkynyl substituents were introduced at the heterobicyclic base C-5 position via Sonogashira coupling of 5-iodo-2'-deoxyribofuranosyl-furo[2,3- d ]pyrimidin-2-ones. The resulting compounds had fluorescence emissions of 452 to 481 nm. High quantum yields of 0.53-0.60 were observed for 9-ethynyl-9-fluorenol and propargyl alcohol/methyl ether-modified furopyrimidines. These modified nucleosides, designed in the form of ribose acetyl esters, represent potential tools for fluorescent tagging, studying nucleoside metabolism, 2′-deoxyribonucleoside kinase activity, and antiviral activity. Antiviral assays against a broad spectrum of DNA and RNA viruses showed that in human embryonic lung (HEL) cell cultures some of the compounds showed antiviral activity (EC 50 1.3-13.2 μM) against varicella-zoster virus (VZV). The alkynyl furopyrimidine with two p -pentylphenyl substituents emerged as the best compound with reasonable and selective anti-VZV activity, confirming p -pentylphenyl potency as a pharmacophore.

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“…Among modified nucleosides, furopyrimidine nucleosides are recognized as potent and selective antiviral agents with high specific activity against varicella-zoster virus (VZV). − The most active analogs, such as 7 , contain p -alkylphenyl substituents at C-6 (Figure ). − …”

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confidence: 99%

Synthesis and Determination of Anticancer Activity of Dicobalt Hexacarbonyl 2′-Deoxy-5-alkynylfuropyrimidines

Kaczmarek

Radzikowska

Królewska-Golińska

et al. 2023

ACS Med. Chem. Lett.

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Dicobalt hexacarbonyl 5-alkynyl furopyrimidine nucleoside analogs, with 4-methylphenyl (p-tolyl) and 4-pentylphenyl substituents attached at the C-6 base position, designed in the form of ribose acetyl esters, were synthesized (42–96%). Attached at the C-5 position were propargyl alcohol, its methyl ether and acetate derivatives, butynol, and the 4-methylphenyl- (p-tolyl) and 4-pentylphenyl-substituted alkynyl groups, which were coordinated to a dicobalt hexacarbonyl unit. The structure of 5-(3-acetoxyprop-1-yn-1-yl)-6-p-tolyl-2′-deoxyribofuranosyl-furo[2,3-d]pyrimidin-2-one was determined by X-ray crystallography. Density functional theory calculations performed on the corresponding derivative yielded geometric parameters for the dicobalt hexacarbonyl adduct of this ligand. The cytotoxic activity of each of dicobalt modified nucleosides on cancer cells of different phenotypes was determined in vitro. The investigated compounds showed antiproliferative effects with median inhibitory concentration (IC50) values in the ranges of 14–90 and 9–50 μM for HeLa and K562 cells, respectively. The formation of reactive oxygen species in the presence of modified nucleosides was determined in K562 cells. The results indicate that the mechanism of action for the studied compounds may be related to the induction of oxidative stress.

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Synthesis of Pyrimidine-Annulated Five-Membered Heterocycles: An Overview

Cited by 13 publications

References 144 publications

Formation and Uses of Imidazo[1,2-a]pyrimidines and Related Compounds: A Review Comprising Years 2000-2021

Formation and Uses of Imidazo[1,2-a]pyrimidines and Related Compounds: A Review Comprising Years 2000-2021

Extension of furopyrimidine nucleosides with 5-alkynyl substituent: Synthesis, high fluorescence, and antiviral effect in the absence of free ribose hydroxyl groups

Synthesis and Determination of Anticancer Activity of Dicobalt Hexacarbonyl 2′-Deoxy-5-alkynylfuropyrimidines

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