Pyrrolo[2,3‐<i>d</i>]pyrimidine (7‐deazapurine) as a privileged scaffold in design of antitumor and antiviral nucleosides

Perlíková, Pavla; Hocek, Michal

doi:10.1002/med.21465

Cited by 96 publications

(93 citation statements)

References 163 publications

(377 reference statements)

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“…15,16 The triphosphates are inhibitors of DNA or RNA polymerases, preferably with specificity for the targeted organism. Nucleoside analogues missing the ribosyl 3′-hydroxyl group are chain terminators of nucleic acid synthesis.…”

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confidence: 99%

Immucillins in Infectious Diseases

2017

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The Immucillins are chemically stable analogues that mimic the ribocation and leaving-group features of N-ribosyltransferase transition states. Infectious disease agents often rely on ribosyltransferase chemistry in pathways involving precursor synthesis for nucleic acids, salvage of nucleic acid precursors, or synthetic pathways with nucleoside intermediates. Here, we review three infectious agents and the use of the Immucillins to taget enzymes essential to the parasites. First, DADMe-Immucillin-G is a purine nucleoside phosphorylase (PNP) inhibitor that blocks purine salvage and shows clinical potential for treatment for the malaria parasite Plasmodium falciparum, a purine auxotroph requiring hypoxanthine for purine nucleotide synthesis. Inhibition of the PNPs in the host and in parasite cells leads to apurinic starvation and death. Second, Helicobacter pylori, a causative agent of human ulcers, synthesizes menaquinone, an essential electron transfer agent, in a pathway requiring aminofutalosine nucleoside hydrolysis. Inhibitors of the H. pylori methylthioadenosine nucleosidase (MTAN) are powerful antibiotics for this organism. Synthesis of menaquinone by the aminofutalosine pathway does not occur in most bacteria populating the human gut microbiome. Thus, MTAN inhibitors provide high-specificity antibiotics for H. pylori and are not expected to disrupt the normal gut bacterial flora. Third, Immucillin-A was designed as a transition state analogue of the atypical PNP from Trichomonas vaginalis. In antiviral screens, Immucillin-A was shown to act as a prodrug. It is active against filoviruses and flaviviruses. In virus-infected cells, Immucillin-A is converted to the triphosphate, is incorporated into the viral transcript, and functions as an atypical chain-terminator for RNA-dependent RNA polymerases. Immucillin-A has entered clinical trials for use as an antiviral. We also summarize other Immucillins that have been characterized in successful clinical trials for T-cell lymphoma and gout. The human trials support the potential development of the Immucillins in infectious diseases.

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confidence: 99%

Immucillins in Infectious Diseases

2017

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“…Pyrimidines play a crucial role in the human being life because they are widely distributed in several important organic compounds . Many of these compounds exhibit outstanding biological and pharmacological effectiveness including antihypertensive, antiplatelet, antiviral, antidiabetic, antimicrobial, and antioxidant activities. In addition, many vital natural products such as vitamin B1 contain pyrimidine nucleus.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Computational Analysis of New Antioxidant and Antimicrobial Angular Chromenopyrimidines

Abozeid

El‐Kholany

Abou-Zeid

et al. 2019

Journal of Heterocyclic Chem

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A convenient synthetic protocol for the synthesis of novel chromenopyrimidine derivatives based on angular scaffold has been developed from the readily available enaminonitrile precursor 1. The skeleton of chromenopyrimidines has been decorated with different moieties in order to approach compounds with improved antioxidant and antimicrobial activities. Compound 1 was reacted with Ac2O to yield benzochromenopyrimidine 6 that gave chloropyrimidine 7 via chlorination reaction. The reaction of chloropyrimidine 7 with different amines afforded a series of benzochromenopyrimidines 9–12. The hydrazine 11 and hydrazide 13 derivatives showed excellent antioxidant activity in addition to the potent antimicrobial activity revealed by aminopyrimidines 10 and 16. Computational docking studies indicated the potential recognition of compound 13 towards antioxidant binding site. Dual evaluations of the antimicrobial affinity of compound 16 indicated its promising activity as antimicrobial lead.

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“…In contrast, modified nucleosides and their components have been in the focus of chemical studies for decades . As a result, many modified nucleosides have found therapeutic applications, mainly as antiviral and anticancer drugs …”

Section: Introductionmentioning

confidence: 99%

Ferrocenyl GNA Nucleosides: A Bridge between Organic and Organometallic Xeno‐nucleic Acids

et al. 2018

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The enantioselective synthesis and electrochemistry of the first ferrocenyl GNA nucleosides is reported. These compounds were obtained by a Sharpless asymmetric dihydroxylation reaction of [3‐(N1‐thyminyl)‐1‐(ferrocenyl)]propene as S,R and R,S enantiomers in about 70 % yield with enantiomeric excesses of >99 % and 71 %, respectively. The absolute configurations of the chiral carbon atoms in the nucleosides were assigned by single‐crystal X‐ray diffraction analysis of the methyl derivatives in the solid state. The compounds were also studied with circular dichroism (CD) spectroscopy in solution. The enantiomeric relationship between the S,R and R,S isomers was confirmed by the near‐mirror‐image CD spectra. The redox properties of the nucleosides and their methylated derivatives were investigated using cyclic voltammetry. The cyclic voltammograms revealed reversible redox processes for the entire series of compounds at potentials of −25 mV (for nonmethylated derivatives) and 75 mV (for methylated derivatives) versus the ferrocene/ferrocenium reference redox couple.

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Pyrrolo[2,3‐d]pyrimidine (7‐deazapurine) as a privileged scaffold in design of antitumor and antiviral nucleosides

Cited by 96 publications

References 163 publications

Immucillins in Infectious Diseases

Immucillins in Infectious Diseases

Synthesis and Computational Analysis of New Antioxidant and Antimicrobial Angular Chromenopyrimidines

Ferrocenyl GNA Nucleosides: A Bridge between Organic and Organometallic Xeno‐nucleic Acids

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