7-deazapurine Ribonucleosides Research Articles

Synthesis and Biological Profiling of Quinolino-Fused 7-Deazapurine Nucleosides.

A series of quinolino-fused 7-deazapurine (pyrimido[5',4':4,5]pyrrolo[3,2-f]quinoline) ribonucleosides were designed and synthesized. The synthesis of the key 11-chloro-pyrimido[5',4':4,5]pyrrolo[3,2-f]quinoline was based on the Negishi cross-coupling of iodoquinoline with zincated 4,6-dichloropyrimidine followed by azidation and thermal or photochemical cyclization. Vorbrüggen glycosylation of the tetracyclic heterocycle followed by cross-coupling or substitution reactions at position 11 gave the desired set of final nucleosides that showed moderate to weak cytostatic activity and fluorescent properties. The corresponding fused adenosine derivative was converted to the triphosphate and successfully incorporated to RNA using in vitro transcription with T7 RNA polymerase.

Dual N6/C7-Substituted 7-Deazapurine and Tricyclic Ribonucleosides with Affinity for G Protein-Coupled Receptors.

Various purine-based nucleoside analogues have demonstrated unexpected affinity for nonpurinergic G protein-coupled receptors (GPCRs), such as opioid and serotonin receptors. In this work, we synthesized a small library of new 7-deazaadenosine and pyrazolo[3,4-d]pyrimidine riboside analogues, featuring dual C7 and N6 modifications and assessed their affinity for various GPCRs. During the course of the synthesis of 7-ethynyl pyrazolo[3,4-d]pyrimidine ribosides, we observed the formation of an unprecedented tricyclic nucleobase, formed via a 6-endo-dig ring closure. The synthesis of this tricyclic nucleoside was optimized, and the substrate scope for such cyclization was further explored because it might avail further exploration in the nucleoside field. From displacement experiments on a panel of GPCRs and transporters, combining C7 and N6 modifications afforded noncytotoxic nucleosides with micromolar and submicromolar affinity for different GPCRs, such as the 5-hydroxytryptamine (5-HT)2B, κ-opioid (KOR), and σ1/2 receptor. These results corroborate that the novel nucleoside analogues reported here are potentially useful starting points for the further development of modulators of GPCRs and transmembrane proteins.

Antiviral Activity of 7-Substituted 7-Deazapurine Ribonucleosides, Monophosphate Prodrugs, and Triphoshates against Emerging RNA Viruses

A series of 7-deazaadenine ribonucleosides bearing alkyl, alkenyl, alkynyl, aryl, or hetaryl groups at position 7 as well as their 5'-O-triphosphates and two types of monophosphate prodrugs (phosphoramidates and S-acylthioethanol esters) were prepared and tested for antiviral activity against selected RNA viruses (Dengue, Zika, tick-borne encephalitis, West Nile, and SARS-CoV-2). The modified triphosphates inhibited the viral RNA-dependent RNA polymerases at micromolar concentrations through the incorporation of the modified nucleotide and stopping a further extension of the RNA chain. 7-Deazaadenosine nucleosides bearing ethynyl or small hetaryl groups at position 7 showed (sub)micromolar antiviral activities but significant cytotoxicity, whereas the nucleosides bearing bulkier heterocycles were still active but less toxic. Unexpectedly, the monophosphate prodrugs were similarly or less active than the corresponding nucleosides in the in vitro antiviral assays, although the bis(S-acylthioethanol) prodrug 14h was transported to the Huh7 cells and efficiently released the nucleoside monophosphate.

Synthesis and Cytotoxic and Antiviral Activity Profiling of All-Four Isomeric Series of Pyrido-Fused 7-Deazapurine Ribonucleosides.

All four isomeric series of novel 4-substituted pyrido-fused 7-deazapurine ribonucleosides possessing the pyridine nitrogen atom at different positions were designed and synthesized. The total synthesis of each isomeric fused heterocycle through multistep heterocyclization was followed by glycosylation and derivatization at position 4 by cross-coupling reactions or nucleophilic substitutions. All compounds were tested for cytostatic and antiviral activity. The most active were pyrido[4',3':4,5]pyrimidine nucleosides bearing MeO, NH2 , MeS, or CH3 groups at position 4, which showed submicromolar cytotoxic effects and good selectivity for cancer cells. The mechanism involved activation by phosphorylation and incorporation to DNA where the presence of the modified ribonucleosides causes double-strand breaks and apoptosis.

Synthesis and Biological Profiling of Pyrazolo-Fused 7-Deazapurine Nucleosides.

A series of 8-substituted 1-methyl-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[2,3-d]pyrimidine (methylpyrazolo-fused 7-deazapurine) ribonucleosides have been designed and synthesized. Two synthetic approaches to the key heterocyclic aglycon 7, (i) a six-step classical heterocyclization starting from 5-chloro-1-methyl-4-nitropyrazole and (ii) a three-step cross-coupling and cyclization approach starting from the zincated 4,6-dichloropyrimidine, gave comparable total yields of 18% vs 13%. The glycosylation of 7 was attempted by three different methods but only the Vorbrüggen silyl-base protocol was efficient and stereoselective to give desired β-anomeric nucleoside intermediate 17A. Its nucleophilic substitutions or cross-coupling reactions at position 8 and deprotection of the sugar moiety gave eight derivatives of pyrazolo-fused deazapurine ribonucleosides, some of which were weakly fluorescent. Methyl, amino, and methylsulfanyl derivatives exerted submicromolar cytotoxic effects in vitro against a panel of cancer and leukemia cell lines as well as antiviral effects against hepatitis C virus in the replicon assay.

Synthesis, Photophysical Properties, and Biological Profiling of Benzothieno-Fused 7-Deazapurine Ribonucleosides.

Two isomeric series of benzothieno-fused 7-deazapurine (benzo[4',5']thieno[3',2':4,5]- and benzo[4',5']thieno[2',3':4,5]pyrrolo[2,3-d]pyrimidine) ribonucleosides were designed and synthesized. Key steps of the synthesis included the Negishi coupling of zincated dichloropyrimidine with 2- or 3-iodobenzothiophene followed by azidation, thermal or photochemical cyclization, glycosylation, and final functionalization at position 6 through cross-couplings or nucleophilic substitutions. Deprotection gave the final nucleosides, some of which showed moderate cytotoxic and antiviral activity. Most of the free nucleosides showed moderate to strong fluorescence with emission maxima of 362-554 nm. 2'-Deoxyribonucleoside and its 5'-O-triphosphate were also prepared from benzothieno-fused 7-deazaadenine derivative, and the triphosphate was a good substrate for KOD XL DNA polymerase in primer extension synthesis of modified DNA which exerted a weak fluorescence which was slightly enhanced in double-stranded DNA as compared to single-stranded oligonucleotides.

Iron/Copper Co-Catalyzed Cross-Coupling Reaction for the Synthesis of 6-Substituted 7-Deazapurines and the Corresponding Nucleosides.

An efficient access to 6-substituted 7-deazapurine and the corresponding nucleosides by coupling aryl or alkyl Grignard reagents and halogenated purine nucleosides in the presence of Fe(acac)3/CuI is described. A series of 6-substituted 7-deazapurines and the corresponding nucleosides were obtained in medium to good yields. For the synthesis of modified nucleosides that will be the subject of biological testing, we propose to use iron-catalyzed instead of palladium-catalyzed reaction. The synthesized compounds were tested for their antiproliferative activity. The cytotoxicity study of compounds 11a-q shows that by modifying the 6-position of 7-deazapurine ribonucleosides, the compounds may become selective for certain cancer cell lines.

Correction to “Synthesis and Cytotoxic and Antiviral Profiling of Pyrrolo- and Furo-Fused 7-Deazapurine Ribonucleosides”

ADVERTISEMENT RETURN TO ISSUEPREVAddition/CorrectionNEXTORIGINAL ARTICLEThis notice is a correctionCorrection to “Synthesis and Cytotoxic and Antiviral Profiling of Pyrrolo- and Furo-Fused 7-Deazapurine Ribonucleosides”Anna TokarenkoAnna TokarenkoMore by Anna Tokarenkohttp://orcid.org/0000-0003-0085-026X, Barbora LiškováBarbora LiškováMore by Barbora Lišková, Sabina SmoleńSabina SmoleńMore by Sabina Smoleń, Natálie TáborskáNatálie TáborskáMore by Natálie Táborská, Michal TichýMichal TichýMore by Michal Tichýhttp://orcid.org/0000-0002-8460-7680, Soňa GurskáSoňa GurskáMore by Soňa Gurská, Pavla PerlíkováPavla PerlíkováMore by Pavla Perlíková, Ivo FrydrychIvo FrydrychMore by Ivo Frydrychhttp://orcid.org/0000-0003-1412-1607, Eva Tloušt’ováEva Tloušt’ováMore by Eva Tloušt’ová, Pawel ZnojekPawel ZnojekMore by Pawel Znojek, Helena Mertlíková-KaiserováHelena Mertlíková-KaiserováMore by Helena Mertlíková-Kaiserová, Lenka Poštová SlavětínskáLenka Poštová SlavětínskáMore by Lenka Poštová Slavětínská, Radek PohlRadek PohlMore by Radek Pohl, Blanka KlepetářováBlanka KlepetářováMore by Blanka Klepetářová, Noor-Ul-Ain KhalidNoor-Ul-Ain KhalidMore by Noor-Ul-Ain Khalid, Yiqian WenrenYiqian WenrenMore by Yiqian Wenren, Rebecca R. LaposaRebecca R. LaposaMore by Rebecca R. Laposa, Petr DžubákPetr DžubákMore by Petr Džubák, Marián Hajdúch*Marián HajdúchMore by Marián Hajdúch, and Michal Hocek*Michal HocekMore by Michal Hocekhttp://orcid.org/0000-0002-1113-2047Cite this: J. Med. Chem. 2019, 62, 3, 1698Publication Date (Web):January 25, 2019Publication History Published online25 January 2019Published inissue 14 February 2019https://doi.org/10.1021/acs.jmedchem.9b00114Copyright © 2019 American Chemical SocietyRIGHTS & PERMISSIONSACS AuthorChoiceArticle Views976Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (320 KB) Get e-Alerts Get e-Alerts

Synthesis and Cytotoxic and Antiviral Profiling of Pyrrolo- and Furo-Fused 7-Deazapurine Ribonucleosides

Three series of isomeric pyrrolo- and furo-fused 7-deazapurine ribonucleosides were synthesized and screened for cytostatic and antiviral activity. The synthesis was based on heterocyclizations of hetaryl-azidopyrimidines to form the tricyclic heterocyclic bases, followed by glycosylation and final derivatizations through cross-coupling reactions or nucleophilic substitutions. The pyrrolo[2',3':4,5]pyrrolo[2,3- d]pyrimidine and furo[2',3':4,5]pyrrolo[2,3- d]pyrimidine ribonucleosides were found to be potent cytostatics, whereas the isomeric pyrrolo[3',2',4,5]pyrrolo[2,3- d]pyrimidine nucleosides were inactive. The most active were the methyl, methoxy, and methylsulfanyl derivatives exerting submicromolar cytostatic effects and good selectivity toward cancer cells. We have shown that the nucleosides are activated by intracellular phosphorylation and the nucleotides get incorporated to both RNA and DNA, where they cause DNA damage. They represent a new type of promising candidates for preclinical development toward antitumor agents.

Synthesis and Cytostatic and Antiviral Profiling of Thieno-Fused 7-Deazapurine Ribonucleosides

Two isomeric series of new thieno-fused 7-deazapurine ribonucleosides (derived from 4-substituted thieno[2',3':4,5]pyrrolo[2,3-d]pyrimidines and thieno[3',2':4,5]pyrrolo[2,3-d]pyrimidines) were synthesized by a sequence involving Negishi coupling of 4,6-dichloropyrimidine with iodothiophenes, nucleophilic azidation, and cyclization of tetrazolopyrimidines, followed by glycosylation and cross-couplings or nucleophilic substitutions at position 4. Most nucleosides (from both isomeric series) exerted low micromolar or submicromolar in vitro cytostatic activities against a broad panel of cancer and leukemia cell lines and some antiviral activity against HCV. The most active were the 6-methoxy, 6-methylsulfanyl, and 6-methyl derivatives, which were highly active to cancer cells and less toxic or nontoxic to fibroblasts.

Abstract 3657: 6-(Het)aryl-7-Deazapurine Ribonucleosides as Potent Novel Cytostatic Agents that Interfere with RNA Synthesis

Abstract A series of 33 7-deazapurine ribonucleosides bearing an alkyl, aryl or hetaryl group in position 6 and H, F or Cl atom in position 7 was successfully synthesized. Significant cytostatic effects against both hematological and solid tumor cell lines were found for most of these compounds under in vitro conditions. The most potent were 7-H and 7-F derivatives of 6-furyl-/ 6-thienyl-7-deazapurine ribosides displaying nanomolar GIC50 values (comparable to gemcitabine or clofarabine) in several cancer cell lines. Intracellular phosphorylation to mono- and tri-phosphates and consequent inhibition of RNA synthesis, but not DNA synthesis, were demonstrated in preliminary studies of metabolism and mechanism of action. One of the most active compounds (6-thienyl-7-F-7-deazapurine riboside) was tested for in vivo toxicology in mice, and dose limiting toxicities were weight lost and leucopenia. However, the compound demonstrated highly significant antitumor activity at doses equivalent to MTD and ½ MTD, and afforded the extension of survival in treated mice bearing P388D1 leukemia (p<0.001 compared to untreated animals). Antitumor effect was comparable to doxorubicin in P388D1 model. Interestingly, the intraperitoneal administration of the compound resulted in good local control of intraperitoneally transplanted tumors. Supported by grants awarded by the Czech Ministry of Education (MSM 6198959216 and LC07017). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3657.

6-(Het)aryl-7-Deazapurine Ribonucleosides as Novel Potent Cytostatic Agents

A series of novel 7-deazapurine ribonucleosides bearing an alkyl, aryl, or hetaryl group in position 6 and H, F, or Cl atom in position 7 has been prepared either by Pd-catalyzed cross-coupling reactions of the corresponding protected 6-chloro-(7-halogenated-)7-deazapurine ribonucleosides with alkyl- or (het)arylorganometallics followed by deprotection, or by single-step aqueous phase cross-coupling reactions of unprotected 6-chloro-(7-halogenated-)7-deazapurine ribonucleosides with (het)arylboronic acids. Significant cytostatic effect was detected with a substantial proportion of the prepared compounds. The most potent were 7-H or 7-F derivatives of 6-furyl- or 6-thienyl-7-deazapurines displaying cytostatic activity in multiple cancer cell lines with a geometric mean of 50% growth inhibition concentration ranging from 16 to 96 nM, a potency comparable to or better than that of the nucleoside analogue clofarabine. Intracellular phosphorylation to mono- and triphosphates and the inhibition of total RNA synthesis was demonstrated in preliminary study of metabolism and mechanism of action studies.

7-Functionalized 7-deazapurine β- d and β- l-ribonucleosides related to tubercidin and 7-deazainosine: glycosylation of pyrrolo[2,3- d]pyrimidines with 1- O-acetyl-2,3,5-tri- O-benzoyl-β- d or β- l-ribofuranose

Several 7-functionalized 7-deazapurine ribonucleosides were prepared. Glycosylation of 7-halogenated 6-chloro-7-deazapurines with 1- O-acetyl-2,3,5-tri- O-benzoyl-β- d-ribofuranose or 1- O-acetyl-2,3,5-tri- O-benzoyl-β- l-ribofuranose gave the protected β- d-nucleosides 8c– e (53–62%) and the β- l-nucleosides 9b– e (57–72%), which were transformed to 7-halogenated 7-deazapurine ribonucleosides related to tubercidin and 7-deazainosine. 7-Alkynyl derivatives ( 1f, g) and ( 2f, g) were obtained from the 7-iodo nucleosides 1e and 2e employing the palladium-catalyzed Sonogashira cross-coupling reaction. Within the series of 7-deazaadenosine (tubercidin) analogues and 7-deazainosine derivatives physical data such as p K a values, chromatographic mobilities, 13C NMR chemical shifts were determined and correlated to each other.

Progress in 7‐Deazapurine: Pyrrolo[2,3‐d]pyrimidine — Ribonucleoside Synthesis

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Progress in 7-Deazapurine - Pyrrolo[2,3-d]pyrimidine - Ribonucleoside Synthesis

This review reports on the synthesis of 7-deazapurine ribonucleosides, including C-nucleosides, 2'-C-methyl derivatives and L-enantiomers. It covers the various aspects of convergent nucleoside synthesis such as the Schiff base procedure, the fusion reaction, the metal salt procedures, the Silyl-Hilbert-Johnson reaction, and the nucleobase anion glycosylation. The review discusses the scope and limitations of glycosylation reactions performed on 7-deazapurines. Peracylated ribose derivatives were now employed in the glycosylation, which overcome difficulties reported earlier.

7-Functionalized 7-Deazapurine Ribonucleosides Related to 2-Aminoadenosine, Guanosine, and Xanthosine: Glycosylation of Pyrrolo[2,3-d]pyrimidines with 1-O-Acetyl-2,3,5-tri-O-benzoyl-d-ribofuranose

[reaction: see text] The Silyl-Hilbert-Johnson reaction as well as the nucleobase-anion glycosylation of a series of 7-deazapurines has been investigated, and the 7-functionalized 7-deazapurine ribonucleosides were prepared. Glycosylation of the 7-halogenated 6-chloro-2-pivaloylamino-7-deazapurines 9b-d with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose (5) gave the beta-D-nucleosides 11b-d (73-75% yield), which were transformed to a number of novel 7-halogenated 7-deazapurine ribonucleosides (2b-d, 3b-d, and 4b-d) related to guanosine, 2-aminoadenosine, and xanthosine. 7-Alkynyl derivatives (2e-i, 3e-h, or 4g) have been prepared from the corresponding 7-iodonucleosides 2d, 3d, or 4d employing the palladium-catalyzed Sonogashira cross-coupling reaction. The 7-halogenated 2-amino-7-deazapurine ribonucleosides with a reactive 6-chloro substituent (18b-d) were synthesized in an alternative way using nucleobase-anion glycosylation performed on the 7-halogenated 2-amino-6-chloro-7-deazapurines 13b-d with 5-O-[(1,1-dimethylethyl)dimethylsilyl]-2,3-O-(1-methylethylidene)-alpha-D-ribofuranosyl chloride (17). Compounds 18b-d have been converted to the nucleosides 19b-d carrying reactive substituents in the pyrimidine moiety. Conformational analysis of selected nucleosides on the basis of proton coupling constants and using the program PSEUROT showed that these ribonucleosides exist in a preferred S conformation in solution.