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A series of benzofuro‐fused 7‐deazapurine (6H‐furo[2,3‐e]pyrimido[4,5‐b]indole) 2'‐deoxyribo‐ and ribonucleosides was designed and synthesized. The synthesis of key compound 10‐chloro‐6H‐furo[2,3‐e]pyrimido[4,5‐b]indole was based on the Negishi cross‐coupling of iodobenzofurane with zincated 4,6‐dichloropyrimidine followed by azidation and photochemical cyclization. Glycosylation of the heterocycle with either Hoffer's chlorodeoxyribose or protected ribose followed by cross‐coupling or substitution reactions at position 10 gave the desired two sets of final nucleosides that showed moderate to weak cytostatic activity and interesting fluorescence properties. [ABSTRACT FROM AUTHOR]

2‐Formyl‐2′‐deoxyadenosine triphosphate (dCHOATP) was synthesized and tested as a substrate in enzymatic synthesis of DNA modified in the minor groove with a reactive aldehyde group. The multistep synthesis of dCHOATP was based on the preparation of protected 2‐dihydroxyethyl‐2′‐deoxyadenosine intemediate, which was triphosphorylated and converted to aldehyde through oxidative cleavage. The dCHOATP triphosphate was a moderate substrate for KOD XL DNA polymerase, and was used for enzymatic synthesis of some sequences using primer extension (PEX). On the other hand, longer sequences (31‐mer) with higher number of modifications, or sequences with modifications at adjacent positions did not give full extension. Single‐nucleotide extension followed by PEX was used for site‐specific incorporation of one aldehyde‐linked adenosine into a longer 49‐mer sequence. The reactive formyl group was used for cross‐linking with peptides and proteins using reductive amination and for fluorescent labelling through oxime formation with an AlexaFluor647‐linked hydroxylamine. [ABSTRACT FROM AUTHOR]

Ribonuclosides derived from 6‐hetaryl‐7‐dezapurines are potent cytostatics, but their mechanism of action is unknown. Here we designed and synthesized a series of cyclic and acyclic nucleoside phosphonates, as well as carboxy, cyano, sulfo, and sulfonamide acyclic analogues derived from 6‐thiophen‐2‐yl‐7‐deazapurine and 7‐fluoro‐6‐thiophen‐2‐yl‐7‐deazapurine as ribonucleoside monophosphate mimics. None of these analogues exerted significant cytotoxic and antiviral activity. [ABSTRACT FROM AUTHOR]

Suitably protected (R)‐ and (S)‐HPEP {9‐[3‐hydroxy‐2‐(phosphonoethoxy)propyl]} derivatives containing adenine and thymine nucleobases were prepared as monomers for the introduction of acyclic nucleotide units into oligonucleotides. The solid phase synthesis of a series of ribo and 2′‐deoxyribo nonamers containing (R)‐HPEP and (S)‐HPEP units was successfully performed in both 5′ → 3′ and 3′ → 5′ directions. The measurement of thermal characteristics of the complexes of modified nonamers with complementary DNA and RNA strands revealed a general destabilizing effect of the introduced acyclic units on the thermal stability, but in several cases [modif.RNA*RNA and modif.DNA*RNA with (S)‐HPEPA units], the duplexes were characterized in terms of Tm values. A solid‐phase synthesis afforded a series of ribo and 2′‐deoxyribo nonamers containing acyclic nucleotide units. A general destabilizing effect of the introduced acyclic units on the thermal stability of complexes of modified nonamers with the complementary DNA and RNA strands was observed, but in cases with (S)‐HPEPA units, the duplexes were characterized in terms of Tm values. [ABSTRACT FROM AUTHOR]

The Mn(OAc)3-promoted C-H phosphonation of 7-deazapurines (pyrrolo[2,3-d]pyrimidines) and 9-deazapurines (pyrrolo[3,2-d]pyrimidines) with diethylphosphite was developed. The reactions occur regioselectively at position 8 both in 7 and 9-deazapurines, leading to new deazapurine-8-phosphonate derivatives, which can be further modified and transformed to 6-(het)aryl-deazapurine derivatives or deprotected to free phosphonic acids. [ABSTRACT FROM AUTHOR]

A general access to 4-substituted 6-arylpyrrolo[2,3- d]pyrimidine (6-substituted 8-aryl-7-deazapurine derivatives) was developed based on iridium-catalyzed C-H borylations of pyrrolo[2,3- d]pyrimidines at the 6-position followed by the Suzuki cross-coupling reactions or other functional group transformations of the boronates. Biologically relevant 6-arylpyrrolo[2,3- d]pyrimidin-4-amines (8-aryl-7-deazaadenines) and pyrrolo[2,3- d]pyrimidin-4-ones (-7-deazahypoxanthines) were synthesized starting from SEM-protected 4-methylsulfanyl- or 4-methoxypyrrolo[2,3- d]pyrimidine. The one-pot borylation/Suzuki coupling reactions were followed either by demethylation and deprotection to yield deazahypoxanthine bases, or by oxidation of sulfide to sulfone, amination and deprotection to give deazaadenines. In addition, the boronate intermediates were converted into 6-halo- or 6-(trifluoromethyl)pyrrolo[2,3- d]pyrimidine (8-halo- or 8-trifluoromethyl-7-deazapurine) derivatives. [ABSTRACT FROM AUTHOR]

A general and modular synthesis of substituted benzene and pyridine 2′- C-methyl- C-ribonucleosides was developed. Benzyl-protected haloaryl- C-nucleoside intermediates were prepared by the addition of bromo(het)aryllithium reagents to a protected lactone, followed by acetylation and reduction. These halogenated intermediates were further transformed by Pd-catalysed cross-couplings, aminations, or hydroxylations. The final deprotection was rather troublesome, and different procedures involving catalytic hydrogenation on Pd/C, or treatment with BCl3, were optimized for each derivative. The final C-nucleosides were also all converted into the corresponding NTPs. None of the C-nucleosides showed any activity in the HCV replicon assay, and none of the NTPs showed any significant inhibition of the HCV polymerase. [ABSTRACT FROM AUTHOR]

An efficient route to acylated acyclic nucleosides containing a branched hemiaminal ether moiety is reported via three-component alkylation of N-heterocycle (purine nucleobase) with acetal (cyclic or acyclic, variously branched) and anhydride (preferentially acetic anhydride). The procedure employs cheap and easily available acetals, acetic anhydride, and trimethylsilyl trifluoromethanesulfonate (TMSOTf). The multi-component reaction is carried out in acetonitrile at room temperature for 15 min and provides moderate to high yields (up to 88%) of diverse acyclonucleosides branched at the aliphatic side chain. The procedure exhibits a broad substrate scope of N-heterocycles and acetals, and, in the case of purine derivatives, also excellent regioselectivity, giving almost exclusively N-9 isomers. [ABSTRACT FROM AUTHOR]

The RNA-dependent RNA polymerase (RdRp) represents a prominent target in the discovery and development of new antivirotics against RNA viruses, inhibiting the replication process. One of the most targeted RNA viruses of the last years is, without doubt, SARS-CoV-2, the cause of the recent COVID-19 pandemic. HeE1-2Tyr, a known inhibitor of flaviviral RdRp, has been discovered to also have antiviral potency against this coronavirus. In this study, we report three distinct modifications of HeE1-2Tyr: conversion of the core from a benzothiazole to a benzoxazole moiety and two different scaffold simplifications, respectively. We provide a novel synthetic approach and, in addition, evaluate the final molecules in an in vitro polymerase assay for biological activity., (Copyright © 2024, Tóth et al.)

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., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

The only known sulfur-containing karrikin, 3-methyl-2 H -thiopyrano[3,4- b ]furan-2-one, has been recently identified as an extremely efficient neuroprotective butenolide. Herein, we report the targeted synthesis of this compound as well as new synthetic protocols toward a class of compounds derived from 2 H -furo[2,3- c ]pyran-2-ones (karrikins) via bioisosteric exchange of oxygen with sulfur. In particular, we present synthetic procedures toward bioisosteres of karrikins with one or two sulfur heteroatoms incorporated into the core backbone together with evaluation of their biological activity in inhibition of acetylcholinesterase., (Copyright © 2022, Pošta et al.)

We developed and presented here a ferrocene-catalyzed C-H imidation of 7-deazapurines (pyrrolo[2,3- d ]pyrimidines) with N -imidyl peroxyesters. The reactions occur regioselectively at position 8 in 7-deazapurines, leading to a series of 8-succinimido-, phtalimido-, or naphthalimido-7-deazapurine derivatives. Attempted hydrazinolysis of resulting 8-imidyl-7-deazapurines led to corresponding 8-amino-7-deazapurine, which was very unstable and quickly decomposed., Competing Interests: The authors declare no competing financial interest.

Conformational preferences of the pyrrolidine ring in nucleotide analogs 7-14 were investigated by means of NMR and molecular modeling. The effect of the relative configuration of hydroxy and nucleobase substituents as well as the effect of the alkylation or acylation of the pyrrolidine nitrogen atom on the conformation of the pyrrolidine ring were studied. The results of a conformational analysis show that the alkylation/acylation can be effectively used for tuning the pyrrolidine conformation over the whole pseudorotation cycle.