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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]

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]

The lack of antiviral activity of recently described (S) -3-(adenin-9-yl)-2-(phosphonomethoxy)propanoic acid, or ( S )-CPMEA in brief, has been speculated to possibly be due to the increased hydrophilicity of the molecule and, thus, by its limited cellular permeability. Efficient syntheses of novel lipophilic prodrugs of ( S )-CPMEA masking either the carboxylic group or preferably both the phosphonate and carboxylic moieties, have been developed in order to increase bioavailability of the parent compound. Two prodrugs of ( S )-CPMEA, namely phosphonate bis-amidate 15 and phenyloxy amidate 16 , exhibited pan-genotypic anti-HCV activity at submicromolar concentrations. [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]

A study of the Ir-catalyzed C–H silylation of 6-phenyl-7-deazapurines or -9-deazapurines with trialkylsilanes revealed that this reaction preferentially proceeded via ortho -silylation at the aryl group due to the directing effect of the N1 nitrogen of the deazapurine, rather than C–H silylation at the heterocycle which was only a minor side-reaction. A preparative protocol for the ortho -silylation of aryldeazapurines is presented. [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]

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 synthesis and biological activity profiling of a large series of diverse pyrrolo[2,3- d ]pyrimidine 4′- C -methylribonucleosides bearing an (het)aryl group at position 4 or 5 is reported as well as the synthesis of several phosphoramidate prodrugs. These compounds are 4′-C-methyl derivatives of previously reported cytostatic hetaryl-7-deazapurine ribonucleosides. The synthesis is based on glycosylation of halogenated 7-deazapurine bases with 1,2-di- O -acetyl-3,5-di- O -benzyl-4- C -methyl-β- d -ribofuranose followed by cross-coupling and nucleophilic substitution reactions. The final compounds showed low cytotoxicity and several derivatives exerted antiviral activity against HCV or Dengue viruses at micromolar concentrations. [ABSTRACT FROM AUTHOR]

Glutamate carboxypeptidase II (GCPII), also known as prostate specific membrane antigen (PSMA), is an established prostate cancer marker and is considered a promising target for specific anticancer drug delivery. Low-molecular-weight inhibitors of GCPII are advantageous specific ligands for this purpose. However, they must be modified with a linker to enable connection of the ligand with an imaging molecule, anticancer drug, and/or nanocarrier. Here, we describe a structure-activity relationship (SAR) study of GCPII inhibitors with linkers suitable for imaging and drug delivery. Structure-assisted inhibitor design and targeting of a specific GCPII exosite resulted in a 7-fold improvement in Ki value compared to the parent structure. X-ray structural analysis of the inhibitor series led to the identification of several inhibitor binding modes. We also optimized the length of the inhibitor linker for effective attachment to a biotin-binding molecule and showed that the optimized inhibitor could be used to target nanoparticles to cells expressing GCPII. [ABSTRACT FROM AUTHOR]

Abstract: The six-membered saturated heterocycles—4-tert-butyl-1-methylpiperidine, 4-tert-butyl-1-methylphosphine, 4-tert-butyl-tetrahydro-2H-thiopyran, and 4-tert-butyl-tetrahydro-2H-selenopyran—were prepared as suitable model compounds with well-defined geometry for an NMR study of their oxidation products. The corresponding epimeric N-oxides, phosphinoxides, sulfoxides, and selenoxides were obtained by standard chemical preparation and also by in situ oxidation with meta-chloroperbenzoic acid directly in the NMR tube. The experimental 1H and 13C chemical shifts were compared with corresponding calculated data obtained by GIAO approach with DFT, MP2, and HF methods and various basis sets. The correlation of experimental versus calculated data showed the possibility to determine the stereochemistry of the epimeric oxidation products using fast DFT B3LYP/6-31G* method for both geometry optimization and NMR chemical shifts calculation. [Copyright &y& Elsevier]

• New acyclic nucleotide analogs with 1,2,4-thiadiazole base were synthesized. • 5-Amino-1,2,4-thiadiazol-3(2 H)-one derivatives inhibit Cathepsin K and GSK-3β. • 1,2,4-Thiadiazol-3(2 H)-one ring is stabilized by substitution at the 5-amino group. In analogy to antiviral acyclic nucleoside phosphonates, a series of 5-amino-3-oxo-1,2,4-thiadiazol-3(2 H)-ones bearing a 2-phosphonomethoxyethyl (PME) or 3-hydroxy-2-(phosphonomethoxy)propyl (HPMP) group at the position 2 of the heterocyclic moiety has been synthesized. Diisopropyl esters of PME- and HPMP-amines have been converted to the N -substituted ureas and then reacted with benzoyl, ethoxycarbonyl, and Fmoc isothiocyanates to give the corresponding thiobiurets, which were oxidatively cyclized to diisopropyl esters of 5-amino-3-oxo-2-PME- or 2-HPMP- 1,2,4-thiadiazol-3(2 H)-ones. The phosphonate ester groups were cleaved with bromotrimethylsilane, yielding N 5-protected phosphonic acids. The subsequent attempts to remove the protecting group from N 5 under alkaline conditions resulted in the cleavage of the 1,2,4-thiadiazole ring. Similarly, compounds with a previously unprotected 5-amino-1,2,4-thiadiazolone base moiety were stable only in the form of phosphonate esters. The series of twenty-one newly prepared 1,2,4-thiadiazol-3(2 H)-ones were explored as potential inhibitors of cysteine-dependent enzymes – human cathepsin K (CatK) and glycogen synthase kinase 3β (GSK-3β). Several compounds exhibited an inhibitory activity toward both enzymes in the low micromolar range. The inhibitory potency of some of them toward GSK-3β was similar to that of the thiadiazole GSK-3β inhibitor tideglusib, whereas others exhibited more favorable toxicity profile while retaining good inhibitory activity. [ABSTRACT FROM AUTHOR]