Joanna Zeidler

5-Ethynyl-1-β-D-ribofuranosyl-1H-[1,2,3]triazole-4-carboxylic acid amide (ETCAR) and its analogues: synthesis and cytotoxic properties.

Efficient Pd(0)-catalysed synthesis of 5-alkynyl-1-β-D-ribofuranosyl-1H-[1,2,3]triazole-4-carboxylic acid amide depends on the presence of different protecting groups of the ribose moiety. Peracetylated 5-iodo substrate (15) couples with terminal alkynes or trimethyl-[(tributylstannyl)ethynyl]silane in 50-71% and 72% yield (ETCAR), respectively, although its hydrodehalogenation to 19 is noticeable. On the other hand, hydrodehalogenation of acetonide (16) predominates over coupling with terminal alkyne and slightly decreases a yield of cross-coupling reaction with trimethyl[(tributylstannyl)ethynyl]silane. Alternative conditions of reaction with terminal alkynes, to exclude so far identified hydride sources to produce hydridopalladium species, have been established for acetonide 16 and allowed to achieve 72% of coupling. Fluoromethyl derivative (42) was prepared from its 5-hydroxymethyl precursor by fluorination with DAST. Additionally, X-ray structural analysis of 42 was performed. All 1,2,3-triazolonucleosides and two synthesized cycloSal-pronucleotides were evaluated for cytotoxic activity against K562, HeLa and HUVEC cells.

Antivirally active ribavirin analogues--4,5-disubstituted 1,2,3-triazole nucleosides: biological evaluation against certain respiratory viruses and computational modelling.

Background: Ribavirin is a broad-spectrum antiviral agent that derives some of its activity from inhibition of cellular inosine monophosphate dehydrogenase (IMPDH), resulting in lower guanosine triphosphate (GTP) levels. Here we report the biological activities of three ribavirin analogues. Methods: Antiviral activities of test compounds were performed by in vitro cytopathic effect inhibition assays against influenza A (H1N1, H3N2 and H5N1), influenza B, measles, parainfluenza type 3 (PIV-3) and respiratory syncytial viruses. Compounds were modelled into the ribavirin 5‘-monophosphate binding site of the crystallographic structure of the human type II IMPDH (hIMPDH2) ternary complex. Effects of compounds on intracellular GTP levels were performed by strong anion exchange HPLC analysis. Results: Of the three compounds evaluated, the 5-ethynyl nucleoside (ETCAR) exhibited virus-inhibitory activities (at 1.2–20 μM, depending upon the virus) against most of the viruses, except for weak activity against PIV-3 (62 μM). Antiviral activity of ETCAR was similar to ribavirin; however, cytotoxicity of ETCAR was greater than ribavirin. Replacing the 5-ethynyl group with a 5-propynyl or bromo substituent (BrCAR) considerably reduced antiviral activity. Computational studies of ternary complexes of hIMPDH2 enzyme with 5‘-monophosphates of the compounds helped rationalize the observed differences in biological activity. All compounds suppressed GTP levels in cells; additionally, BrCAR suppressed adenosine triphosphate and elevated uridine triphosphate levels. Conclusions: Three compounds related to ribavirin inhibited IMPDH and had weak to moderate antiviral activity. Cytotoxicity adversely affected the antiviral selectivity of ETCAR. As with ribavirin, reduction in intracellular GTP may play a role in virus inhibition.

Bioactive nucleoside analogues possessing selected five-membered azaheterocyclic bases.

This review summarizes briefly literature reports on nucleoside analogues containing five-membered aglycones based on imidazole-4-carboxamide, 1,2,4-triazole-3-carboxamide or 1,2,3-triazole-4-carboxamide structural motifs, which exhibit diverse therapeutically useful or promising biological properties. We do not describe synthetic approaches but try to present the essential activities of compounds and their established or postulated mechanisms of action.

α-Oligodeoxynucleotides containing 5-propynyl analogs of α-deoxyuridine and α-deoxycytidine: Synthesis and base pairing properties

Abstract From propyne and 5-iodo-α,2-deoxyuridine, obtained by glycosylation, 5-propynyl-α,2′-deoxyuridine was synthesized following the procedure of Hobbs. One part was then transformed through displacement of its C4-triazolo derivative with ammonia into 5-propynyl-α,2′-deoxycytidine derivative. Finally, the corresponding α 5-propynyl nucleoside phosphoramidites were prepared, and 5-propynyl-α oligonucleotides (12-mer) with either phosphodiester and phosphorothioate were synthesized. The melting temperatures showed that duplexes with complementary DNA are stabilized between 0.65 and 1.2°C/mod, and duplexes with RNA are stabilized between 1.2 and 1.4°C/mod.

A CASE OF UNUSUAL STERICALLY DRIVEN C-TRITYLATION REACTION OF TRICYCLIC ANALOGUES OF ACYCLOVIR

Abstract 3,9-Dihydro-3-[(2-hydroxyethoxy)methyl]-6-methyl-9-oxo-5 H -imidazo[1,2- a ]purine ( 1 ) and its silylated derivative ( 2 ) when tritylated under conditions suitable for regioselective N-5 alkylation underwent instead C-substitution to give 7-trityl ( 12, 3 ) and 7-(4-benzhydrylphenyl) ( 13, 4 ) derivatives as major and minor products, respectively. Substrates lacking 6-Me group ( 5, 6 ) yielded 5-tritylated ( 10, 7 ) and 5,7-ditritylated ( 11, 8 ) major products and 7-tritylated ( 9 ) minor product. The regioselectivity of the reaction seems to be driven mainly by steric hindrance of the 6-Me substituent.

Substituent — Directed Aralkylation and Alkylation Reactions of the Tricyclic Analogues of Acyclovir and Guanosine

Abstract Aryl or tert-butyl substituent in the 6 position of 3,9-dihydro-3-[(2-hydroxyethoxy)methyl]-9-oxo-6-R-5H-imidazo[1,2-α]purine (6-R-TACV)1 1 partly directs aralkylation reactions into unusual positions: N-4 to give 3 and C-7 to give N-5, 7-disubstituted or N-4, 7-disubstituted derivatives. In the case of alkylation the effect is limited to aryl substituent and position N-4. Replacement of acyclic moiety of 1 with a ribosyl one like in 7 prevents N-4 substitution. Cleavage of the third ring of 3b to give 3-benzylacyclovir 10 is an example of a new short route to 3-aralkyl-9-substituted guanines.

Synthesis of 5-ethynyl-1-β-D-ribofuranosyl-1H-[1,2,3]triazole-4-carboxylic acid amide (isosteric to EICAR) and its derivatives

The synthesis of 5-ethynyl-1H-[1,2,3]triazole-4-carboxylic acid amide riboside 1 and its derivatives exploits Pd(0)-catalyzed cross-coupling reactions. The iodinated key intermediate 3a, when coupled with alkynes affords 5-alkynylated products 1b,c,e,f in diverse yields. Methanolysis of 1b and 1c provides the title compound 1 and the 5-propynyl derivative 1d, respectively. When coupled with methyl acrylate, 3a gives the E-isomer 4c, although in low yield, while the other 5-iodo precursor 3b undergoes reduction to 4b.

An efficient route to novel 4,5-di- and 2,4,5-tri substituted imidazoles from imidazo[1,5-a]-1,3,5-triazine (5,8-diaza-7,9-dideazapurine) derivatives.

Two new types of imidazole derivatives: N‐(2‐R1‐5‐R2‐1H‐imidazol‐4‐yl) thioureas 7a–g and N‐(2‐R1‐5‐R2‐1H‐imidazol‐4‐yl) formamides 8b,c,g were obtained in high yields by the hydrolytic degradation of 6‐R1‐8‐R2‐2‐thioxo‐2,3‐dihydroimidazo[1,5‐a]‐1,3,5‐triazin‐4(1H)‐ones 5a–g and 6‐R1‐8‐R2‐imidazo[1,5‐a]‐1,3,5‐triazin‐4(3H)‐ones 6b,c,d, respectively. The tautomeric preferences of the new imidazoles were determined. †In honor and celebration of the 70th birthday of Professor Leroy B. Townsend.

A CONVENIENT APPROACH TO N-3 ALKYLATION OF 9-SUBSTITUTED GUANINES

Abstract Aryl or tert-butyl substituent in the 6 position of 3,9-dihydro-3-[(2-hydroxy-ethoxy)methyl]-9-oxo-6-R-5H-imidazo[1,2-α]purine 1 directs the benzylation reaction partly into N-4 position to give 3. Cleavage of the third ring of 3 gives 3-benzylacycloguanosine 5, a first 3-aralkilo-9-substituted guanine.

Determination of the tautomerism of 5,5-disubstituted analogues of 6-amino-2-thiouracil by 1H and 13C nuclear magnetic resonance spectroscopy

5,5-Disubstituted 6-amino-2-thiouracil analogues (1)–(6), prepared by condensation of 2-acylamino-2-cyano aliphatic acids ethyl esters with thiourea, have been studied by 1H and 13C NMR. It has been found that in dimethyl sulphoxide solution the compounds exist as 5-acylamino-5-alkyl-6-imino-2-thioxo-1,2,5,6-tetrahydropyrimidin-4(3H)ones (1B)–(6B). The assignment of this tautomeric form has been based mainly on 13C NMR spectra selectively 1H decoupled with low-power 1H irradiation.