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Conformational features of pyridine- and pyrimidine-based bistriazolyl anion receptors dissolved in acetonitrile-d3 were assessed by multidimensional, heteronuclear NMR spectroscopy. NOESY correlation signals suggested preorganization of both host molecules in solution in the absence of anions. In addition, only a single set of signals was observed in the 1H NMR spectra, which suggested a symmetrical conformation of anion receptors or their conformational exchange that is fast on the NMR time-scale. Furthermore, the predominant conformations of the pyridine- and pyrimidine-based anion receptors are preserved upon addition of chloride, bromide, and acetate anions. Chemical shift changes observed upon addition of anions showed that the NH (thio)urea and triazole protons are involved in anion-receptor interactions through hydrogen bonding.

Keeping the potential synergy of biological activity of synthetic anomalous derivatives of deazapurines and l-ascorbic acid (l-AA) in mind, we have synthesized new 3-, 7- and 9-deazapurine derivatives of l-ascorbic (1–4, 8–10, 13–15) and imino-l-ascorbic acid (5–7, 11, 12, 16–19). These novel compounds were evaluated for their cytostatic and antiviral activity in vitro against a panel of human malignant tumour cell lines and normal murine fibroblasts (3T3). Among all evaluated compounds, the 9-deazapurine derivative of l-AA (13) exerted the most potent inhibitory activity on the growth of CEM/0 cells (IC50 = 4.1 ± 1.8 μM) and strong antiproliferative effect against L1210/0 (IC50 = 4.7 ± 0.1 μM) while the 9-deazahypoxanthine derivative of l-AA (15) showed the best effect against HeLa cells (IC50 = 5.6 ± 1.3 μM) and prominent effect on L1210/0 (IC50 = 4.5 ± 0.5 μM). Furthermore, the 9-deazapurine derivative disubstituted with two imino-l-AA moieties (18) showed the best activity against L1210/0 tumour cells (IC50 = 4.4 ± 0.3 μM) and the most pronounced antiproliferative effects against MiaPaCa-2 cells (IC50 = 5.7 ± 0.2 μM). All these compounds showed selective cytostatic effect on tumour cell lines in comparison with embryonal murine fibroblasts (3T3). When evaluating their antiviral activity, the 3-deazapurine derivative of l-AA (3) exhibited the highest activity against both laboratory-adapted strains of human cytomegalovirus (HCMV) (AD-169 and Davis) with EC50 values comparable to those of the well-known anti-HCMV drug ganciclovir and without cytotoxic effects on normal human embryonal lung (HEL) cells., Graphical abstract, Highlights • Deazapurine derivatives of l-ascorbic and imino-l-ascorbic acid were synthesized. • Compound 13 exerted strong activity on the growth of CEM/0 and L1210/0 cells. • Compound 15 showed the best cytostatic effect against HeLa cells. • Compound 18 showed the best cytostatic activity against L1210/0 and MiaPaCa-2. • Compound 3 exhibited highest effect against HCMV comparable to ganciclovir.

Super-statins are synthetic inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, which is the rate-limiting enzyme responsible for the biosynthesis of cholesterol. All of the super-statins with a C=C double bond spacer between the heterocyclic and the dihydroxycarboxylic moiety that are currently on the market exist as E-isomers. To extend the understanding of conformational and thermodynamic preferences of Z-isomeric super-statin analogues, this study focused on analyzing pitavastatin and its lactonized derivatives via NMR spectroscopy and ab initio calculations. Z-isomeric pitavastatin analogues exist in solution as a pair of interconverting rotamers, where the Gibbs free energies between the major and minor rotamers are within 0.12 and 0.25 kcal mol−1 and the rotational energy barriers are between 15.0 and 15.9 kcal mol−1. The analysis of long-range coupling constants and ab initio calculations revealed that rotation across the C5'–C7 single bond is essential for generating a pair of atropisomers. The overall comparison of the results between Z-isomeric pitavastatin and rosuvastatin analogues demonstrated that the former are to some extent more flexible to attain numerous conformations. Demonstrating how structural differences between super-statin analogues induce distinctive conformational preferences provides important insight into the super-statins’ conformational variability and may well improve future drug design.

Most of the super-statins contain a CC double bond spacer between the heterocyclic and the chiral dihydroxycarboxylic moieties. The known drugs are E-geometric isomers, whereas very little is known about their Z-isomeric analogues. This study explains the unusual resonance line broadening observed in 1H NMR spectra of Z-isomeric rosuvastatin analogues at room temperature, which originates from dynamic exchange between different conformers. Conformational equilibria and intrinsic preferences of Z-isomeric rosuvastatin analogues provide valuable insight into conformational variability that is important for studying potential interactions within the binding site of the enzyme.

Two small molecules showed intriguing properties of analytical multipurpose probes, whereby one chromophore gives different signal for many different DNA/RNA by application of several highly sensitive spectroscopic methods. Dyes revealed pronounced fluorescence ratiomeric differentiation between ds-AU-RNA, AT-DNA and GC-DNA in approximate order 10:8:1. Particularly interesting, dyes showed specific fluorimetric response for poly rA even at 10-fold excess of any other ss-RNA, and moreover such emission selectivity is preserved in multicomponent ss-RNA mixtures. The dyes also showed specific chiral recognition of poly rU in respect to the other ss-RNA by induced CD (ICD) pattern in visible range (400–500 nm), which was attributed to the dye-side-chain contribution to binding (confirmed by absence of any ICD band for reference compound lacking side-chain). Most intriguingly, minor difference in the side-chain attached to dye chromophore resulted in opposite sign of dye-ICD pattern, whereby differences in NMR NOESY contacts and proton chemical shifts between two dye/oligo rU complexes combined with MD simulations and CD calculations attributed observed bisignate ICD to the dimeric dye aggregate within oligo rU.

A new series of conformationally restricted pyrimidine derivatives bearing C-6 isobutenyl side-chain (2–9) has been prepared. The novel fluoroalkenyl pyrimidine nucleoside mimetic 3 as model compound for development of tracer molecule in positron emission tomography (PET) was synthesized by fluorination reaction of methoxytritylated pyrimidine derivative using diethylaminosulfur trifluoride (DAST). Conversion of one hydroxyl group to methoxytritylated, fluorinated, mesylated and acetylated pyrimidine derivatives (2, 3, 5–7 and 9) afforded a mixture of Z- and E-isomers in which Z-isomers were predominant. Conformational study of 1, and its fluorinated structural congeners 3 and 4 by the use of NOE experiments revealed predominant conformation of compounds where vinyl H-10 proton is spatially close to N-1 methyl and H-30b methylene protons and on the other hand H-30a methylene protons are close to C-5 methyl protons. The stereostructure of 1, 3-dihydroxyisobutenyl N- methyl thymine 1 was unambiguously confirmed by X- ray crystal structure analysis.

We report on the synthesis of 4-hydroxycoumarin dimers 1-15 bearing an aryl substituent on the central linker and fused benzopyranocoumarin derivatives 16-20 and on their in vitro broad anti-DNA and RNA virus activity evaluations. The chemical identities and structure of compounds 1-20 were deduced from their homo- and heteronuclear NMR measurements whereas the conformational properties of 5, 14 and 20 were assessed by the use of 1D difference NOE enhancements. Unequivocal proof of the stereostructure of compounds 7, 9, 16 and 18 was obtained by single crystal X-ray diffraction method. The X-ray crystal structure analysis revealed that two 4-hydroxycoumarin moieties in the 4-trifluoromethylphenyl- and 2-nitrophenyl derivatives (compounds 7 and 9, respectively) are intramolecularly hydrogen-bonded between hydroxyl and carbonyl oxygen atoms. Consequently, the compounds 7 and 9 adopt conformations in which two 4-hydroxy-coumarin moieties are anti-disposed. Antiviral activity evaluation results indicated that the 4-bromobenzylidene derivative of bis-(4-hydroxycoumarin) (compound 3) possesses inhibitory activity against HSV-1 (KOS), HSV-2 (G), vaccinia virus and HSV-1 TK- KOS (ACVr) at a concentration of 9-12 μM and at a minimum cytotoxic concentration (MCC) greater than 20 μM. Compounds 4-6, 8, and 20 were active against feline herpes virus (50% effective concentration, EC(50) = 5-8.1 μM), that is at a 4-7-fold lower concentration than the MCC. ispartof: Molecules vol:16 issue:7 pages:6023-40 ispartof: location:Switzerland status: published

Novel N-methoxymethylated (MOM) pyrimidine (4-13) and pyrimidine-2,4-diones (15-17) nucleoside mimetics in which an isobutyl side-chain is attached at the C-6 position of the pyrimidine moiety were synthesized. Synthetic methods via O-persilylated or N-anionic uracil derivatives have been evaluated for the synthesis of N-1- and/or N-3-MOM pyrimidine derivatives with C-6 acyclic side-chains. A synthetic approach using an activated N-anionic pyrimidine derivative afforded the desired N,N-1,3-diMOM and N-1-MOM pyrimidines 4 and 5 in good yield. Introduction of fluorine into the side-chain was performed with DAST as the fluorinating reagent to give a N,N-1,3-diMOM pyrimidine 13 with a 1-fluoro-3-hydroxyisobutyl moiety at C-6. Conformational study of the monotritylated N-1-MOM pyrimidine 12 by the use of the NOE experiments revealed the predominant conformation of the compound to be one where the hydroxymethyl group in the C-6 side-chain is close to the N-1-MOM moiety, while the OMTr is in proximity to the CH3-5 group. Contrary to this no NOE enhancements between the N-1-MOM group and hydroxymethyl or fluoromethyl protons in 13 were observed, which suggested a nonrestricted rotation along the C-6 side-chain. Fluorinated N,N-1,3-diMOM pyrimidine 13 emerged as a model compound for development of tracer molecules for non-invasive imaging of gene expression using positron emission tomography (PET). ISSN:1420-3049

The conformational analysis of four C2-amido and C7-ureido functionalised indole anion receptors was performed by a combination of heteronuclear NMR spectroscopy and ab initio quantum mechanical calculations. NOE experiments showed that anti–anti conformation across C2–C2α and C7–N7α bonds is predominant in acetone solution in the absence of anions. Upon anion binding to receptors, syn–syn conformation becomes predominant. The conformational changes upon anion binding are in good agreement with energetic preferences established by ab initio calculations. Chemical shift changes induced by interaction of anions suggest that binding of chloride and bromide anions occurs primarily to H1 and H7α protons. Nitrate anions favour interaction with H7α and H7γ ureido protons, whereas acetate anions interact strongly with all four available hydrogen bond donor groups.

Indole-based anion receptors with an carboxamide unit in 2- and an urea in 7-position were prepared and found to bind halides (as well as acetate and nitrate) in chloroform solutions at room temperature. Investigations of the binding behaviour show that the receptor is selective for chloride. Surprisingly, the truncated receptor 3 without the 2-carbamoyl substituent shows the highest affinity for Cl–. Thorough 1H, 13C and 15N NMR investigations indicate different binding modes for acetate, nitrate and halides to the receptor 2. The observation of a major conformational change of this receptor during the binding of the halide ions leads to an understanding of the relative binding affinities of 3 > 4 > 2 for chloride. The results of the NMR study are supported by ab initio calculations. In addition, ESI FTICR MS competition experiments of the indole 2 and the quinoline 1 reveal the “self-aggregation” of the receptors and show that halides have a higher affinity to 2 than to 1.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Graphical abstract, A series of the novel C-5 alkynyl pyrimidine nucleoside analogues (1–14) in which the sugar moiety was replaced by the conformationally restricted Z- and E-2-butenyl spacer between the phthalimido and pyrimidine ring were synthesized by using Sonogashira cross-coupling reaction. Cytostatic activity evaluation of the novel compounds showed that E-isomers exhibited, in general, better cytostatic activities than the corresponding Z-isomers. E-isomer 14 exhibited the best cytostatic effect against all evaluated malignant cell lines, particularly against hepatocellular carcinoma (Hep G2, IC50 = 4.3 μM). However, this compound was also cytotoxic to human normal fibroblasts (WI 38). Its Z-isomer 7 showed highly specific antiproliferative activity against Hep G2 (IC50 = 18 μM) and no cytotoxicity to WI 38. Moreover, compounds 3, 4 and 14 expressed some marginal inhibitory activity against HIV-1 and HIV-2.

The 5,6-di- O -tosylated derivative of l -ascorbic acid was synthesized by selective protection and deprotection of 2,3- and 5,6-dihydroxy functional groups involving 5,6-ditosylation in the final step, while the novel 6-acetoxy, 6-hydroxy, and 6-chloro derivatives of 4,5-didehydro- l -ascorbic acid were obtained by reaction of ditosylated compound with nucleophilic reagents. The analysis of 3 J H-4–H-5 homonuclear coupling constants shows that all l -ascorbic acid derivatives except for epoxy and 4,5-didehydro compounds exist in high population as gauche conformers across C-4–C-5 bonds, while 3 J C-3–H-5 heteronuclear coupling constants in 4,5-didehydro derivatives indicate cis geometry along C-4–C-5 double bond. The X-ray crystal structure analysis of 2,3-di- O -benzyl-5,6-epoxy- and 5,6-isopropylidene- l -ascorbic acid shows that the oxygen atoms attached at positions 2 and 3 of the lactone ring are disposed in a synperiplanar fashion. Besides that, the dioxolane ring adopts half-chair conformation. The molecules of epoxy derivative are joined into infinite chains by one weak hydrogen bond of C–H⋯O type. Two O–H⋯O, and C–H⋯O hydrogen bonds link the molecules of 5,6-di- O -isopropylidene compound into two-dimensional network. 6-Chloro derivative of 2,3-di- O -benzyl- l -ascorbic acid showed the best cytostatic effects against all tested malignant tumor cells (IC 50 : ∼18 μM).

In the present paper, we report on the synthesis, and in vitro antiviral and cytostatic activities of a series of novel imidazole[4,5-e][1,3]diazepine-4,8-dione (compounds 9-11) and acyclic carbamoyl imino-ureido imidazole (compounds 12 and 13) derivatives. These new type of chemical entities showed no significant activity on the broad spectrum of DNA and RNA viruses. Results of antiproliferative assays performed on a panel of selected human tumor cell lines revealed that only compounds 1 and 5 showed moderate and selective cytostatic effect against HeLa cells (IC50 = 24 and 32 µM) with no concomitant cytotoxic effects on human normal fibroblasts (BJ). Importantly, an imidazole derivative containing a pyrrolidine moiety linked via an ethylenic spacer (3) showed a selective cytostatic effect toward cervical carcinoma (HeLa) cells (IC50 = 9.5 µM) with no apparent cytotoxicity on human normal fibroblasts (BJ). This compound can be therefore considered as a potential anti-tumor lead compound for further synthetic structure optimization. ispartof: Molecules vol:18 issue:11 pages:13385-97 ispartof: location:Switzerland status: published

Synthesis of novel 5-(2-hydroxyethyl) and 5-(3-hydroxypropyl) acyclic pyrimidine nucleosides is described. Introduction of penciclovir-like side chain in C-5 substituted pyrimidines occurred both at N-1 and O-2 position of pyrimidine moiety that was corroborated by correlation of signals in 2D HMBC spectra. Therefore, alkylation of 5-(acetoxyethyl)-4-methoxypyrimidin-2-one (2a) and 5-(acetoxypropyl)-4-methoxypyrimidin-2-one (2b) afforded mixture of N- and O-acyclic pyrimidine nucleosides in the ratio of 49: 45 (4a: 5a) and 41: 21 (4b: 5b). Structures of 5-(acetoxyalkyl)-4-methoxypyrimidin-2-ones, as the first examples of 4-methoxypyrimidin-2-ones, were unambiguously confirmed by single crystal X-ray diffraction analysis.

The synthetic route for introduction of fluorophenylalkyl (compounds 5, 7, 14 and 15) and fluorophenylalkenyl (compounds 4E and 13) side chains at C-6 of the pyrimidine nucleus involved the lithiation of the pyrimidine derivatives 1, 2 and 11 and subsequent nucleophilic addition or substitution reactions of the organolithium intermediate thus obtained with 2-fluorophenylacetone, 4-fluoroacetophenone or ethyl 4-fluorobenzoate as electrophiles. The structures of novel compounds were confirmed by (1)H-, (19)F- and (13)C-NMR and MS. Compounds 8 and 10 containing unsaturated fluorophenylalkyl side chains showed better inhibitory effect than their saturated fluorophenylalkylated pyrimidine counterparts 7 and 9. A conformational study based on NOE enhancements showed the importance of the double bond and substitution in the side chain for the conformational preferences in relation to inhibitory activity. Among all tested compounds, C-5 furyl (12) and phenyl (13 and 15) substituted pyrimidine derivatives showed significant cytostatic activities against all tested tumor cell lines.

C-6 substituted fluoroalkenyl 2, 4-dimethoxypyrimidine derivative (4) was synthesized by lithiation of 2, 4-dimethoxy-6-methylpyrimidine (3) and subsequent reaction of thus obtained organolithium intermediate with ethyl pentafluoropropionate. The novel 2, 4-pyrimidinedione containing 3, 3, 4, 4, 4-pentafluoro-1-butenyl side chain (5) was prepared by demethoxylation of 4 using sodium iodide and chlorotrimethylsilane. The structures of 4 and 5 were confirmed by 1H, 13C and 19F NMR spectra, as well as IR spectra. The structure of 4 was also unambiguously confirmed by X-ray crystal structure analysis. The molecules of 4 are weakly linked by aromatic pi• • • pi stacking interactions into infinite chains parallel to the a axis.

The synthetic route for introduction of a fluoroalkyl (7-12, 14), fluoroalkenyl (15 and 16), fluorophenylalkyl (17, 19, 20, and 22), and fluorophenylalkenyl (18, 21) side chain at C-6 of the pyrimidine involved the lithiation of the pyrimidine derivatives 3 and 3a and subsequent nucleophilic addition or substitution reactions of the organolithium intermediate thus obtained with various electrophiles. Conformational properties of the novel fluorinated pyrimidine derivatives were assessed by the use of 1D difference NOE enhancements and C-F coupling constants. Compounds 4-22 were evaluated for their antiviral and cytostatic activities. Of all compounds evaluated, the 5-bromopyrimidine derivatives 5 and 6 showed the highest inhibitory activities. Among the series of fluoroalkylated pyrimidines, which is generally more active than the series of fluorophenylalkylated pyrimidines, compounds 8 and 14 displayed moderate cytostatic activities against the tested tumor cell lines. Moreover, compound 8 containing a 2-fluoromethylpropyl side chain expressed some but not highly specific activity against varicella-zoster virus (VZV). From C-6 fluorophenylalkylated pyrimidine derivatives, 17a and 21 showed a slight activity against cytomegalovirus (CMV), VZV, and Coxsackie B4 virus, respectively. Besides, compounds 17a and 21 showed no cytotoxic effect.

A series of the novel 5-methyl pyrimidine derivatives with an acyclic side chain at the C-6 position were synthesized using lithiation of a 2,4-dimethoxy-5,6-dimethyl pyrimidine and subsequent nucleophilic addition or substitution reactions of the organolithium intermediate thus obtained with acetaldehyde, epichlorhydrine, fluorinated ketones and fluorinated ester. The novel compounds were evaluated for their cytostatic and antiviral activities. Among all the compounds evaluated, two fluorinated acyclic pyrimidine derivatives showed the highest cytostatic activities. The compound containing a 2-hydroxy-3,3,3-trifluoro-1-propenyl side chain exhibited a pronounced effect against breast carcinoma (MCF-7, IC50=8.38 μg/ml), while the compound with a 2-fluoromethyl-2-acetoxypropyl chain exhibited moderate effect against cervical carcinoma (HeLa, IC50=19.73 μg/ml).