Lajos Kovács

Thiazole C-nucleosides. III, Synthesis of pyranose analogues of tiazofurin

Abstract A large-scale synthesis of 3,4,5-tri-0-acetyl-2,6-anhydro-L-mannono-and-D-gulonothioamides (5, 6) has been achieved from the corresponding nitriles. The Hantzsch reaction of (5) or (6) with ethyl bromopyruvate afforded the expected thiazoles (7.8) only in a low yield along with furan derivatives (9-11), the formation of which is rationalized by an acid-catalysed rearrangement-elimination process. The some Hantzsch reaction in the presence of barium carbonate yielded hydroxythiazolines (16,17). Attempted dehydration of (16) or (17) with trifluoroacetic anhydride or trifluoroacetic anhydride/pyridine resulted in the formation of pent-1′-enopyranosylthiazoles (18-20). Deprotected thioamides (24,25) furnished with ethyl bromopyruvate thiazoles (27,28). The obtained thiazole esters (7,8, 18-20. 27,28) were transformed into new tiazofurin analogues (12, 13, 21- 23).

3-Substituted xanthines as promising candidates for quadruplex formation: computational, synthetic and analytical studies

Our computational studies suggest that 3-substituted xanthines are good candidates for tetrad and quadruplex structures. 3-Methylxanthine (3MX) has been synthesized from 7-benzylxanthine, and the existence of tetrameric and octameric aggregates of 3MX with NH4+, Na+ and K+ ions in the gas phase (MS) and in DMSO-d6 solution (NMR) has been observed. The “internal” H-bonds (N1H⋯O6) are stronger than the “external” ones (N7H⋯O2) in these clusters (NMR).

Interaction between Mo(VI) and siderophore models in aqueous solution

A series of dihydroxamic acids (HORNOC-(CH2)n-CONROH, where if R=H– then n=2,5–7 and if R=CH3– then n=4,5) and two new dihydroxamate-based siderophore models, hexanedioic acid bis (3-hydroxycarbamoyl-methyl)amide (DhaI) and hexanedioic acid bis(3-hydroxycarbamoyl-propyl)amide (DhaII) have been characterized in terms of chelating properties toward molybdenum(VI). For comparison, the molybdenum(VI)–acetohydroxamic acid (Aha) and molybdenum(VI)–aminohydroxamic acid systems have also been studied. Potentiometric and spectrophotometric studies at ionic strength of 0.2 mol/dm3 (KCl) and at 25∘C have been performed and the equilibrium constants have been determined. It has been found, that of the dihydroxamic acids, only the DhaI and DhaII form water soluble complexes with molybdenum(VI). Polynuclear complexes most probably precipitate with the other dihydroxamic acids. Complexes are formed up to ca. the neutral pH in all systems. Above this pH MoO42− and the free ligands exist. Although, very stable complexes are formed especially with DhaII, none of the studied ligands form a single bis(hydroxamato)dioxomolybdenum(VI) species. Mono(hydroxamato)trioxomolybdenum(VI) species are also formed, containing the uncoordinated moiety of the DhaI or DhaII in its protonated form. Out of aminohydroxamic acids, the β-alaninehydroxamic acid (β-Alaha) shows “Aha-like” coordination properties as the glutamic acid-γ-hydroxamic acid (Glu-γ-ha) does. The small differences with this latter ligand are possibly due to weak coordination of the carboxylate which makes the mono(hydroxamato)trioxomolybdenum(VI) species more stable and the uncoordinated carboxylates in bis(hydroxamato) dioxomolybdenum(VI) can protonate below pH 3. The tridentate coordination mode of aspartic acid-β-hydroxamic acid (Asp-β-ha) via the hydroxamate and carboxylate oxygens results in the formation of a dinuclear complex, [Mo2O5(LH)2]2− in addition to [MoO3(LH)]− (the protons are on the amino groups) in the pH-range 2.5–7.0.

Fmoc/Acyl protecting groups in the synthesis of polyamide (peptide) nucleic acid monomers

The chemical synthesis of polyamide (peptide) nucleic acid (PNA) monomers 22–25 has been accomplished using Fmoc [N-(2-aminoethyl)glycine backbone], anisoyl (adenine), 4-tert-butylbenzoyl (cytosine) and isobutyryl/diphenylcarbamoyl (guanine) protecting-group combinations, thus allowing oligomer synthesis on both peptide and oligonucleotide synthesizers. An alternative method for the preparation of (N 6-anisoyladenin-9-yl)acetic acid 7 is described using partial hydrolysis of a dianisoylated derivative. Different methods were studied for guanine alkylation including (a) Mitsunobu reaction; (b) low-temperature, sodium hydride- and (c) N,N-diisopropylethylamine-mediated alkylation reactions to give preferentially N 9-substituted derivatives. Empirical rules are proposed for differentiating N 9/N 7-substituted guanines based on their 13C NMR chemical-shift differences.

Neutral and positively charged new purine tetramer structures: a computational study of xanthine and uric acid derivatives

New tetramer structures, based on 9-methylxanthine (Xa), 9-methylxanthine protonated at N7 (XaH+) and 9-methyluric acid (Ua), were investigated by high-level density functional calculations. We have found that homo- and heterotetrads (XaH+)4, (XaH+–Xa)2, (XaH+–Ua)2 carrying positive charges can be formed by low barrier hydrogen bonds. Systems with zero charge [(Xa)4, (Xa–Ua)2, (Ua)4] were also constructed, investigated and compared to the guanine tetrad [(G)4]. It was shown that the new tetramers can bind cations and anions without the necessity of stacking interactions. Application of the calculated systems in higher-ordered structures (e.g. quadruplexes) is promising with or without intercalating ions.

Supramolecular H-bonded porous networks at surfaces: exploiting primary and secondary interactions in a bi-component melamine–xanthine system

The control over the formation of a bi-component porous network was attained by the self-assembly at a solid-liquid interface by exploiting both primary and secondary non-covalent interactions between melamine and N(3)-alkylated xanthine modules.

Self-assembly of n3-substituted xanthines in the solid state and at the solid–liquid interface

The self-assembly of small molecular modules interacting through noncovalent forces is increasingly being used to generate functional structures and materials for electronic, catalytic, and biomedical applications. The greatest control over the geometry in H-bond supramolecular architectures, especially in H-bonded supramolecular polymers, can be achieved by exploiting the rich programmability of artificial nucleobases undergoing self-assembly through strong H bonds. Here N(3)-functionalized xanthine modules are described, which are capable of self-associating through self-complementary H-bonding patterns to form H-bonded supramolecular ribbons. The self-association of xanthines through directional H bonding between neighboring molecules allows the controlled generation of highly compact 1D supramolecular polymeric ribbons on graphite. These architectures have been characterized by scanning tunneling microscopy at the solid-liquid interface, corroborated by dispersion-corrected density functional theory (DFT) studies and X-ray diffraction.

Synthesis and biological evaluation of triazolyl 13α-estrone-nucleoside bioconjugates

2′-Deoxynucleoside conjugates of 13α-estrone were synthesized by applying the copper-catalyzed alkyne–azide click reaction (CuAAC). For the introduction of the azido group the 5′-position of the nucleosides and a propargyl ether functional group on the 3-hydroxy group of 13α-estrone were chosen. The best yields were realized in our hands when the 3′-hydroxy groups of the nucleosides were protected by acetyl groups and the 5′-hydroxy groups were modified by the tosyl–azide exchange method. The commonly used conditions for click reaction between the protected-5′-azidonucleosides and the steroid alkyne was slightly modified by using 1.5 equivalent of Cu(I) catalyst. All the prepared conjugates were evaluated in vitro by means of MTT assays for antiproliferative activity against a panel of human adherent cell lines (HeLa, MCF-7 and A2780) and the potential inhibitory activity of the new conjugates on human 17β-hydroxysteroid dehydrogenase 1 (17β-HSD1) was investigated via in vitro radiosubstrate incubation. Some protected conjugates displayed moderate antiproliferative properties against a panel of human adherent cancer cell lines (the protected cytidine conjugate proved to be the most potent with IC50 value of 9 μM). The thymidine conjugate displayed considerable 17β-HSD1 inhibitory activity (IC50 = 19 μM).

Synthesis and analysis of peptide nucleic acid oligomers using Fmoc/acyl-protected monomers

The optimization of PNA oligomer synthesis has been accomplished employing Fmoc/acyl-protected monomers on TentaGel™ and Wang resins. Among the tested activating agents (CMP, BET, HATU) the latter was of choice in solid phase syntheses. “Leakage” of TentaGel™ resin greatly hampers the solution and MS analyses. Synthesis and acyl group deprotection steps have been separately examined using Wang resin. Optimal conditions also worked well on the CPG support. HPLC and MS analyses of the PNA oligomers were carried out under various conditions.

Thiazole C-nucleosides IV. An entry to pent-1′-enopyranosylthiazole derivatives

Abstract Starting from ethyl 2-(3′,4′-di-O-acetyl-2′-deoxy- L -erythro-or - D -threo-pent-1′-enopyranosyl)thiazole-4-carboxylate ( 1, 2 ) the synthesis of variously functionalized pent-1′-enopyranosylthiazoles ( 4–11, 15–20 ) was carried out with different O-, C-, S-, N-, and H-nucleophiles in the presence of Lewis acids. The regio- and stereoselective reactions proceeded with the Lewis acid-mediated formation of a carbocation ( I ) and the stereochemistry of the incoming nucleophile was determined by the neighbouring 4′-acetoxy group. However, with trimethylsilyl cyanide a 2′,3′-unsaturated 1′-C-cyano derivative ( 26 ) was formed. The configuration and conformation of prepared unsaturated compounds was thoroughly studied and the presence of a conformational equilibrium 4 H 5 ⇌ 5 H 4 was deduced.