Tricyclic Form Research Articles

Research into complexes of triethanolamine with ZnCl<sub>2</sub> and CdCl<sub>2</sub> using NMR Spectroscopy and Quantum Chemistry methods

Complexes of triethanolamin with ZnCl 2 and CdCl 2 were studied using the methods of quantum chemistry and NMR spectroscopy. Triethanolamine complexes are prone to ligand exchange, which make them suitable as metal transporters. Therefore, research into the biological action of such compounds is of particular importance. 1 H and 13 C NMR spectra were recorded using a Bruker DPX250 pulsed spectrometer operated at 298 K. Non-empirical quantum-chemical calculations were performed by the B3LYP method using the Gaussian 09 software package. Changes in the chemical shifts and spin-spin coupling constants during the formation of triethanolamine complexes with heavy metals were studied. The obtained experimental data indicate that changes in the NMR spectrum shifts are accompanied by an increase in the spinspin coupling constants, with the 1 J(C, H) constants of the methylene group associated with nitrogen being the most significant. On the basis of the conducted NMR spectrum analysis, the authors propose a scheme for describing the structure and intermolecular dynamics of the complexes under study. In order to elucidate the observed changes in the NMR spectra of triethanolamine in the process of complex formation, a series of quantum-chemical calculations was carried out. Three states corresponding to mono-, bi- and tricyclic structures were taken into account. According to the obtained theoretical and experimental results, the complexes under study are characterized by intermolecular metabolic processes that lead to the averaging of NMR signals from various compounds existing in the solution. For triethanolamine complexes with CdCl 2 , the existence of bi- and tricyclic forms is equally probable. For triethanolamine complexes with ZnCl 2 , the tricyclic form seems to be more beneficial.

Bicyclic Boronates as Potent Inhibitors of AmpC, the Class C β-Lactamase from Escherichia coli.

Resistance to β-lactam antibacterials, importantly via production of β-lactamases, threatens their widespread use. Bicyclic boronates show promise as clinically useful, dual-action inhibitors of both serine- (SBL) and metallo- (MBL) β-lactamases. In combination with cefepime, the bicyclic boronate taniborbactam is in phase 3 clinical trials for treatment of complicated urinary tract infections. We report kinetic and crystallographic studies on the inhibition of AmpC, the class C β-lactamase from Escherichia coli, by bicyclic boronates, including taniborbactam, with different C-3 side chains. The combined studies reveal that an acylamino side chain is not essential for potent AmpC inhibition by active site binding bicyclic boronates. The tricyclic form of taniborbactam was observed bound to the surface of crystalline AmpC, but not at the active site, where the bicyclic form was observed. Structural comparisons reveal insights into why active site binding of a tricyclic form has been observed with the NDM-1 MBL, but not with other studied β-lactamases. Together with reported studies on the structural basis of inhibition of class A, B and D β-lactamases, our data support the proposal that bicyclic boronates are broad-spectrum β-lactamase inhibitors that work by mimicking a high energy ‘tetrahedral’ intermediate. These results suggest further SAR guided development could improve the breadth of clinically useful β-lactamase inhibition.

Valence tautomerism of new pyrazolo[4,3-e]tetrazole[4,5-b][1,2,4]triazines

New pyrazolo[4,3-e]tetrazolo[4,5-b][1,2,4]triazines 5 and 6 were prepared as new biological active compounds with potential anticancer activity referring to our previous study. The 1H NMR spectra reveal tautomeric equilibrium azido and tricyclic forms of these compounds in solution. The molecular and crystal structures of 5 and 6 were determined by the X-ray analysis. The X-ray investigations show that in the crystalline state the compounds 5 and 6 exist as the linear tricyclic pyrazolo[4,3-e]tetrazolo[4,5-b][1,2,4]triazine tautomeric form. The analysis of the intra- and intermolecular interactions indicates the weak C–H⋯N hydrogen bonds and π⋯π interactions in crystal of 6 and van der Waals forces only in crystal of 5 as the non-covalent interactions influencing the molecular packing. The theoretical calculations at the ab initio DFT/B3LYP/6-311++G(d,p) level showed the azido form (3 and 4) as one existing in the gaseous phase and the coexistence of the tricyclic linear (5 and 6) and azido tautomeric forms in solution, wherein the contribution of the linear form compared to the azido form changes with polarity of the solvent.

Oxidation of thiamine on reaction with nitrogen dioxide generated by ferric myoglobin and hemoglobin in the presence of nitrite and hydrogen peroxide

It is shown that nitrogen dioxide oxidizes thiamine to thiamine disulfide, thiochrome, and oxodihydrothiochrome (ODTch). The latter is formed during oxidation of thiochrome by nitrogen dioxide. Nitrogen dioxide was produced by incubation of nitrite with horse ferric myoglobin and human hemoglobin in the presence of hydrogen peroxide. After addition of tyrosine or phenol to aqueous solutions containing oxoferryl forms of the hemoproteins, thiamine, and nitrite, the yield of thiochrome greatly increased, whereas the yield of ODTch decreased. In the presence of high concentrations of tyrosine or phenol compounds ODTch was not formed at all. The neutral form of thiamine with the closed thiazole cycle and minor tricyclic form of thiamine do not enter the heme pocket of the protein and do not interact with the oxoferryl heme complex Fe(IV=O) or porphyrin radical. The tricyclic form of thiamine is oxidized to thiochrome by tyrosyl radicals located on the surface of the hemoprotein. The thiol form of thiamine is oxidized to thiamine disulfide by both hemoprotein tyrosyl radicals and oxoferryl heme complexes. Nitrite and also tyrosine, tyramine, and phenol readily penetrate into the heme pocket of the protein and reduce the oxyferryl complex to ferric cation. These reactions yield nitrogen dioxide as well as tyrosyl and phenoxyl radicals of tyrosine molecules and phenol compounds, respectively. Tyrosyl and phenoxyl radicals of low molecular weight compounds oxidize thiamine only to thiochrome and thiamine disulfide. The effect of oxoferryl forms of myoglobin and hemoglobin, nitrogen dioxide, and phenol on thiamine oxidative transformation as well as antioxidant properties of the hydrophobic thiamine metabolitesthiochrome and ODTch are discussed.

Reduction of Cytochrome c in Its Reaction with Thiamine and Its Structural Analogs

The kinetics of reduction of ferricytochrome c in its reaction with thiamine and its O-substituted structural analogs in phosphate buffer at pH 7.5-7.8 were studied. The reduction rate is proportional to the concentration of thiamine or its derivatives. The dependence of the reaction rate on the oxidant concentration is characterized by negative deviations from linearity. In oxidation with ferricytochrome c, the reactivity of thiamine consdierably exceeds the reactivity of thiamine diphosphate and thiamine monophosphate, and in oxidation with ferricyanide the reaction rate increases in the order thiamine monophosphate < thiamine < thiamine diphosphate. With O-(2-norbornoyl)thiamine, O-(2-adamantyl)acetylthiamine, O-benzoylthiamine, O-(4-nitrobenzoyl)thiamine, or O-(5-nitro-2-chlorobenzoyl)thiamine, the rate of ferricytochrome c reduction is higher than with thiamine. Presumably, the electron transfer to the heme group of the oxidant is preceded by formation of a complex of ferricytochrome c with the neutral tricyclic form of the substrate.

Transanular Interactions in Difunctional Medium Rings, 6. Spectroscopic Investigations of Bicyclic Amino Ketones

The endo‐7‐(aminomethyl)bicyclo[3.3.1]nonan‐3‐ones 1–4 with a primary, secondary, or tertiary amino group have been synthesized, and their tendency to form the corresponding tricyclic amino carbinols has been investigated by theoretical (MMX, AM1) and experimental (PE, 13C‐NMR spectroscopy) methods. Comparison of the characteristic spectroscopic properties of 1–4 with those of the isochromophoric monofunctional compounds 7–11 indicates that 1 and 2 form mixtures with the tricyclic isomers 5 and 6, respectively, whereas 3 and 4 show no interactions between the amino and the carbonyl group in the solely present bicyclic structures.

Transanular Interactions in Difunctional Medium Rings, 5. Spectroscopic Investigations of Bicyclic Boraamines

AbstractThe endo‐7‐[(dialkylamino)methyl]‐3‐borabicyclo[3.3.1]nonanes 1 and 2 have been synthesized and their intramolecular complex formation of the corresponding 2‐azonia‐1‐boratatricyclo[4.3.1.14,8]undecanes 3 and 4 has been studied in the gas phase by UV photoelectron spectroscopy and in solution by 11‐NMR spectroscopy. Deviations of the characteristic spectral features from those of the monofunctional bicyclic boranes 5 and amines 6 and 7 indicate that in the gas phase the (dimethylamino)boranes with a B‐alkyl substituent adopt the tricyclic form 3a–c whereas the diethylamino and the B‐methoxy derivatives 1e and 2 prefer the bicyclic structure. In solution some deviations from this behavior are observed.

Thermal Reaction of Azulene‐1‐carbaldehydes with Dimethyl Acetylenedicarboxylate

AbstractAzulene‐1‐carbaldehydes which have Me substituents at C(3) and C(8) and no substituent at C(6) react with excess dimethyl acetylenedicarboxylate (ADM) in decalin at 200° to yield exclusively the Diels‐Alder adduct at the seven‐membered ring (cf. Scheme 3). The corresponding 1‐carboxylates behave similarly (Scheme 4). Azulene‐1‐carbaldehydes which possess no Me substituent at C(8) (e.g. 11, 12 in Scheme 2) gave no defined products when heated with ADM in decalin. On the other hand, Me substitutents at C(2) may also assist the thermal addition of ADM at the seven‐membered ring of azulene‐1‐carbaldehydes (Scheme 6). However, in these cases the primary tricyclic adducts react with a second molecule of ADM to yield corresponding tetracyclic compounds. The new tricyclic aldehydes 16 and 17 which were obtained in up to 50% yield (Scheme 3) could quantitatively be decarbonylated with [RhCl(PPh3)3] in toluene at 140° to yield a thermally equilibrated mixture of four tricycles (Scheme 8). It was found that the thermal isomerization of these tricycles occur at temperatures as low as 0° and that at temperatures &gt; 40° the thermal equilibrium between the four tricycles is rapidly established via [1,5]‐C shifts. The establishment of the equilibrium makes the existence of two further tricycles necessary (cf. Scheme 8). However, in the temperature range of up to 85° these two further tricycles could not be detected by 1H‐NMR. When heated in the presence of excess ADM in decalin at 180°, the ‘missing’ tricyclic forms could be evidenced by their tetracyclic trapping products ‘anti’‐45 and ‘anti’‐48, respectively (Scheme 9).

Synthesis of the major urinary metabolite of prostaglandin D2

Starting from the Corey lactone (3), the total synthesis of a specific urinary metabolite of prostaglandin D2, viz., (Z)-9α,11β-dihydroxy-15-oxo-2,3,18,19-tetranorprost-5-ene-1,20-dioic acid (1) and its 5E-isomer is described. The synthetic material was isolated in a tricyclic form as the corresponding hemiacetal lactone (2). The g.c.m.s. characteristics of the methyl ester, trimethylsilyl ether derivative of this compound were identical with those previously described for the same derivative of the 11β-tetranor metabolite of PGD2.

Chemistry of the tricyclic form of thiamine with aldehydes in basic ethanol

Thiamine chloride hydrochloride 1 is converted to its neutral tricyclic form 2 when suspended in a solution of ethanol containing two equivalents of NaOEt (G. D. Maier and D. E. Metzler (1957) J. Amer. Chem. Soc. 79, 4387). Upon the addition of benzaldehyde to this basic thiamine solution an intermediate accumulates which gives rise to 2-(1-hydroxyphenylmethyl)thiamine hydrochloride (HBT-HCl) 3 upon acidification of the reaction mixture with HCL after 5 min, and high yields of both 3-[(4-amino-2-methylpyrimidin-5-yl)methyl]-2-benzoyl-3a-methyl-perhydrofuro-[2,3-d]-thiazole (HBT ketone) 4 and benzoin when the reaction mixture is stirred for 5 h. Given that thiamine is unstable under these conditions such that it is converted completely to its tricyclic species, we argue that the 2-(1-hydroxylalkyl) thiamine salts, which have an increased base lability due to the addition of a C-2 N-3 torsional interaction to the base-labile thiazolium ring, would also not be expected to accumulate in appreciable concentrations under identical conditions. Based on product isolation and the synthesis of 2-benzoyl-3,4-dimethyl-5-ethoxycarbonyl-[2H]-thiazoline 12 in the reaction of 3,4-dimethyl-5-ethyoxycarbonylthiazolium iodide 11 with benzaldehyde in basic methanol, we conclude that the intermediate which accumulates during the reaction of the tricyclic form of thiamine with benzaldehyde is a 2-benzoylthiazoline 8 in equilibrium with a low concentration of its enol isomer 9, i.e., the C-2α reactive “active aldehyde.” Reasons for the increased catalytic power of thiamine under these conditions, as well as the relevance of this chemistry to the active site chemistry of thiamine pyrophosphate, are discussed.

ChemInform Abstract: Studies on the Aminopyrimidinyl Group of Thiamine.

AbstractBeim Erwärmen des Thiazoliumchlorids (I) entsteht der Tricyclus (II), der mit Sauerstoff zur Verbindung (III) dehydriert wird.

Metabolic fate of radiolabeled prostaglandin D2 in a normal human male volunteer.

50 microCi of [3H]prostaglandin D2 tracer (100 Ci/mmol) was infused intravenously into a normal human male volunteer. 75% of the infused radioactivity was excreted into the urine within 5 h. This urine was added to urine obtained from two mastocytosis patients with marked overproduction of prostaglandin D2. Radiolabeled prostaglandin D2 urinary metabolites were chromatographically isolated and purified and subsequently identified by gas chromatography-mass spectrometry. 25 metabolites were identified. 23 of these compounds comprising 37% of the recovered radioactivity had prostaglandin F-ring structures, and only two metabolites comprising 2.7% of the recovered radioactivity retained the prostaglandin D-ring structure. The single most abundant metabolite identified was 9,11-dihydroxy-15-oxo-2,3,18,19-tetranorprost-5-ene-1,20-dioic acid which was isolated in a tricyclic form as a result of formation of a lower side chain hemiketal followed by lactonization of the terminal carboxyl and the hemiketal hydroxyl. Different isomeric forms of several prostaglandin F-ring metabolites were identified. An isomer of prostaglandin F2 alpha was also excreted intact into the urine as a metabolite of prostaglandin D2. 15 PGF-ring compounds were treated with n-butylboronic acid and 13 failed to form a boronate derivative, suggesting that the orientation of the hydroxyl group at C-11 in these 13 metabolites is beta. This study documents that prostaglandin D2 is metabolized to prostaglandin F-ring metabolites in vivo in humans. These results also bring into question the accuracy of quantifying prostaglandin F2 alpha metabolites as a specific index of endogenous prostaglandin F2 alpha biosynthesis, as well as quantifying urinary prostaglandin F2 alpha as an accurate index of renal production of prostaglandin F2 alpha.

Studies on the aminopyrimidinyl group of thiamine

Although 3-(4-amono-2-methyl-pyromidin-5-yl)mehtyl-5-ethoxycarbonyl-4-methylthiazolium chlorine (2) undergoes a rapid C-2 H/D exchange in acidic D2O, formation of its neutral tricyclic form in basic solution completely inhibits the ability of this thiamine analogue to catalyse the benzoin condensation.

Symmetry and selectivity in the formation of inclusion complexes by macrotricyclic hosts

The tricyclic host molecules (1) and (5) form inclusion complexes with bis-primary-alkylammonium salts (3) in which the n.m.r. spectrum of the guest salt reflects the symmetry of the host molecule in the complex; the hosts (1) are rigid and highly selective, whereas the host (5a) has one flexible bridge and selectivity is modified by this flexibility.

Mutagenicity of intermediates produced in the early stage of the browning reaction of triose reductone with nucleic acid related compounds on bacterial tests.

Two types of reductive intermediates, linear and tricyclic forms, isolated from browning mixtures of triose reductone (TR) with guanine and its derivatives showed evident mutagenicity on Salmonella typhimurium TA 100 without S-9 mixture. The linear intermediates, N2-(3-oxo-2-hydroxypropenyl) compounds of guanine, guanosine, 2′(3′)-guanylic acid and 5′-guanylic acid were more effective than the tricyclic one, l, N2-(2-hydroxypropenylidene)guanine, though they were far less active than 4-nitroquinoline-N-oxide. No acceleration in mutagenicity was observed with Cu2 + and other metal ions. The reaction mixtures of TR and nucleic acid bases were also mutagenic on TA 100. Intermediates of TR with guanine and its derivatives did not have a lethal effect in Recassays with Bacillus subtilis.

A tricyclic form of thiamine.

A tricyclic form of thiamine.