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The reaction of mer-(Ru(H)2(CO)(PPh3)3) (1) with one equivalent of thymine acetic acid (THAcH) unexpectedly produces the macrocyclic dimer k1(O), k2(N,O)-(Ru(CO)(PPh3)2THAc)2 (4) and, concomitantly, the doubly coordinated species k1(O), k2(O,O)-(Ru(CO)(PPh3)2THAc) (5). The reaction promptly forms a complicated mixture of Ru-coordinated mononuclear species. With the aim of shedding some light in this context, two plausible reaction paths were proposed by attributing the isolated or spectroscopically intercepted intermediates on the basis of DFT-calculated energetic considerations. The cleavage of the sterically demanding equatorial phosphine in the mer-species releases enough energy to enable self-aggregation, producing the stable, symmetric 14-membered binuclear macrocycle of 4. The k1-acetate iminol (C=N-OH) unit of the mer-tautomer k1(O)-(Ru(CO)(PPh3)2(THAc)) (2) likely exhibits a stronger nucleophilic aptitude than the prevalent N(H)-C(O) amido species, thus accomplishing extra stabilization through concomitant k2(N,O)-thymine heteroleptic side-chelation. Furthermore, both the ESI-Ms and IR simulation spectra validated the related dimeric arrangement in solution, in agreement with the X-ray determination of the structure. The latter showed tautomerization to the iminol form. The 1H NMR spectra in chlorinated solvents of the kinetic mixture showed the simultaneous presence of 4 and the doubly coordinated 5, in rather similar amounts. THAcH added in excess preferentially reacts with 2 or trans-k2(O,O)-(RuH(CO)(PPh3)2THAc) (3) rather than attacking the starting Complex 1, promptly forming the species of 5. The proposed reaction paths were inferred by spectroscopically monitoring the intermediate species, for which the results were strongly dependent on the of conditions the reaction (stoichiometry, solvent polarity, time, and the concentration of the mixture). The selected mechanism proved to be more reliable, due to the final dimeric product stereochemistry. [ABSTRACT FROM AUTHOR]

Ruthenium complexes have proved to exhibit antineoplastic activity, related to the interaction of the metal ion with DNA. In this context, synthetic and theoretical studies on ruthenium binding modes of thymine acetate (THAc) have been focused to shed light on the structure-activity relationship. This report deals with the reaction between dihydride ruthenium mer-[Ru(H)2(CO)(PPh3)3], 1 and the thymine acetic acid (THAcOH) selected as model for nucleobase derivatives. The reaction in refluxing toluene between 1 and THAcOH excess, by H2 release affords the double coordinating species κ1-(O)THAc-, κ2-(O,O)THAc-[Ru(CO)(PPh3)2], 2. The X-ray crystal structure confirms a simultaneous monohapto, dihapto- THAc coordination in a reciprocal facial disposition. Stepwise additions of THAcOH allowed to intercept the monohapto mer-κ1(O)THAc-Ru(CO)H(PPh3)3] 3 and dihapto trans(P,P)-κ2(O,O)THAc-[Ru(CO)H(PPh3)2] 4 species. Nuclear magnetic resonance (NMR) studies, associated with DFT (Density Function Theory)-calculations energies and analogous reactions with acetic acid, supported the proposed reaction path. As evidenced by the crystal supramolecular hydrogen-binding packing and 1H NMR spectra, metal coordination seems to play a pivotal role in stabilizing the minor [(N=C(OH)] lactim tautomers, which may promote mismatching to DNA nucleobase pairs as a clue for its anticancer activity. [ABSTRACT FROM AUTHOR]

The roots of two cultivars of Paeonia, namely Paeonia officinalis "Rubra Plena" and Paeonia "Pink Hawaiian Coral", have been extracted with chloroform. The composition of the lipid fraction, analyzed by GC–MS technique, revealed the absence of paeonol and the presence of phenol, benzoic acid, fatty acid—and some sterol—derivatives. The chloroformic extracts have been tested on normal and several cancer cell lines but showed antiproliferative activity only on the ovarian carcinoma and the osteosarcoma. The biological activity of extracts was investigated mainly by confocal microscopy, flow cytometry and quantum phase imaging. The results indicated that the root extracts induced a hyperpolarization of mitochondria and an increase in reactive oxygen species levels, without inducing cell death. These effects are associated to an increased doubling time and a retarded confluence. [ABSTRACT FROM AUTHOR]

Among the functions exerted by eukaryotic lactate dehydrogenases, it is of importance the generation of lactate in muscles subjected to fatigue or to limited oxygen availability, with both these conditions triggering a decrease of cellular pH. However, the mutual dependence between lactate dehydrogenase (LDH) catalytic action and lactic acidosis is far from being fully understood. Here we show that the tetrameric LDH from rabbit skeletal muscle undergoes allosteric transitions as a function of pH, i.e. the enzyme obeys Michaelis-Menten kinetics at neutral or slightly alkaline pH values, and features sigmoidal kinetics at pH 6.5 or lower. Remarkably, we also report that a significant dissociation of tetrameric rabbit LDH occurs under acidic conditions, with pyruvate/NAD+ or citrate counteracting this effect. Moreover, citrate strongly activates rabbit LDH, inducing the enzyme to feature Michaelis-Menten kinetics. Further, using primary rabbit skeletal muscle cells we tested the generation of lactate as a function of pH, and we detected a parallel decrease of cytosolic pH and secretion of lactate. Overall, our observations indicate that lactic acidosis is antagonized by LDH dissociation, the occurrence of which is regulated by citrate and by allosteric transitions of the enzyme induced by pyruvate. • Acidic pH conditions trigger allosteric transitions in rabbit lactate dehydrogenase. • The dissociation of lactate dehydrogenase tetramer induces allosteric kinetics. • Allosteric kinetics does not depend on enzyme post-translational modifications. • Citrate, isocitrate, fructose 1,6-bisphosphate, and malate activate rabbit lactate dehydrogenase. • The acidification of cytosolic pH inhibits lactate secretion by rabbit muscle cells. [ABSTRACT FROM AUTHOR]

The azido transfer procedure of heteroaryllithium and tosyl azide was used to synthesize selected 2- and 5-azidoazoles. This procedure, which is based on the fragmentation of the appropriate lithium triazene salts 1a-7a, successfully afforded 2-azido-N-methylimidazole 1, 2-azido-1,3-thiazole 2, 2-azidobenzo-1,3-thiazole 3, 5-azido-N-methylpyrazole 4, 5-azido-N-methylimidazole 6[via 2-(trimethylsilyl)-5-azido-N-methylimidazole 5], and 5-azido-1,3-thiazole 7 (via 5-lithio-1,3-thiazole), but attempts to prepare 5-azido-2-(trimethylsilyl)-1,3-thiazole 8 from the corresponding triazene 7a failed, affording only the desilylated azide in poor yield. Azides - underwent 1,3-dipolar cycloaddition when mixed with neat (trimethylsilyl)acetylene, giving 1-heteroaryl-4-trimethylsilyl-1,2,3-triazoles 1b-7b generally in very high yields.