Metformin combined with sodium dichloroacetate promotes B leukemic cell death by suppressing anti-apoptotic protein Mcl-1.

Metformin and the mitochondrial targeting dichloroacetate (DCA) have recently received attention due to their ability to inhibit anaerobic glycolysis, which renders most cancer cells resistant to apoptosis induction. We observed that Metformin alone exhibited a dose-dependent anti-leukemic activity in both B leukemic cell lines and primary B-chronic lymphocytic leukemia (B-CLL) patients' cells and its anti-leukemic activity was enhanced when used in combination with DCA. In order to overcome the problems of poor bioavailability and cellular uptake, which limit DCA efficacy, we have designed and synthetized cocrystals consisting of Metformin and DCA (Met-DCA) at different stoichiometric ratios.

Predicting hydrogen-bond strengths from acid-base molecular properties. The pK(a) slide rule: toward the solution of a long-lasting problem.

Unlike normal chemical bonds, hydrogen bonds (H-bonds) characteristically feature binding energies and contact distances that do not simply depend on the donor (D) and acceptor (:A) nature. Instead, their chemical context can lead to large variations even for a same donor-acceptor couple. As a striking example, the weak HO-H.

Interplay between steric and electronic factors in determining the strength of intramolecular N-H...O resonance-assisted hydrogen bonds in beta-enaminones.

The crystal structures of five beta-enaminones are reported: (2Z)-3-(benzylamino)-1,3-diphenyl-prop-2-en-1-one, (2Z)-3-(benzylamino)-3-(2-hydroxyphenyl)-1-phenyl-prop-2-en-1-one, (2Z)-3-(benzylamino)-3-(4-methoxyphenyl)-1-(3-nitrophenyl)-prop-2-en-1-one, 2-{1-[(4-methoxyphenyl)amino]ethylidene}cyclohexene-1,3-dione and 2-{1-[(3-methoxyphenyl)amino]ethylidene}cyclohexene-1,3-dione. The structures were analysed and compared with those of similar compounds in order to establish which factors determine the range (2.53-2.

pi-Bond cooperativity and anticooperativity effects in resonance-assisted hydrogen bonds (RAHBs).

Bond cooperativity effects, which are typical of ;resonant' chains or rings of pi-conjugated hydrocarbons, can also occur in hydrogen-bonded systems in the form of sigma-bond and pi-bond cooperativity or anticooperativity. sigma-Bond cooperativity is associated with the long chains of O-H..

Role of strong intramolecular N-H...N hydrogen bonds in determining the conformation of adenosine-receptor antagonists.

Over the last few years many efforts have been devoted to the discovery of new adenosine antagonists which can selectively bind to one of the four adenosine receptors, called A(1), A(2A), A(2B) and A(3), in order to develop new drugs with few side effects. The present paper reports the crystal structures of four newly synthesized antagonists belonging to the chemical class of pyrazolo-triazolo-pyrimidine derivatives, which display good affinity and selectivity properties towards the A(2A) or A(3) receptor subtypes. These molecules assume an overall planar conformation due to the formation of strong intramolecular N-H.

Variable-temperature X-ray crystallographic and DFT computational study of the N-H...O/N...H-O tautomeric competition in 1-(Arylazo)-2-naphthols. Outline of a transition-state hydrogen-bond theory.

Phenyl-substituted 1-arylazo-2-naphthols (AAN) display ...

Binding thermodynamics as a tool to investigate the mechanisms of drug-receptor interactions: thermodynamics of cytoplasmic steroid/nuclear receptors in comparison with membrane receptors.

Drug-receptor binding thermodynamics has proved to be a valid tool for pharmacological and pharmaceutical characterization of molecular mechanisms of receptor-recognition phenomena. The large number of membrane receptors so far studied has led to the discovery of enthalpy-entropy compensation effects in drug-receptor binding and discrimination between agonists and antagonists by thermodynamic methods. Since a single thermodynamic study on cytoplasmic receptors was known, this paper reports on binding thermodynamics of estradiol, ORG2058, and R1881 bound to estrogen, progesterone, and androgen steroid/nuclear receptors, respectively, as determined by variable-temperature binding constant measurements.

Structural features controlling the binding of beta-carbolines to the benzodiazepine receptor.

Beta-carbolines are a class of drug which can interact with a high affinity with the benzodiazepine (BDZ) binding site of the GABAA receptor. The present paper, aimed at obtaining a deeper insight into the structure-properties relationships of this class of molecules, reports the crystal structures of four beta-carbolines: ZK93423 (3-carboethoxy-4-methoxymethyl-6-benzyloxy-beta-carboline), ZK91296 (3-carboethoxy-4-methoxymethyl-5-benzyloxy-beta-carboline), FG7142 (N-methyl-3-carbamoyl-beta-carboline) and the low-affinity ligand harmine hydrochloride (1-methyl-7-methoxy-beta-carboline). This set of structural data is completed by the X-ray structures of other carbolines of known biological activity retrieved from the Cambridge Crystallographic Database and by the structures of beta-CCE (3-carboethoxy-beta-carboline), 6-PBC (3-carboethoxy-4-methoxymethyl-6-isopropoxy-beta-carboline), PRCC (3-isopropoxy-beta-carboline) and ZK93426 (3-carboethoxy-4-methyl-5-isopropoxy-beta-carboline), which have been obtained by molecular-mechanics simulations.

Covalent versus electrostatic nature of the strong hydrogen bond: discrimination among single, double, and asymmetric single-well hydrogen bonds by variable-temperature X-ray crystallographic methods in beta-diketone enol RAHB systems.

Beta-diketone enols are known to form intramolecular...

Receptor binding thermodynamics at the neuronal nicotinic receptor.

Simple determination of K(A) or K(D) values makes it possible to calculate the standard free energy DeltaG degrees = -RTlnK(A) = RT lnK(D)(T= 298.15 K) of the binding equilibrium but not that of its two components as defined by the Gibbs equation DeltaG degrees = DeltaH degrees - TDeltaS degrees where DeltaH degrees and DeltaS degrees are the equilibrium standard enthalpy and entropy, respectively. Recently, it has been shown that the relative DeltaH degrees and DeltaS degrees magnitudes can often give a simple "in vitro" way for discriminating "the effect", that is the manner in which the drug interferes with the signal transduction pathways.

The nature of solid-state N-H triplebondO/O-H triplebond N tautomeric competition in resonant systems. Intramolecular proton transfer in low-barrier hydrogen bonds formed by the triplebond O=C-C=N-NH triple bond --> <-- triplebond HO-C=C-N=N triplebond Ketohydrazone-Azoenol system. A variable-temperature X-ray crystallographic and DFT computational study.

The tautomeric.O=C-C=N-NH triplebond --> <-- HO-C=C-N=N triplebond ketohydrazone-azoenol system may form strong N-H triplebond O/O-H triplebond N intramolecular resonance-assisted H-bonds (RAHBs) which are sometimes of the low-barrier H-bond type (LBHB) with dynamic exchange of the proton in the solid state. The problem of the N-H triplebond O/O-H triplebond N competition in these compounds is studied here through variable-temperature (100, 150, 200, and 295 K) crystal-structure determination of pF = 1-(4-F-phenylazo)2-naphthol and oF = 1-(2-F-phenylazo)2-naphthol, two molecules that, on the ground of previous studies (Gilli, P; Bertolasi, V.

X-ray diffraction and molecular simulation study of the crystalline and liquid states of succinic anhydride.

The crystal structure of succinic anhydride was studied at five temperatures between 100 K and the melting point by single-crystal X-ray diffraction. The temperature dependence of molecular libration tensors was determined. Intermolecular interactions, in particular through unusually close molecule-molecule contacts, are discussed, with a detailed calculation of electrostatic energies.