Binding mode of Pyridoclax to myeloid cell leukemia-1 (Mcl-1) revealed by nuclear magnetic resonance spectroscopy, docking and molecular dynamics approaches.

Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic member of the Bcl-2 family proteins. Its amplification is one of the most frequent genetic aberrations found in human cancers. Pyridoclax, a promising BH3 mimetic inhibitor, interacts directly with Mcl-1 and induces massive apoptosis at a concentration of 15 µM in combination with anti-Bcl-xL strategies in chemo-resistant ovarian cancer cell lines. In this study, a combined experimental and theoretical approach was used to investigate the binding mode of Pyridoclax to Mcl-1. The representative poses generated from dynamics simulations compared with NMR data revealed: (i) Pyridoclax bound to P1 and P2 pockets of Mcl-1 BH3 binding groove through its styryl and methyl groups establishing mainly hydrophobic contacts, (ii) one of the ending pyridines interacts through electrostatic interaction with K234 side chain, a negatively charged residue present only in this position in Mcl-1. Communicated by Ramaswamy H. Sarma.

2D 7Li Ultrafast CT-COSY: a new tool for the rapid measurement of tiny homonuclear lithium scalar couplings.

The measurement of small homonuclear 2J7Li-7Li scalar couplings relying on constant time (CT) COSY NMR suffers from strong time limitations. We describe the first Ultrafast CT COSY experiment on lithium 7, which provides a considerable acceleration in the study of the aggregation state and dynamics of n-BuLi/MeLi complexes.

1H Pure Shift DOSY: a handy tool to evaluate the aggregation and solvation of organolithium derivatives.

Determination of the structure and solvation states of organolithium aggregates in complex solution remains a challenging task. Here, we show that (1)H Pure Shift DOSY NMR provides better resolution spectra without overlapping, even for complex solutions of mixed aggregates of n-BuLi/n-BuOLi. This ensures the direct observation of the apparent diffusion constant for each component in the solution and therefore allows a fast assignment of aggregation states, and solvation degree.

A data-mining approach to spacer oligonucleotide typing of Mycobacterium tuberculosis.

MOTIVATION: The Direct Repeat (DR) locus of Mycobacterium tuberculosis is a suitable model to study (i) molecular epidemiology and (ii) the evolutionary genetics of tuberculosis. This is achieved by a DNA analysis technique (genotyping), called sp acer oligo nucleotide typing (spoligotyping ). In this paper, we investigated data analysis methods to discover intelligible knowledge rules from spoligotyping, that has not yet been applied on such representation. This processing was achieved by applying the C4.5 induction algorithm and knowledge rules were produced. Finally, a Prototype Selection (PS) procedure was applied to eliminate noisy data. This both simplified decision rules, as well as the number of spacers to be tested to solve classification tasks. In the second part of this paper, the contribution of 25 new additional spacers and the knowledge rules inferred were studied from a machine learning point of view. From a statistical point of view, the correlations between spacers were analyzed and suggested that both negative and positive ones may be related to potential structural constraints within the DR locus that may shape its evolution directly or indirectly. RESULTS: By generating knowledge rules induced from decision trees, it was shown that not only the expert knowledge may be modeled but also improved and simplified to solve automatic classification tasks on unknown patterns. A practical consequence of this study may be a simplification of the spoligotyping technique, resulting in a reduction of the experimental constraints and an increase in the number of samples processed.

Dual behavior of 4-aza-6-nitrobenzofuroxan. A powerful electrophile in hydration and sigma-complex formation and a potential dienophile or heterodiene in diels-alder type reactions

In investigating the reactivities of aza analogues of super-electrophile 4,6-dinitrobenzofuroxan (DNBF, 1), we have found that the nitro-substituted pyridofuroxan 2 gives a remarkably stable hydrate 3 in aqueous solution (as evidenced by the requirement of ca. 50% H(2)SO(4) (H(0) approximately -3) for complete recovery of 2). The equilibrium constant K(H)()2(O) for hydration of 2 is estimated to be >/= 100, being comparable only with the K(H)()2(O) values reported for hydration of highly activated neutral polyazaaromatics such as 2- and 6-hydroxypteridines or 7-azapteridine. Interestingly, the NH group of 3 undergoes ionization at rather low pH (p = 5.79), affording an anionic hydroxy sigma-adduct 4 which is thermodynamically 10(8) times more stable than the related sigma-adduct of pteridine. The experimental evidence is that 4 is slightly more stable than the hydroxy sigma-adduct of DNBF, indicating not only that 2 ranks among the most electrophilic heteroaromatics known to date but also than an aza group may in fact be as efficient as a nitro group in promoting sigma-complex formation. 2 is also found to be a versatile Diels-Alder reagent, as a result of the low aromatic character of its six-membered ring. Upon treatment of 2 with cyclopentadiene and 2,3-dimethylbutadiene, various reactivity patterns have been observed. These led to different cycloadducts arising from normal as well as inverse electron-demand condensations involving the pyridine ring as the dienophile or the heterodiene contributor. Altogether, the results reveal major differences between the reactivity of 2 and that of DNBF, with in particular a remarkable tendency of the pyridofuroxan adducts to undergo covalent hydration, resulting in the formation of stable carbinolamines. Also noteworthy is the characterization of a diadduct which results from a Diels-Alder trapping of the o-dinitroso intermediate involved in the exchange of the 1-oxide and 3-oxide tautomers of 2.

[The effects of phenylbutazone on the decrease of lithium clearance]. / Baisse de la clearance rénale du lithium sous l'effet de la phénylbutazone.

During the treatment of a manic depressive patient, the authors reported some lithium toxicity signs, as lithium carbonate (3 X 300 mg p.d.) and phenylbutazone suppository (3 X 250 mg/p.d.) were associated, this last medication being prescribed for a phlebitis. Lithiemia increased from .70 to 1,44 mEq/l., the lithiemia clearance falling from 10 ml to 5 ml/mn/1.73 m2) and the lithium tubular reabsorption percentage increasing from 85 to 94% (standard rates: 77.4 +/- 1.3%). In a second time, a rat experimentation corroborated these findings: phenylbutazone treatment (100 mg/kg/p.o. for five days) resulted in a lithium tubular reabsorption increase. It seems that the association of lithium carbonate with phenylbutazone should be avoided. The authors point out the risk of prescribing lithium and pyrazolic by-products as phenylbutazone, which are potentially nephrotoxic.