Potent "clicked" MMP2 inhibitors: synthesis, molecular modeling and biological exploration

A new series of MMP2 inhibitors is described, following a fragment-based drug design approach. One fragment containing an azide group and a well known hydroxamate Zinc Binding Group in a α-sulfone, α-tetrahydropyrane scaffold, has been synthesized. Water-LOGSY, STD and competition-STD experiments indicate that this fragment binds to the active site of the enzyme. A click chemistry reaction was used to connect the azide to lipophilic alkynes selected to interact selectively with the S1' subunit of MMP2, as shown by docking and molecular dynamic experiments of the designed compounds. The most potent compounds 18 and 19 displayed an IC(50) of 1.4 and 0.3 nM against MMP2 respectively, and showed negligible activity towards MMP1 and MMP7, two metalloproteinases which have a shallow S1' subsite. Compound 18 also showed a promising selectivity profile against some antitarget metalloproteinases, such as MMP8, and considerably less activity against MMP14 (IC(50) = 65 nM), and MMP9 (IC(50) = 98 nM), other MMPs characterized by having a deep S1' pocket and, therefore, more similar to MMP2.     

Reactions of 1-hydroxy-1-methylethyl radicals with NO2-: time-resolved electron spin resonance

The reaction of the alpha-hydroxyalkyl radical of 2-propanol (1-hydroxy-1-methylethyl radical) with nitrite ions was characterized. A product of the reaction was assigned as the adduct nitro radical anion, [HO-C(CH(3))(2)NO(2)](*-). This radical was identified using time-resolved electron spin resonance (TRESR). The radical's magnetic parameters, the nitrogen hyperfine coupling constant (a(N) = 26.39 G), and its g-factor (2.0052) were the same as those of the nitro radical anion previously discovered in (*)OH spin-trapping experiments with the aci-anion of (CH(3))(2)CHNO(2). Production of [HO-C(CH(3))(2)NO(2)](*-) was determined to be 38% +/- 4% of the reaction of (CH(3))(2)C(*)-OH with nitrite. The reason why this fraction was less than 100% was rationalized by invoking the competitive addition at oxygen, which forms [HO-C(CH(3))(2)ONO](*-), followed by a rapid loss of (*)NO. Furthermore, by taking this mechanism into account, the bimolecular rate constant for the total reaction of (CH(3))(2)C(*)-OH with nitrite at reaction pH 7 was determined to be 1.6 x 10(6) M(-1) s(-1), using both decay traces of (CH(3))(2)C(*)-OH and growth traces of [HO-C(CH(3))(2)NO(2)](*-). This correspondence further confirms the nature of the reaction. The reaction mechanism is discussed with guidance by computations using density functional theory.     

A fast and sensitive continuous flow nanobiodetector based on polyaniline nanofibrils

Polyaniline nanofibrils, fabricated as a freestanding nanonetwork in a micro gap between two gold electrodes, have been applied in a fast and sensitive analytical device for detecting microorganism cells in a flowing liquid, including the “on-line” regime. The electrical response of the device (in this case an increase in the electrical conductivity of the nanonetwork) depends on the number of cells in the sample analyzed: it is linear within the range of 0–5000 and 0–15 × 10⁶ cells injected for yeast and bacteria examined, respectively. The detection limit depends on the type of microorganism: it is about 300 and 1.9 × 10⁵ (per mL) for yeast (Saccharomyces cerevisiae) and bacteria cells (Lactobacillus rhamnosus), respectively. The results are registered within few seconds (typically 5–15 s). The device is designed to detect a low level of bio-contamination and it is expected to be useful in biomedical applications, environmental protection and anti bioterrorism systems, including “on-line” monitoring.     

Electron-transfer-induced tautomerization in methylindanones: electronic control of the tunneling rate for enolization.

The radical cations generated from 4-methyl- and 4,7-dimethylindanone, as well as their deuterated isotopomers, isolated in Argon matrices, were found to undergo enolization to the corresponding enol radical cations at rates that differ by orders of magnitude. It is shown by quantum chemical calculations that the effect of the remote methyl group in the 4-position is of purely electronic nature in that it stabilizes the unreactive pi-radical relative to the reactive sigma-radical state of the 7-methylindanone radical cation. The observed kinetic behavior of the two compounds can be reproduced satisfactorily on the basis of calculated height and width of the thermal barrier for enolization, using the Bell model for quantum mechanical tunneling. High-level calculations on the methylacrolein radical cation show that barriers for enolization in radical cations are overestimated by B3LYP/6-31G.     

Maximal determinant over a certain class of matrices and its application to D-optimality of designs

It is known that some optimality criteria of experimental designs are functionals of the eigenvalues of their information matrices. In this context we study the problem of maximizing the determinant of $\alpha {\mathbf{I}}_t-(\mathbf{P}+{\mathbf{P}}^T)$, $\alpha >2$, over the class of t-by-t permutation matrices, and the determinant of $\alpha {\mathbf{I}}_t+\mathbf{P}+{\mathbf{P}}^T$, $\alpha \ge 2.5$, over the class of t-by-t permutation matrices with zero diagonal (derangement matrices). The results are used to characterize D-optimal complete block designs under an interference model.     

Universally optimal designs under an interference model with equal left- and right-neighbor effects

In this paper, the interference model with equal left- and right-neighbor effects is considered. We base this work on the method of Kunert and Martin (2000) to give a sufficient condition for universal optimality of circular neighbor designs. We show that some of neighbor designs by Rees (1967), Azaïs et al. (1993) and Druilhet (1999) satisfy this condition.     

Mechanical, rheological, fatigue, and degradation behavior of PLLA, PGLA and PDGLA as materials for vascular implants

The biggest challenge in the treatment of arterial stenosis remains the issue of optimization of stent design. Despite continuous improvement in surgical techniques and use of intensive pharmacotherapy, the results of stent coronary interventions may be unsatisfactory, and long-term interaction of a metal implant with a blood vessel results in complications such as recurrent stenosis and thrombosis. Therefore, it is necessary to search for new materials and stent designs to obtain a stent capable of restoring flow in the vessel and disappearing after fulfilling its function. Such stent must also be compatible with the vessel wall to enable regeneration of new structure of endothelium and deeper artery layers damaged during implantation. Consequently, there is ongoing search for functional solutions with minimum effects of long-term implant-tissue interaction. In light of the above, the team investigated the possibility of using biodegradable polymers already mentioned in the literature as a construction material for vascular stent. The study used three polyhydroxyacids based on lactic acid and glycolic acid: poly(l-lactide), poly(lactide-co-glycolide) and poly(d,l-lactide-co-glycolide). The research focused on assessing changes in mechanical, thermomechanical, rheological, and fatigue properties during the process of hydrolytic degradation. The analysis also covered the rate of release of degradation products. The results of the conducted tests indicate the possibility of developing a vascular stent with biodegradable polymers.     

Diffusion-equation model of slightly loaded M/M/1 queue

Another derivation of the diffusion approximation of the M/M/1 queue is presented, which results in a new boundary condition. The model proposed approximates the time-dependent behavior of the M/M/1 system for all values of channel utilization.