Het(aryl)isatin to het(aryl)aminoindoline scaffold hopping: A route to selective inhibitors of matrix metalloproteinases

Matrix metalloproteinases (MMPs) are a large family of zinc-dependent endoproteases known to exert multiple regulatory roles in tumor progression. A variety of chemical classes have been explored for targeting individual MMP isoforms. In the present study, we further developed our isatin based scaffold BB0223107 capable of binding to and inactivating MMP-2 in a zinc-independent manner (Agamennone et al., 2016). Forty four new compounds were synthesized based on the modified BB0223107. All compounds were tested in enzyme inhibition assays against MMP-2, ?8 and ?13. SAR studies demonstrated that 5-het(aryl)-3-aminoindolin-2-ones (37–39) were active toward MMP-2 and MMP-13. The most potent compounds 33 and 37 displayed an IC₅₀ of 3 µM against MMP-13 and showed a negligible activity toward MMP-8; almost all new compounds were inactive toward MMP-8. Replacement of the isatin ring with a biaryl system (compound 33) did not decrease the potency against MMP-13 but reduced the selectivity. Structure-based computational studies were carried out to rationalize the inhibitory activity data. The analysis of binding geometries confirmed that all fragments occupied the S1′ site in the three enzymes while no ligand was able to bind the catalytic zinc ion. To the best of our knowledge, this is the first example of 3-aminoindolin-2-one-based MMP inhibitors that, based on the computer modeling study, do not coordinate the zinc ion. Thus, the het(aryl)-3-aminoindolin-2-one derivatives emerge as a drug-like and promising chemotype that, along with the hetaryl variations, represents an alternative and thrifty tool for chemical space exploration aimed at MMP inhibitor design.     

TOF-SIMS imaging of chlorhexidine-digluconate transport in frozen hydrated biofilms of the fungus Candida albicans

The diffusion of the anti-microbial chlorhexidine digluconate (CHG) has been studied in C. albicans biofilms by time-of-flight secondary-ion mass spectrometry (TOF-SIMS). C. albicans has been shown to become resistant to common anti-microbial agents, including CHG, when growing as a biofilm. Mass transport resistance within biofilms has commonly been suggested as a resistance mechanism, but measurement of transport for most anti-microbial agents in biofilms has proven extremely difficult because of the heterogeneity of the biofilms and the difficulty in detecting these agents within an intact biofilm. In this study, TOF-SIMS has been used to study the transport of CHG and glucose in a frozen hydrated biofilm. The TOF-SIMS images reveal a progression of CHG from the top of the biofilm to its base with time. Images suggest that there are channels within the biofilm and show preferential binding of CHG to cellular components of the biofilm. Additionally, both living and dead cells can be identified in the TOF-SIMS images by the sequestration of K⁺ and the presence of cell markers. This study demonstrates that TOF-SIMS has the unique potential to simultaneously observe the presence of an antimicrobial agent, concentration of nutrients, and the viability of the cell population.     

EXAFS study of liposome-encapsulated cisplatin

The anticancer agent cisplatin encapsulated in sterically stabilized liposomes is studied with extended X-ray absorption fine structure (EXAFS) method. Analysis of local atomic structure around Pt atoms clearly indicates that the liposome-encapsulated drug is chemically stable and does not hydrolyze. Cisplatin forms a supersaturated solution in the liposome interior at a concentration about eight-fold above its aqueous solubility.     

High performance liquid chromatographic separation of polar and non-polar chlorophyll pigments from algae using a wide pore polymeric octadecylsilica column

A method employing a wide pore polymeric reversed phase column has been developed for the separation of most of the chlorophylls and related compounds previously described as occurring in marine microalgae. The high selectivity toward molecular shape of this kind of stationary phase has enabled compounds of very similar structure, such as chlorophylls c₁, c₂ and Mg-divinylpheoporphyrin a₅ monomethyl ester, and chlorophyll a and the phytol-substituted chlorophyll c-like pigments, which commonly coelute on monomeric bonded phases, to be resolved in a single run. Some of these pigments, formerly thought to be a single compound, have, in fact, been demonstrated to be groups of two or more. The method has been successfully applied to both algal cultures and natural sea water samples. When visible light absorbance detection was used, the method proved suitable for separation of various carotenoids.     

Optimal vaccine scheduling in cancer immunotherapy

Cancer immunotherapy aims at stimulating the immune system to react against cancer stealth capabilities. It consists of repeatedly injecting small doses of a tumor-associated molecule one wants the immune system to recognize, until a consistent immune response directed against the tumor cells is observed.

We have applied the theory of optimal control to the problem of finding the optimal schedule of injections of an immunotherapeutic agent against cancer. The method employed works for a general ODE system and can be applied to find the optimal protocol in a variety of clinical problems where the kinetics of the drug or treatment and its influence on the normal physiologic functions have been described by a mathematical model.

We show that the choice of the cost function has dramatic effects on the kind of solution the optimization algorithm is able to find. This provides evidence that a careful ODE model and optimization schema must be designed by mathematicians and clinicians using their proper different perspectives.     

Synthesis and electrical characteristics of polyaniline nanoparticles and their polymeric composite

Monodisperse polyaniline nanoparticles (PAPSSA) were synthesized from an oxidative dispersion polymerization using poly(sodium 4-styrenesulfonate) (PSSA) as both a polymeric stabilizer and a dopant agent due to its acidity. The nanoparticles were being stabilized with two different molecular weight of PSSA. Size effect of PAPSSA particles were examined by scanning electron microscopy (SEM), transmission electron microscopy (TEM) and dynamic light scattering (DLS). The d.c. electrical conductivity of composite films on the glass substrate was measured by a four-probe method. It was found that the electrical properties of the composite films are affected by the content of nano-sized polyaniline and different molecular weights of stabilizer in the poly(vinyl alcohol) (PVA) matrix.     

Precipitation and characterization of uniform submicrometer lead titanate particles. Part II: Reaction mechanism

The chemical mechanism of the precipitation of lead titanium peroxohydroxide particles in a solution of nitrilotriacetate (NTA) complexes of lead and titanium peroxo-hydroxide is envisioned as the interaction between cations of lead hydroxide and anions of polymeric titanium peroxo-hydroxide.     

Future pathways for combinatorial chemistry

Summary Investment in combinatorial chemistry (combichem) in the pharmaceutical industry is being driven by the need for increased efficiency. Results from pioneers in the field have demonstrated where mixture or discrete compound synthesis is useful, and what mixture sizes and compound concentrations are appropriate. To make the techniques of combichem of general utility in drug discovery, a broad range of advances is still required. Conversion of organic chemistry to solid phase conditions is key, as are developments in linkers and resins. Library design methodology requires further development. Combinatorial biosynthesis of focused libraries of natural products holds great promise for capitalising on hardwon natural product leads. Miniaturisation of screens is required to reduce the cost of screening combinatorial libraries. Developments in the processes preceding and following synthesis are required to enable the flow of increased numbers of compounds without new bottlenecks developing. The impact of combinatorial chemistry will be greatly enhanced by synergy with ongoing parallel developments in genetic technologies, screening technologies and bioinformatics.     

Effect of surfactants on the voltammetric response and determination of an antihypertensive drug

The effect of adding surface-active agents to electrolytes containing terazosin, an antihypertensive drug, on the voltammetric response of glassy carbon electrode was studied. The current signal due to the oxidation process was a function of the amount of terazosin, pH of the medium, type of surfactant, and accumulation time at the electrode surface. Two surfactants were used, an anionic type, sodium dodecyl sulfate (SDS) and a cationic type, cetyl trimethyl ammonium bromide (CTAB). Addition of SDS to the terazosin-containing electrolyte was found to enhance the oxidation current signal while CTAB showed an opposite effect. Beside the interfacial interaction of the surfactant with the electrode surface in reference to the bias applied potential and the charge of surfactant, terazosin-surfactant interaction in the electrolytic solution was found to be critical to the magnitude of current signal. Addition of SDS to terazosin-containing buffer solution resulted in a decrease in the drug absorption spectrum both in the ultra-violet and visible (UV-vis) regions. Moreover, NMR measurements showed considerable chemical shifts for the aromatic protons of the quinazolinyl moiety of the terazosin in presence of SDS. The affected aromatic protons are positioned next to the interacting protonated amino-group of the terazosin with the charged sulfonate-group of SDS. On the other hand, addition of CTAB did not cause noticeable changes both to the UV-vis and NMR spectra of the drug. The use of SDS in the electrochemical determination of terazosin using linear sweep voltammetry and differential pulse voltammetry at solid glassy carbon electrode enhanced the detection limit from 6.00 × 10⁻⁷ mol L⁻¹ in absence of surfactant to 4.58 × 10⁻⁹ mol L⁻¹ when present. The validity of using this method in the determination of drug active ingredient in urine samples and tablet formulations was also demonstrated.