Two Possible Strategies for Drug Modification of Gemcitabine and Future Contributions to Personalized Medicine

Drug repurposing is an emerging strategy, which uses already approved drugs for new medical indications. One such drug is gemcitabine, an anticancer drug that only works at high doses since a portion is deactivated in the serum, which causes toxicity. In this review, two methods were discussed that could improve the anticancer effect of gemcitabine. The first is a chemical modification by conjugation with cell-penetrating peptides, namely penetratin, pVEC, and different kinds of CPP6, which mostly all showed an increased anticancer effect. The other method is combining gemcitabine with repurposed drugs, namely itraconazole, which also showed great cancer cell inhibition growth. Besides these two strategies, physiologically based pharmacokinetic models (PBPK models) are also the key for predicting drug distribution based on physiological data, which is very important for personalized medicine, so that the correct drug and dosage regimen can be administered according to each patient’s physiology. Taking all of this into consideration, it is believed that gemcitabine can be repurposed to have better anticancer effects.     

Iboga Inspired N-Indolylethyl-Substituted Isoquinuclidines as a Bioactive Scaffold: Chemoenzymatic Synthesis and Characterization as GDNF Releasers and Antitrypanosoma Agents

The first stage of the drug discovery process involves the identification of small compounds with biological activity. Iboga alkaloids are monoterpene indole alkaloids (MIAs) containing a fused isoquinuclidine-tetrahydroazepine ring. Both the natural products and the iboga-inspired synthetic analogs have shown a wide variety of biological activities. Herein, we describe the chemoenzymatic preparation of a small library of novel N-indolylethyl-substituted isoquinuclidines as iboga-inspired compounds, using toluene as a starting material and an imine Diels–Alder reaction as the key step in the synthesis. The new iboga series was investigated for its potential to promote the release of glial cell line-derived neurotrophic factor (GDNF) by C6 glioma cells, and to inhibit the growth of infective trypanosomes. GDNF is a neurotrophic factor widely recognized by its crucial role in development, survival, maintenance, and protection of dopaminergic neuronal circuitries affected in several neurological and psychiatric pathologies. Four compounds of the series showed promising activity as GDNF releasers, and a leading structure (compound 11) was identified for further studies. The same four compounds impaired the growth of bloodstream Trypanosoma brucei brucei (EC₅₀ 1–8 μM) and two of them (compounds 6 and 14) showed a good selectivity index.     

An Edible Oil Enriched with Lycopene from Pink Guava (Psidium guajava L.) Using Different Mechanical Treatments

According to the regulations of the United States Food and Drug Administration (FDA), organic solvents should be limited in pharmaceutical and food products due to their inherent toxicity. For this reason, this short paper proposes different mechanical treatments to extract lycopene without organic solvents to produce an edible sunflower oil (SFO) enriched with lycopene from fresh pink guavas (Psidium guajava L.) (FPGs). The methodology involves the use of SFO and a combination of mechanical treatments: a waring blender (WB), WB+ high-shear mixing (HSM) and WB+ ultrafine friction grinding (UFFG). The solid:solvent (FPG:SFO) ratios used in all the techniques were 1:5, 1:10 and 1:20. The results from optical microscopy and UV–vis spectroscopy showed a correlation between the concentration of lycopene in SFO, vegetable tissue diameters and FPG:SFO ratio. The highest lycopene concentration, 18.215 ± 1.834 mg/g FPG, was achieved in WB + UFFG with an FPG:SFO ratio of 1:20. The yield of this treatment was 66% in comparison to the conventional extraction method. The maximal lycopene concentration achieved in this work was significantly higher than the values reported by other authors, using high-pressure homogenization for tomato peel and several solvents such as water, SFO, ethyl lactate and acetone.     

Synthesis and thermal characterization of copper and calcium mixed phosphates

A series of compounds with composition of Ca_1–xCu_xHPO₄, where x varied from 0.05 to 0.5 were synthesized by precipitation method. The compounds were characterized by elemental analysis, X-ray diffraction, infrared spectroscopy, scanning electron microscopy, and thermogravimetry. The chemical stabilities of solids were investigated at several pH. Elemental analysis of copper, calcium and phosphorus are in agreement with the proposed composition. The formation of lamellar phosphates was evidenced. The stability of the set of compounds was better for samples with high copper content.     

Production and Characterization of β-Glucanase Secreted by the Yeast Kluyveromyces marxianus

An extracellular β-glucanase secreted by Kluyveromyces marxianus was identified for the first time. The optimal conditions for the production of this enzyme were evaluated by response surface methodology. The optimal conditions to produce β-glucanase were a glucose concentration of 4 % (w/v), a pH of 5.5, and an incubation temperature of 35 °C. Response surface methodology was also used to determine the pH and temperature required for the optimal enzymatic activity. The highest enzyme activity was obtained at a pH of 5.5 and a temperature of 55 °C. Furthermore, the enzyme was partially purified and sequenced, and its specificity for different substrates was evaluated. The results suggest that the enzyme is an endo-β-1,3(4)-glucanase. After optimizing the conditions for β-glucanase production, the culture supernatant was found to be effective in digesting the cell wall of the yeast Saccharomyces cerevisiae, showing the great potential of β-glucanase in the biotechnological production of soluble β-glucan.     

Adhesion hysteresis in dynamic atomic force microscopy

The effects of adhesion hysteresis in the dynamic‐dissipation curves measured in amplitude‐modulation atomic force microscopy are discussed. Hysteresis in the interaction forces is shown to modify the dynamics of the cantilever leading to different power dissipation curves in the repulsive and attractive regimes. Experimental results together with numerical simulations show that power dissipation, as measured in force microscopy, is not always proportional to the energy dissipated in the tip–sample interaction process. (© 2008 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)     

High resolution NMR spectroscopy of heteroaromatic cations. II—pyrylium,thiapyrylium and seleninium cations

The barriers to internal rotation about the C? N bond in several thiopiperidides have been determined by the NMR technique. It was found that the barrier height (ΔG^?) increases in the series cinnamoylthiopiperidide<thiobenzoylpiperidide<phenylthioacetylpiperidide. This trend was discussed in terms of the electronic structure, using HMO calculations. For m-and p-substituted cinnamoylthiopiperidides the barriers were shown to increase with the electron withdrawing character of the substituent in the aromatic ring.     

Two-phase channel structures based on alpha-cyclodextrin-polyethylene glycol inclusion complexes

Wide-angle X-ray scattering observations of alpha-cyclodextrin (CD)-poly(ethylene glycol) (PEG) inclusion complexes (ICs) have shown for the first time that two crystalline columnar modifications (forms I and II) are produced in the process of their formation. This was made possible by precise azimuthal X-ray diffraction scanning of oriented IC samples. Form I is characterized by CDs threaded onto PEG chains and arranged along channels in the order head-to-head/tail-to-tail, while form II is formed by unbound CDs also arranged into columns in a head-to-tail and also possibly a head-to-head/tail-to-tail manner, probably as a result of template crystallization on the form I IC crystals. It was shown that similar structural peculiarities are inherent for channel structures based on ICs obtained with PEG with a wide range of molecular weights (MWs). The characteristic feature of ICs based on PEG, especially with MW > 8000, is the presence of unbound polymer in the composition of the complex. The amount of unbound PEG was shown to rise with increasing MW of PEG, resulting in greater imperfections in the IC crystalline structure. The polyblock structure of ICs based on alpha-CD and PEG was therefore proposed.