Butterfly Effect in Cytarabine: Combined NMR-NQR Experiment, Solid-State Computational Modeling, Quantitative Structure-Property Relationships and Molecular Docking Study.

Cytarabine (Ara-C) is a synthetic isomer of cytidine that differs from cytidine and deoxycytidine only in the sugar. The use of arabinose instead of deoxyribose hinders the formation of phosphodiester linkages between pentoses, preventing the DNA chain from elongation and interrupting the DNA synthesis. The minor structural alteration (the inversion of hydroxyl at the 2' positions of the sugar) leads to change of the biological activity from anti-depressant and DNA/RNA block builder to powerful anti-cancer. Our study aimed to determine the molecular nature of this phenomenon. Three 1H-14N NMR-NQR experimental techniques, followed by solid-state computational modelling (Quantum Theory of Atoms in Molecules, Reduced Density Gradient and 3D Hirshfeld surfaces), Quantitative Structure-Property Relationships, Spackman's Hirshfeld surfaces and Molecular Docking were used. Multifaceted analysis-combining experiments, computational modeling and molecular docking-provides deep insight into three-dimensional packing at the atomic and molecular levels, but is challenging. A spectrum with nine lines indicating the existence of three chemically inequivalent nitrogen sites in the Ara-C molecule was recorded, and the lines were assigned to them. The influence of the structural alteration on the NQR parameters was modeled in the solid (GGA/RPBE). For the comprehensive description of the nature of these interactions several factors were considered, including relative reactivity and the involvement of heavy atoms in various non-covalent interactions. The binding modes in the solid state and complex with dCK were investigated using the novel approaches: radial plots, heatmaps and root-mean-square deviation of the binding mode. We identified the intramolecular OH···O hydrogen bond as the key factor responsible for forcing the glycone conformation and strengthening NH···O bonds with Gln97, Asp133 and Ara128, and stacking with Phe137. The titular butterfly effect is associated with both the inversion and the presence of this intramolecular hydrogen bond. Our study elucidates the differences in the binding modes of Ara-C and cytidine, which should guide the design of more potent anti-cancer and anti-viral analogues.

Analysis of stabilization mechanisms in ß-lactoglobulin-based amorphous solid dispersions by experimental and computational approaches.

Our previous work shows that ß-lactoglobulin-stabilized amorphous solid dispersion (ASD) loaded with 70 % indomethacin remains stable for more than 12 months. The stability is probably due to hydrogen bond networks spread throughout the ASD, facilitated by the indomethacin which has both hydrogen donors and acceptors. To investigate the stabilization mechanisms further, here we tested five other drug molecules, including two without any hydrogen bond donors. A combination of experimental techniques (differential scanning calorimetry, X-ray power diffraction) and molecular dynamics simulations was used to find the maximum drug loadings for ASDs with furosemide, griseofulvin, ibuprofen, ketoconazole and rifaximin. This approach revealed the underlying stabilization factors and the capacity of computer simulations to predict ASD stability. We searched the ASD models for crystalline patterns, and analyzed diffusivity of the drug molecules and hydrogen bond formation. ASDs loaded with rifaximin and ketoconazole remained stable for at least 12 months, even at 90 % drug loading, whereas stable drug loadings for furosemide, griseofulvin and ibuprofen were at a maximum of 70, 50 and 40 %, respectively. Steric confinement and hydrogen bonding to the proteins were the most important stabilization mechanisms at low drug loadings (≤ 40 %). Inter-drug hydrogen bond networks (including those with induced donors), ionic interactions, and a high Tg of the drug molecule were additional factors stabilizing the ASDs at drug loading greater than 40 %.

Effect of Amylose and Crystallinity Pattern on the Gelatinization Behavior of Cross-Linked Starches.

Starches from normal maize (NM), normal potato (NP), waxy maize (WM), and waxy potato (WP) were cross-linked with seven different concentrations (0.01, 0.05, 0.1, 0.5, 1, 5, 10%) of sodium trimetaphosphate and sodium tripolyphosphate. The use of low-amylose WM and WP as well as A-crystalline maize and B-crystalline potato starches can determine the influence of the amylose content and crystallinity pattern on the cross-linking of starches. The results showed that the viscosity of the cross-linked starch (CLs) first increased and then deceased, and finally no viscosity was detected; WM showed no viscosity at 5% and NP at 1%. In addition, the viscosity of NM first increased and then became undetectable at 0.5%. Strikingly, the WP developed viscosity even at a 10% reagent level (RL), and it developed the highest viscosity of all samples at 1%. The starch-iodine method was a facile and high-performance method for the characterization of the cross-linking degree (CL%), having been applied to normal starches, because the increase in the CL% resulted in a decrease of iodine-complexed amylose and blue intensity. In this study, the starch-iodine method was extended to waxy starches, which stained brown with iodine, and the brown intensity decreased with the increase of the CL%. Moreover, the CL% and RL showed a linear-log relationship.

Structural changes of A-, B- and C-type starches of corn, potato and pea as influenced by sonication temperature and their relationships with digestibility.

The effect of sonication temperature on the structures and digestion behaviour of corn starch (CS, A-type), potato starch (PtS, B-type), and pea starch (PS, C-type) was investigated. For CS, sonication temperature resulted in a rough surface, decreased apparent amylose content, gelatinization enthalpy and gelatinization degree, increased short-range orders, long-range orders, retrogradation degree and resistant starch content. For PtS, sonication temperature led to a coarser surface with scratches, increased apparent amylose content and gelatinization degree, decreased short-range orders, long-range orders, gelatinization enthalpy, retrogradation degree, and resistant starch content. For PS, sonication temperature showed partial disintegration on surface, increased gelatinization degree, decreased apparent amylose content, short-range orders, long-range orders, gelatinization enthalpy, retrogradation degree and resistant starch content. This study suggested that starch digestion features could be controlled by the crystalline pattern of starch used and the extent of sonication temperature, and thus were of value for rational control of starch digestion features.

Unusual case of desmotropy. Combined spectroscopy (¹H-¹4N NQDR) and quantum chemistry (periodic hybrid DFT/QTAIM and Hirshfeld surface-based) study of solid dacarbazine (anti-neoplastic).

Antineoplastic chemo-therapeutic drug 5-(3,3-dimethyl-1-triazenyl)imidazole-4-carboxamide (Dacarbazine, DTIC), has been studied experimentally in solid state by ¹H-¹4N NQDR double resonance at 295 K and theoretically by the Density Functional Theory (DFT)/Quantum Theory of Atoms in Molecules (QTAIM) and Hirshfeld surfaces analysis. Only one set of eighteen resonance frequencies was found in the experiment. This indicates the presence of six inequivalent nitrogen sites: -N(CH3), -NH2, -NH- and three -N= (of which one is a ring, two are from triazene) in the DTIC molecule. This contradicts the X-ray data which revealed the multiplication of nitrogen sites due to unusual desmotropism. The averaging of NQR frequencies caused by the fast in NQR time-scale exchange of protons in a double-well potential combined with the oscillations of twisted supramolecular synthons was proposed as a potential mechanism responsible for this apparent contradiction. An effective improvement in the quality of the spectrum reproduction was achieved when the calculations were performed assuming the periodic boundary conditions, BLYP functional, the DNP basis set and taking the 3×3×3 k-point separation. The ordering of the nitrogen sites according to the increasing quadrupole coupling constant (QCC): N(3)

Crystallization of Bovine Cervical Mucus at Oestrus: An Update / Cristalización del moco cervical bovino en el estro: una actualización / Cristalização do muco cervical bovino no estro: uma atualização

Bovine cervical mucus changes its biochemical composition and biophysical properties due to the variations in sex steroid levels during the oestrous cycle. As a consequence of oestrogen rise, cervical mucus is produced in larger amounts at oestrus-a stage also characterized by an increase in mucus crystallization when observed under light microscopy. The objective of this article is to provide an updated review of the main aspects regarding crystallization of bovine cervical mucus. First, it makes reference to the composition of cervical mucus and the critical functions that this secretion exerts on bovine reproductive physiology, as well as in other species. Then, the article deals with the phenomenon of crystallization observed in cervical mucus, describing the main models used to classify the crystalline patterns observable in mucus at oestrus stage (some of them resembling ferns, palm leaves and stellar patterns, among others). Finally, it addresses the importance of the phenomenon of cervical mucus crystallization for the understanding of bovine reproductive physiology.

El moco cervical bovino cambia su composición bioquímica y sus propiedades biofísicas durante el ciclo estral debido a las variaciones en los niveles de esteroides sexuales, siendo producido en mayor cantidad durante el estro como consecuencia del aumento en el nivel de estrógenos. En dicho estadio también se observa que el moco aumenta su capacidad de cristalizar. El objetivo de este artículo es proporcionar una visión actualizada de los principales aspectos relativos a la cristalización del moco cervical bovino. En primer lugar se hace referencia a la composición del moco y a las importantes funciones ejercidas por esta secreción en la fisiología reproductiva bovina y de otras especies. Más adelante el artículo trata sobre el fenómeno de cristalización observado en el moco cervical en estro, describiéndose los principales modelos utilizados para clasificar los patrones cristalinos observables en él (algunos semejantes a helechos, hojas de palma o figuras estrelladas, entre otros). Finalmente, se discute la importancia del fenómeno de la cristalización del moco cervical para la comprensión de la reproducción bovina tanto en estados fisiológicos así como fisiopatológicos.

O muco cervical bovino varia a sua composição bioquímica e suas propriedades biofísicas durante o ciclo estral devido às variações nos níveis de esteróides sexuais, sendo produzido em maior quantidade durante o estro como consequência do aumento no nível de estrogênios. Neste estado também se observa que o muco aumenta a sua capacidade de cristalizar. O objetivo deste artigo é proporcionar uma visão atualizada dos principais aspectos relativos à cristalização do muco cervical bovino. Em primeiro lugar faz-se referência à composição do muco e das importantes funções exercidas por esta secreção na fisiologia reprodutiva bovina e de outras espécies. Mais adiante o artigo trata sobre o fenômeno de cristalização observado no muco cervical em estro, descrevendo-se os principais modelos utilizados para classificar os padrões cristalinos observáveis no mesmo (alguns semelhantes a samambaias, folhas de palmeira ou figuras estreladas, entre outros). Finalmente, se discute a importância do fenômeno da cristalização do muco cervical para a compreensão da reprodução bovina tanto em estados fisiológicos quanto em fisiopatológicos.

Viscoelastic behavior of maize kernel studied by dynamic mechanical analyzer.

The creep recovery, stress relaxation, temperature-dependence and their frequency-dependence of maize kernel were determined within a moisture content range of 11.9% to 25.9% (w/w) by using a dynamic mechanical analyzer. The 4-element Burgers model was found to adequately represent the creep behavior of the maize seeds (R(2)>0.97). The 5-element Maxwell model was able to better predict the stress relaxation behavior of maize kernel than the 3-element Maxwell model. The Tg values for the maize kernels decreased with increased moisture content. For example, the Tg values were 114 °C and 65 °C at moisture content values of 11.9% (w/w) and 25.9% (w/w), respectively. The magnitude of the loss moduli and loss tangent and their rate of change with frequency were highest at 20.7% and lowest at 11.9% moisture contents. The maize kernel structure exhibited A-type crystalline pattern and the microstructure was found to expand with increase in moisture content.