Use of quasi-SMILES to model biological activity of “micelle–polymer” samples

The basic task of the drug discovery is the establishing of molecular structure of new pharmaceutical agents. To define the molecular structure is only half of the way to new drug. The transport of active molecules to appropriate targets in an organism should be elucidated in details. The selection of polymeric structures playing the role of basis for transport of therapeutic agents into the body is one of the ways to solve the task. Drug loading capacity (DLC) and critical micelle concentration (CMC) are measures of ability of “polymer–micelle” systems to be suitable for the process of the transport of therapeutic agents into an organism. Polymeric micelles are a type of complex multi-phase and multicomponent chemical process and can be used to transport drug into an organism. Prediction of ability of “micelle–polymer” systems to be a tool for transport of therapeutic agents to targets in organism is an important task. Models, which are a mathematical function of available eclectic information about architecture of micelles and polymers, are suggested. The eclectic data are represented via the so-called quasi-simplified molecular input-line entry system (SMILES), which are analogy of traditional SMILES. The quasi-SMILES contain some additional information besides the molecular architecture (physicochemical and biochemical conditions). Predictive potential of these models is good.

     

Identification of Four Process-Related Impurities in the Bulk Drug Butalbital Using HPLC-UV Photodiode Array Detection,Particle Beam MS,and NMR

Abstract

During the production of bulk active pharmaceutical ingredients, many opportunities for the generation of impurities may arise. In cases such as this, the impurities often result from “primary” impurities in raw materials, which are carried through the manufacturing process. Since these primary sources often are similar to the raw material in which they occur, the net effect is generation of impurities which may have a highly similar structure to the finished product. Due to such a comparable structure many characteristics which permit analytical resolution, such as the partitioning, chromatographic retention, and spectral characteristics (to name a few) of the impurities are also similar to the finished product. Using a combination of analytical techniques, however, it is possible to accurately describe the impurities. This is often necessary in closely regulated industries such as pharmaceutical manufacturing, where generation of accurate impurity profile methodologies is critical to GLP compliance¹.     

ULTRAVIOLET IRRADIATION OF SUSPENSIONS OF MICRO-ORGANISMS: POSSIBLE ERRORS INVOLVED IN THE ESTIMATION OF AVERAGE FLUENCE PER CELL*

Abstract— Experiments on cell survival in concentrated suspensions of Escherichia coli B/r show that application of the well known “Morowitz correction” (H. J. Morowitz, (1950) Science 111 , 229–230) can lead to large errors in estimation of the average fluence per cell if light scattering is not taken into account. The magnitude of the effect is illustrated for this organism, but it is pointed out that experimenters should determine the correction for each organism and set of experimental conditions used.     

Simulated moving bed technology: old and new

The Simulated Moving Bed (SMB) concept has been applied to the separation of different mixtures as a continuous counter current separation process, avoiding several problems related with solid motion. The aim of this work is to present some relevant examples of SMB separations corresponding to the two major ages in the use of the SMB concept, here named “old” and “new” applications. The “old” applications of SMB technology in the petrochemical industry are still important, with large and highly productive units; and the “new” applications of the second “age” of SMB concept are from the fine chemical, pharmaceutical and biochemistry areas, associated with the demand of high purity products during the last 10 years. Different examples are presented for different ages: a UOP Parex ^® process for the “old”, modelled with the equivalent True Moving Bed (TMB) approach; and a chiral resolution for the “new”, modelled by the real SMB model. Some of the latest developments are also mentioned: the non conventional techniques as the Varicol ^® process, PowerFeed, Modicon, M3C or Enriched Extract-SMB (EE-SMB), MultiFeed (MF), Outlet Streams Swing (OSS) or Pseudo-SMB, involving considerable changes in the SMB concept itself. The use of the last optimization/modelling packages for the development of design techniques, either at the conception stage as well as for performance improvements of existing units is emphasized.     

Replication Experiments with Nucleotide Base Analogues

The principles governing the replication fidelity of genomes are not fully understood yet. Watson and Crick's base-pairing principle for matched deoxyribonucleotide (DNA) bases can explain why the guanine–cytosine and adenine-thymine base pairs are approximately one hundred times more stable thermodynamically than mismatched combinations. In vitro, DNA polymerases reduce the number of mismatched base pairs to about 10^?6 per Watson–Crick base pair. Replication fidelity can further be enhanced to a mutation probability of 10^?10or less in vivo if optimal conditions for DNA synthesis are provided by polymerase–assisting proteins and DNA-repairing enzymes. The precise reasons for the formation of mismatched base pairs (mispairs), which are responsible for a substantial part of DNA mutations, are still in debate. Although it is agreed that a template-directed “reading” of the hydrogen-substitution pattern in the heterocyclic bases is crucial for proper base pairing during DNA synthesis, it is not clear which type of “misreading” leads to mispairs. Misreading may be due to a non-Watson–Crick base pairing as well as to a change in the hydrogen-substitution pattern, leading to Watson-Crick-like mispairs. The surprising discovery of the selective and quantitative DNA-polymerase-catalyzed formation of a pyridine-pyrimidine base pair (involving a nucleotide base analogue) indicated that rare tautomeric forms in template DNA strands can lead to Watson-Crick-like mispairings that are hardly recognized by the polymerase's proofreading activity. This reveals new pathways for substitution mutations (replication-dependent DNA point mutations) and suggests a new type of mutagen in vivo.     

Schrödinger's What is Life?—The 75th Anniversary of a Book that Inspired Biology

In his book What is Life?—The Physical Aspect of the Living Cell, Erwin Schrödinger gives a “naïve physicist's” answer to the question “how can the events in space and time which take place within the spatial boundary of a living organism be accounted for by physics and chemistry?” Although his book was met with criticism from some of his colleagues, it has had a large impact and has served as profound inspiration for pioneers of molecular biology as well as for later generations of both scientists and laymen.     

Schrödinger's What is Life?—The 75th Anniversary of a Book that Inspired Biology

In his book What is Life?—The Physical Aspect of the Living Cell, Erwin Schrödinger gives a “naïve physicist's” answer to the question “how can the events in space and time which take place within the spatial boundary of a living organism be accounted for by physics and chemistry?” Although his book was met with criticism from some of his colleagues, it has had a large impact and has served as profound inspiration for pioneers of molecular biology as well as for later generations of both scientists and laymen.     

N,S Co-Doped Carbon Quantum Dots for the Selective and Sensitive Fluorescent Determination of N-Acetyl-l-Cysteine in Pharmaceutical Products and Urine

To design a probe with “turn-on” sensing, nitrogen and sulfur co-doped carbon quantum dots (N, S-CQDs) were prepared and screened against some metallic cations to first induce “turn-off” fluorescence. The ferric iron (Fe³⁺) was shown to be the most responsive and effective in the fluorescence quenching of the N, S-CQDs based on a proposed photo-induced electron transfer mechanism. In addition, the fluorescence of N, S-CQDs-Fe³⁺ system was well recovered using N-acetyl-l-cysteine (NAC) (turn-on) due to a redox reaction, suggesting that the N, S-CQDs-Fe³⁺ system acts as a highly sensitive and selective sensor for the determination of N-acetyl-l-cysteine with a low limit of detection equal to 65.0?nmol/L and wide linear ranges from 0.67 to 25.56 and 25.56 to 193.55?μmol/L. The “turn-off/on” fluorescence method was successfully employed to monitor N-acetyl-l-cysteine in pharmaceutical products and human urine samples with a recovery range from 99.2 to 101.3%. In addition, the fluorescence switch properties of the nitrogen and sulfur co-doped carbon quantum dots were also investigated by alternate additions of Fe³⁺ and N-acetyl-l-cysteine.     

Disappearing Polymorphs in Metal–Organic Framework Chemistry: Unexpected Stabilization of a Layered Polymorph over an Interpenetrated Three-Dimensional Structure in Mercury Imidazolate

The “disappearing polymorph” phenomenon is well established in organic solids, and has had a profound effect in pharmaceutical materials science. The first example of this effect in metal-containing systems in general, and in coordination-network solids in particular, is here reported. Specifically, attempts to mechanochemically synthesize a known interpenetrated diamondoid (dia) mercury(II) imidazolate metal–organic framework (MOF) yielded a novel, more stable polymorph based on square-grid (sql) layers. Simultaneously, the dia-form was found to be highly elusive, observed only as a short-lived intermediate in monitoring solvent-free synthesis and not at all from solution. The destabilization of a dense dia-framework relative to a lower dimensionality one is in contrast to the behavior of other imidazolate MOFs, with periodic density functional theory (DFT) calculations showing that it arises from weak interactions, including structure-stabilizing agostic C−H⋅⋅⋅Hg contacts. While providing a new link between MOFs and crystal engineering of organic solids, these findings highlight a possible role for agostic interactions in directing topology and stability of MOF polymorphs.     

Transmutation Theory in the Greek Alchemical Corpus

This paper studies transmutation theory as found in the texts attributed to Zosimus of Panopolis, “the philosopher Synesius,” and “the philosopher Olympiodorus of Alexandria.” It shows that transmutation theory (i.e. a theory explaining the complete transformation of substances) is mostly absent from the work attributed to these three authors. The text attributed to Synesius describes a gilding process, which is similar to those described by Pliny and Vitruvius. The commentary attributed to Olympiodorus is the only text studied here that describes something similar to a transmutation theory. It is unclear, however, if this was a theory of transmutation or if the writer meant something more like the literal meaning of the word “ekstrophē,” a term used to describe the transformation of metals, as the “turning inside-out” of what is hidden in a substance. A similar conception of ekstrophē can be found in the works of Zosimus, who discussed transmutation to make an analogy with self-purification processes, which, from the perspective of his own anthropogony, consisted in the “turning inside-out” of the “inner human” (esō anthrōpos).     

Nonadiabatic core polarization and penetration correction in alkali-like atoms: Model computations on excited states of helium

Correlation between the motion of a highly excited outer electron and that of the remaining ionic “core” of an atom is generally treated in an adiabatic approximation, in which it is assumed that the outer electron affects the core in the same way as a stationary point charge. An alternative approach to this correlation problem which avoids the adiabatic approximation is tested here on the 1s2p, 1s3d, and 1s4f states of helium. The results provide the first accurate test of the adiabatic approximation and of a simple correction for the nonzero velocity of the outer electron. The approach used here is based on neglect, in the “correlation” part of the wave function, of the possibility that the outer electron comes closer to the nucleus than any core electron (“penetration”). A correction for this neglect is derived and tested on a version of the adiabatic approximation that likewise neglects penetration.     

IRRADIATION-ENHANCED PHYTOCHROME PELLETABILITY IN AVENA: IN VIVO DEVELOPMENT OF A POTENTIAL TO PELLET AND THE ROLE OF Mg2+ IN ITS EXPRESSION IN VITRO

The enhanced phytochrome pelletability that results from in vivo irradiation of Avena shoots may be divided into two operationally defined sequential stages: the in vivo development of a “potential to pellet” and the “expression” of this potential in vitro. Kinetic studies confirm previous findings that the generation of this “potential to pellet” is a very rapid (complete in < 10 s, 25°C), genuinely intracellular process, itself photoreversibly induced by P_fr. In addition, it is shown that the sustained development of the “potential to pellet”, that proceeds in the dark at 0°C following a red pulse, requires P_fr continually in the cell over the entire development period. Far red light immediately terminates further development of the red-induced “potential” at any point during the development phase. No immediate reduction is observed, however, in that level of “potential pelletability” already attained at the time of the far red pulse. This indicates that the level of “potential pelletability” established in vivo is insensitive to the form of the pigment at extraction regardless of the level reached. “Expression” of the “potential to pellet” refers to the actual detection in homogenates of an enhanced physical association of phytochrome with pelletable material. Maximum “expression” requires the presence of a divalent cation in the medium during homogenization. Rapid posthomogenization addition of Mg²⁺ to Mg²⁺-free extracts sustains enhanced pelletability but with rapidly declining effectiveness over the fmt 1–2 min after extraction. The rate of decline is faster if the phytochrome is present as P_fr than as P_r in the homogenate. Neither these nor previous data permit a distinction to be made between (a) preservation by the cation of a pre-existing intracellular interaction, and (b) a Mg²⁺-mediated induction of an artifactual, in vitro association predetermined in the cell by a genuine phyto-chrome-controlled process. Various formalistic models are discussed in the context of these and other data.     

Effect of Caustic Addition in Epoxy Polymerization Process: A Single and Multi‐Objective Evolutionary Approach

Summary: An epoxy polymerization process is studied in semi‐batch mode. Caustic has a very critical influence on epoxy polymerization process, which is modeled as a set of highly nonlinear coupled ODE's (ordinary differential equations). Owing to the highly complicated, nonlinear domain of analysis, “Differential Evolution (DE)” and “Genetic Algorithm (GA)” are used as optimization tools to identify the ‐PDI Pareto set and study the best operating strategy with respect to NaOH addition. The moment of various oligomeric components during the semi‐batch polymerization is also presented for a better understanding of the process. This study demonstrates the potential of evolutionary optimization algorithm to identify various operating philosophies of a semi‐batch epoxy reactor for a targeted product quality.

Pareto plot for epoxy polymerization process with intermediate NaOH addition varying from 0.0 to 1.0 kmol · m⁻³.     

A “Cell‐Friendly” Window for the Interaction of Cells with Hyaluronic Acid/Poly‐l‐Lysine Multilayers

Polyelectrolyte multilayers assembled from hyaluronic acid (HA) and poly‐l ‐lysine (PLL) are most widely studied showing excellent reservoir characteristics to host molecules of diverse nature; however, thick (HA/PLL)_n films are often found cell repellent. By a systematic study of the adhesion and proliferation of various cells as a function of bilayer number “n” a correlation with the mechanical and chemical properties of films is developed. The following cell lines have been studied: mouse 3T3 and L929 fibroblasts, human foreskin primary fibroblasts VH‐Fib, human embryonic kidney HEK‐293, human bone cell line U‐2‐OS, Chinese hamster ovary CHO‐K and mouse embryonic stem cells. All cells adhere and spread well in a narrow “cell‐friendly” window identify in the range of n = 12–15. At n < 12, the film is inhomogeneous and at n > 15, the film is cell repellent for all cell lines. Cellular adhesion correlates with the mechanical properties of the films showing that softer films at higher “n” number exhibiting a significant decrease of the Young's modulus below 100 kPa are weakly adherent to cells. This trend cannot be reversed even by coating a strong cell‐adhesive protein fibronectin onto the film. This indicates that mechanical cues plays a major role for cell behavior, also in respect to biochemical ones.     

The variation of spectroscopic properties with numbers of electrons

A formalism that describes the variation of the spectroscopic properties, D_e, R_e, and k_e, of homonuclear, diatomic molecules, with the number of molecular electrons has been developed. The theory describes the interrelation of these properties and predicts “critical” behavior in sequences of “isonuclear” and neutral molecules. Detailed calculations are possible with the help of experimental data in lieu of a deeper, dynamical theory of molecular behavior with respect to electron number. The present work points the way toward a first-principle's theory. © 1992 John Wiley & Sons, Inc.     

Time Programmable Locking/Unlocking of the Calix[4]arene Scaffold by Means of Chemical Fuels

In this work, we report that 2-cyano-2-phenylpropanoic acid and its p-Cl, p-CH₃ and p-OCH₃ derivatives can be used as chemical fuels to control the geometry of the calix[4]arene scaffold in its cone conformation. It is shown that, under the action of the fuel, the cone calix[4]arene platform assumes a “locked” shape with two opposite aromatic rings strongly convergent and the other two strongly divergent (“pinched cone” conformation). Only when the fuel is exhausted, the cone calix[4]arene scaffold returns to its resting, “unlocked” shape. Remarkably, the duration of the “locked” state can be controlled at will by varying the fuel structure or amount. A kinetic study of the process shows that the consume of the fuel is catalyzed by the “unlocked” calixarene that behaves as an autocatalyst for its own production. A mechanism is proposed for the reaction of fuel consumption.     

Switch From Pauli-Lowering to LUMO-Lowering Catalysis in Brønsted Acid-Catalyzed Aza-Diels-Alder Reactions

Brønsted acid-catalyzed inverse-electron demand (IED) aza-Diels-Alder reactions between 2-aza-dienes and ethylene were studied using quantum chemical calculations. The computed activation energy systematically decreases as the basic sites of the diene progressively become protonated. Our activation strain and Kohn-Sham molecular orbital analyses traced the origin of this enhanced reactivity to i) “Pauli-lowering catalysis” for mono-protonated 2-aza-dienes due to the induction of an asynchronous, but still concerted, reaction pathway that reduces the Pauli repulsion between the reactants; and ii) “LUMO-lowering catalysis” for multi-protonated 2-aza-dienes due to their highly stabilized LUMO(s) and more concerted synchronous reaction path that facilitates more efficient orbital overlaps in IED interactions. In all, we illustrate how the novel concept of “Pauli-lowering catalysis” can be overruled by the traditional concept of “LUMO-lowering catalysis” when the degree of LUMO stabilization is extreme as in the case of multi-protonated 2-aza-dienes.     

Synthesis and biosynthesis of alkoxylipids.

Chromatographic methods have shown that lipids with long alkyl or 1-alkenyl chains–called alkoxylipids or ether lipids–are widely distributed in human and animal tissues. These compounds comprise neutral alkoxylipids, i. e. 1-O-alkyl or 1-O-(1-alkenyl)-2,3-di-O-acylglycerols, and alkoxylipids which are linked by a phosphate residue at C-3 to aminoethanol, choline or serine. 1-O-Alkylglycerols, 1-O-(1-alkenyl)glycerols and other natural alkoxylipids can be synthesized in high yields. 2-Alkyl, 1,3-dialkyl and trialkylglycerols which are not found in nature are also accessible by synthesis. The neutral alkoxylipids are employed in biomedical investigations, e.g. as substrates in acyl-hydrolase systems or in fat absorption studies. The principal features of alkoxylipid biosynthesis have been elucidated. The alkyl residue is derived from a saturated or monounsaturated fatty acid via the corresponding alcohol. 1-O-(1-alkenyl)-2-O-acylglycerophosphoryl aminoethanols (“plasmalogens”) are apparently formed from the appropriate 1-alkyl compounds; this is not possible in the case of the choline series. Both “aminoethanol” and “choline” plasmalogens are, nevertheless, present in most tissues.     

Polymorphy in the stereostructure of periodic polymer backbones

We theoretically investigated the polymorphy of the stereostructures of a periodic polymer. Using the polymer's internal conformation parameters of bond lengths, bond angles, and internal rotation angles, we extended the mathematical treatment for designing polymer backbones. We considered those periodic polymers whose unit cell consists of one (m = 1), two (m = 2), or three (m = 3) kinds of atoms. Moreover, for these three types of polymers, we supposed two catenation types for the skeleton atoms; one is a “homorotatory” sequence and the other is a “heterorotatory” one. To specify the backbone's stereostructure, we introduced several conformation parameters such as the helical pitch number n, the translation distance d, and the inclination angle of the skeleton plane Θ. By combining these parameters, we can systematically understand the variety and the possible polymorphy in the stereostructure of a periodic polymer backbone. © 2003 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 41: 2829–2849, 2003