Synthesis of N-acyl-2-pyrrolidinones from the corresponding N-acyl-GABA derivatives

In this work, the synthesis of 1-(pyridine-3-carbonyl)pyrrolidin-2-one ( 1a ) and 1-(2-propyl-1-pentanoyl)pyrrolidin-2-one ( 1b ) by cyclization of the corresponding GABA derivatives, is reported. Two different methods are developed. For the synthesis of 1a , the parent molecule 4-[(pyridine-3-carbonyl)-amino]butanoic acid ( 2a ) is treated first with thionyl chloride and then with triethylamine. The second derivative, 1b , is produced by an intramolecular dehydration of 4-(2-propylpentanoylamino)butanoic acid ( 2b ) using an acid catalyst.     

CORTICOSTEROID (METHYLPREDNISOLONE) MODULATION OF PHOTOPEROXIDATION BY ULTRAVIOLET LIGHT IN LIPOSOMES

Abstract— UV irradiation of ovolecithin liposomes produced a dose dependent wave of peroxidation which reached a peak and then fell again coincident with substrate exhaustion. This correlated well with subsequent increases in membrane permeability. There was a progressive loss of unsaturated fatty acids, and when cholesterol was incorporated into liposomes, the UV produced a progressive loss of this steroid.
Methylprednisolone sodium succinate, a synthetic corticosteroid, was found to inhibit this peroxidation in a dose dependent manner, also ameliorating membrane permeability increases when present during irradiation, but not able to compensate for pre-existing damage. When cholesterol was present in the liposomes, methylprednisolone sodium succinate was also able to protect this steroid from UV peroxidative damage.
The rates of reaction in this system suggested that polyunsaturated fatty acids, even when present in extremely small concentrations, underwent an initial rapid wave of peroxidation, which served to initiate the slower rate of lipoperoxidation within the bulk of mono- and di-"unsaturates". At low concentrations, the corticosteroid preferentially blocked damage to mono- and di-unsaturated fatty acids, affecting the polyunsaturated fatty acids as well, at higher concentrations.
This study suggests that the corticosteroid, methylprednisolone sodium succinate, possesses antioxidant properties in lipid systems subjected to free radical peroxidation.     

A continuous–discontinuous second‐order transition in the satisfiability of random Horn‐SAT formulas

We compute the probability of satisfiability of a class of random Horn‐SAT formulae, motivated by a connection with the nonemptiness problem of finite tree automata. In particular, when the maximum clause length is three, this model displays a curve in its parameter space, along which the probability of satisfiability is discontinuous, ending in a second‐order phase transition where it is continuous but its derivative diverges. This is the first case in which a phase transition of this type has been rigorously established for a random constraint satisfaction problem. © 2007 Wiley Periodicals, Inc. Random Struct. Alg., 2007     

Synthesis of 6,7,8,9-tetrahydro-N,N-di-n-propyl-1H-benz[g] indol-7-amine,a potential dopamine receptor agonist

In this work, the synthesis of 6,7,8,9-tetrahydro-N,N-di -n-propyl-1H-benz[g]indol-7-amine (1) is described. This compound was designed as an indole bioisostere to the known dopamine receptor agonist 5-OH-aminotetraline 2 . The key step of the synthesis was a Mukaiyama type aldol condensation between the dimethyl acetal of 1-(p-toluenesulfonyl)pyrrole-3-acetaldehyde ( 4 ) and 4-di-n-propylamino-1-trimethylsilyloxycyclohexene ( 8 ) followed by cycloaromatization to afford 1-p-toluenesulfonyl-6,7,8,9-tetrahydro-N,N-di-n- propyl-1H-benz[g]indol-7-amine ( 10 ). Scission of the sulfonamide bond in 10 gave the target compound 1 . A byproduct which was isolated was assigned to the structure of 1-(p-toluenesul-fonyl)-6-[3-[1-(p-toluenesulfonyl)]pyrrolyl]indole ( 11 ). This compound was also synthesized in good yield by an acid catalyzed dimerization of the dimethyl acetal of 1-(p-toluenesulfonyl)pyrrole-3-acetaldehyde ( 4 ). Preliminary screening of 1 indicated that it possesses central dopamine receptor agonist properties.     

Synthesis of N-alkyl derivatives of 4-(2′-aminoethyl)indole

N-Substituted 4-(2′-aminoethyl)indoles are attainable in good yields from indole-4-acetic acid ( 2 ). Several methods of preparation for 2 were tried or considered. A new sequence involving Arndt-Eistert homologation of indole-4-carboxylic acid has been devised, which is no more laborious than a literature homologation sequence involving indole-4-acetonitrile, and which provides somewhat better overall yields than the literature method.     

Remark on a paper of Mņczyński

In his paper, Boolean Properties of Observables in Axiomatic Quantum Mechanics,M$\text{n}\text{?}$czyński formulates the notion of a Boolean representation of the magnitudes of a physical theory, and proves the theorem (4.1) that a family P of magnitudes has a Boolean representation if and only if there is a homomorphism from $\text{L}$into a Boolean algebra, where $\text{L}$ is the orthomodular poset associated with P. Exploiting Finch's representation theorem for orthomodular posets, M$\text{n}\text{?}$czyński is able to show that this condition is satisfied if and only if the Boolean subalgebras of $\text{L}$ have a nondegenerate direct limit. The direct limit is then a maximal Boolean representation of P. Homomorphic relations were introduced by Kochen and Specker as a weakening of the concept of an imbedding between partial algebras. The purpose of this remark is to show that the direct limit of the Boolean subalgebras of $\text{L}$ has a natural characterization in terms of the notion of a homomorphic relation between $\text{L}$ and the direct product of its Boolean subalgebras.     

Potential drugs and nondrugs: prediction and identification of important structural features

Using decision trees, a model to discriminate between potential drugs and nondrugs has been developed. Compounds from the Available Chemical Directory and the World Drug Index databases were used as training set; the molecular structures were represented using extended atom types. The error rate on an independent validation data set is 17.4%. The number of false negatives can be reduced by penalizing the misclassification of drugs so that 92 out of 100 potential drugs are correctly recognized. At the same time, 34 out of 100 nondrugs are classified as potential drugs. The predictions of the model can be used to guide the purchase or selection of compounds for biological screening or the design of combinatorial libraries. The visualization of the generated models in the form of colored trees allowed us to identify a few, surprisingly simple features that explain the most significant differences between drugs and nondrugs in the training set: Just by testing the presence of hydroxyl, tertiary or secondary amino, carboxyl, phenol, or enol groups, already three quarters of all drugs could be correctly recognized. The nondrugs, on the other hand, are characterized by their aromatic nature with a low content of functional groups besides halogens. The general applicability of the model is shown by the predictions made for several Organon databases.     

Fraction Lipophilicity Index (FLI). A drug-like metric for orally administered ionizable drugs

ABSTRACT

Fraction Lipophilicity Index (FLI) was developed as a metric for assessing drug likeness of ionizable oral drugs. Considering that both log P and log D have distinct roles in drug action, the metric FLI allocates lipophilicity to a pH dependent neutral fraction of the molecule and is a weighted combination of log P and log D. It is expressed by equation: FLI = 2 x log P–│log D│. A dataset of 368 basic and acidic drugs was analyzed. Based on available % absorption data, drugs were classified into class 1 (268 drugs) and class 2 (100 drugs). The freeware MedChem Designer was used for log P and log D calculations at pH 7.4 and pH 5.5 for acids. Based on class 1, a drug-like FLI range 0–8 was defined. FLI distribution for class 2 is shifted towards significantly lower values. Comparison of FLI with rule of 5 (Ro5) shows that it leads to fewer values outside the established range than the corresponding log P violations for class 1. For class 2 it gives more alerts than Ro5 and can be considered complementary to Ro5, while it also sets lower limits to discriminate drugs with poor absorption.