STRUCTURE-ACTIVITY STUDIES OF PHOTOACTIVATED ANTIVIRAL AND CYTOTOXIC TRICYCLIC THIOPHENES

The photoactivated antiviral and cytotoxic activities of the naturally occurring thiophene, alpha-terthienyl (1), and 15 synthetic analogues were evaluated against murine cytomegalovirus and Sindbis virus, and murine mastocytoma cells. After irradiation with near UV light, alpha-terthienyl and most of its analogues had significant toxicity, with minimum inhibitory concentrations in the range of 0.02-40 microM. In the absence of near UV irradiation, only one analogue had antiviral activity and five were cytotoxic. The most active analogues were those containing carboxylic acid, hydroxyl, or cyano substituents. Quantitative structure-activity relationship analysis of thiophene phototoxicity suggested that the rate of singlet oxygen production is the primary determinant of antiviral and cytotoxic activities. For phototoxicity against murine cytomegalovirus, a significant role for hydrophobicity was also demonstrated. Tricyclic thiophenes show significant potential for photochemotherapy of viral infections and cancer, and further evaluation in animal models is recommended.     

The role of hydrophobicity in the Ames test. The correlation of the mutagenicity of nitropolycyclic hydrocarbons with partition coefficients and molecular orbital indices

A set of 20 nitropolycyclic aromatic hydrocarbons, whose mutagenicity has been determined in the Ames test, has been studied using octanol-water partition coefficients (P) as a measure of relative hydrophobicity and molecular orbital energies to account for variation in their electronic characteristics. A good structure-activity relationship was found using log P and ?_LUMO . The latter were taken from the results of ab initio calculations performed by Maynard, Pedersen, Posner, and McKinney [7] and were also calculated by the MNDO method. The dependence of mutagenicity on hydrophobicity was found to be similar to that observed for triazenes [2]. ?_LUMO values calculated by MNDO and STO -3G were found to be strongly correlated, and the role of hydrophobicity in correlating mutagenicity was not significantly affected by the molecular orbital model employed.     

Comparison of CoMFA Models for Salmonella Typhimurium TA98, TA100+TA98+S9 and TA100+S9 Mutagenicity of Nitroaromatics

Abstract

Comparative Molecular Field Analysis (CoMFA) was applied to a comprehensive data set of heterogeneous nitroaromatics tested in Salmonella typhimurium TA98 and TA100 with and without S9 microsomal activation. The four CoMFA models developed agree with postulated mechanisms of mutagenicity, and explain over 70% of the corresponding mutagenic variance. The standard deviation coefficient contours common in the four models included high electronic density regions equivalent to C4-C5 in the pyrene ring, and an electron deficient site equivalent to C6. These areas are associated with high mutagenicity. Electron deficient areas may be related with the nitroreductive bioactivation of nitroaromatics. Electron rich sites may be involved with oxidative mechanisms analogous to the bioactivation pathway of polycyclic aromatic hydrocarbons. The contribution of steric factors to mutagenicity follows the order TA98 + S9 > TA98 > TA100 + S9 > TA100. The models indicated that increasing bulk perpendicular to the aromatic plane would decrease mutagenicity, but increasing the aromatic ring system along a region corresponding to C6-C7 in 1-nitropyrene would increase mutagenicity.     

Solution Conformation of a Pentapeptide by NMR and Molecular Modeling Studies

High resolution NMR studies and molecular modeling calculations were performed on a linear pentapeptide BOC-Tyr-Gly-Gly-Pro-Leu-OMe. This molecule exhibits two conformations in the solution state. While the ¹³C spectrum in nonpolar solvents such as acetonitrile shows only one form, in DMSO-d₆ and MeOD there are two forms. The appearance of the major (M) and minor (m) resonances is attributed to cis-trans isomerization about the X-Pro bond.

The assignments of several proton resonances for the major conformer were made through the combined analysis of two dimensional (2D) homonuclear correlated spectroscopy (COSY) and available data on similar peptides. The solution conformation of the major moiety was probed using the distance constraints obtained from 2D-NOE spectroscopy (NOESY). In addition, other information such as presence of internal hydrogen bonds and dihedral angle values from coupling constants for the amide protons were also used.     

Liquid chromatography determination of residue levels on apples treated with cetylpyridinium chloride

Cetylpyridinium chloride (CPC) has been found to be effective in reducing microbial contamination in apples. A sensitive and specific HPLC method was developed to determine CPC residues in apples treated with CPC. This method involves ion exchange solid-phase extraction, and the use of stearylpyridinium chloride (SPC) as internal standard. Limit of quantitation, was 0.5 microg/ml of CPC for the apple ethanolic extracts. The observed residues in apple (2.35-4.35 microg/g of apple) were lower than those previously reported for chicken and beef. The method is specific, sensitive, reproducible and accurate.