A new, high-resolution shape-fragment database has been developed
for computing ab initio quality molecular
electron densities for polyaromatic hydrocarbons (PAHs) which play a
significant role as toxicants in the
environment. Using the new PAH electron density fragment database
and the Molecular Electron Density
Lego Assembler (MEDLA) method, one can generate detailed and reliable
electron densities for virtually
any of the PAH molecules. Accurate electron density shape
representations for these molecules is essential
in the study of detailed shape-toxicity correlations. One of our
goals is to investigate the potential of detailed
molecular shape analysis as a predictive tool in toxicological risk
assessment. In this study we report the
results of the first phase of the study: the construction and testing
of a high quality shape-fragment database
for PAHs.
Abstract-The quantitative shape-activity relationship (QShAR) methodology, based on accurate three-dimensional electron densities and detailed shape analysis methods, has been applied to a Lemna gibba photoinduced toxicity data set of 16 polycyclic aromatic hydrocarbon (PAH) molecules. In the first phase of our studies, a shape fragment QShAR database of PAHs was developed. The results provide a very good match to toxicity based on a combination of the local shape features of single rings in comparison to the central ring of anthracene and a more global shape feature involving larger molecular fragments. The local shape feature appears as a descriptor of the susceptibility of PAHs to photomodification and the global shape feature is probably related to photosensitization activity.
The syntheses of a series of 1-aryl-5-diethylamino-1-penten-3-one hydrochlorides 1 and 1-aryl-3-diethylamino-1-propanone hydrochlorides 4 were accomplished. Attempts to prepare the corresponding bis(5-aryl-3-oxo-4-pentenyl)ethylamine hydrochlorides 2 and bis(3-aryl-3-oxopropyl)ethylamine hydrochlorides 5 led to the formation of a series of 4-(beta-arylvinyl)-3-(beta-arylvinylketo)-1-ethyl-4-piperidi nol hydrochlorides 9 and 4-aryl-3-arylketo-1-ethyl-4-piperidinol hydrochlorides 11, most of which were converted subsequently into the corresponding quaternary ammonium salts 10 and 12, respectively. The structures of these compounds were determined by 1H NMR spectroscopy and confirmed by X-ray crystallography of representative molecules. Most compounds displayed significant cytotoxicity toward murine P388 and L1210 cells as well as human tumors. In general, Mannich bases containing olefinic bonds were more cytotoxic than the analogues without this functional group, while the piperidines 9 and 11 were more potent than the acyclic analogues 1 and 4, respectively. Correlations were noted between various physicochemical constants in the aryl rings and cytotoxicity. Compound 9d displayed promising in vivo activity against colon cancers. This study has revealed that the piperidines 9 and 11 constitute new classses of cytotoxic agents.
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