Rationale for Design of Biologically Reversible Drug Derivatives: Prodrugs

The history of the use of quantitative structure–activity relationships (QSARs) in toxicology, both for environmental, and human health effects is described. A particular emphasis is made on the science in response to the United States Toxic Substance Control Act of 1976. Specifically, the basic concepts and objectives of QSARs for toxicity are reviewed. QSARs for environmental and human health effects are discussed separately. Environmental, and more specifically, ecotoxicity, QSARs have focused historically on modeling congeneric series and non-specific effects in aquatic organisms through the use of the logarithm of the 1-octanol/water partition coefficient to describe hydrophobicity, and hence uptake. Compounds that do not fit these QSARs (namely the outliers) have been explained by differences in mechanism of acute toxicity, especially as a result of electro(nucleo)philic interactions. In light of this, mechanisms of acute toxicity are discussed. QSAR approaches to receptor-mediated effects, such as those exhibited by environmental estrogens, and competitive binding to the estrogen receptor, are different from those typically applied to model acute toxic endpoints. Several of these approaches, including three-dimensional QSAR techniques, are reviewed. Human health effects include both local and systemic effects. Local effects (e.g. corrosivity and skin sensitization) are often modeled by multivariate QSAR methods such as linear regression and discriminant analysis. The prediction of systemic effects such as mutagenesis and carcinogenesis requires consideration of the endpoint and a more mechanistic basis for modeling. Approaches to predict these endpoints include the use of expert systems.

Quantitative structure–activity relationships (QSARs) in toxicology: a historical perspective

This paper reviews Quantitative Structure-Activity Relationship (QSAR) models for acute mammalian toxicity published in the last decade. A number of QSAR models based on cytotoxicity data from mammalian cell lines are also included because of their possible use as a surrogate system for predicting acute toxicity to mammals. On the basis of the review, the following conclusions can be made: i) a relatively small number of models for in vivo toxicity are published in the literature. This is due to the nature of the endpoint - acute systemic toxicity is usually related to whole body phenomena and therefore is very complex. The complexity of the mechanisms involved leads to difficulties in the QSAR modelling; ii) most QSAR models identify hydrophobicity as a parameter of high importance for the modelled toxicity. In addition, many models indicate the role of the electronic and steric effects; iii) most of the literature-based models are restricted to single chemical classes. Models based on more heterogeneous data sets are those incorporated in expert systems. In general, the QSAR models for mammalian toxicity identified in this review are considered useful for investigating the mechanisms of toxicity of defined chemical classes. However, for predictive purposes in the regulatory assessment of chemicals most of the models require additional information to satisfy internationally agreed validation principles. In addition, the development of new models covering larger chemical domains would be useful for the regulatory assessment of chemicals.

http://www.clbme.bas.bg/bioautomation/2006/vol_5.1/files/5_4.5.pdf

Review of (Quantitative) Structure–Activity Relationships for Acute Aquatic Toxicity

Structure–toxicity relationships for selected halogenated aliphatic chemicals

Protection by pantothenic acid against apoptosis and cell damage by oxygen free radicals--the role of glutathione.

Synthesis and pharmacological properties of N-derivatives of 5,7,12,13-tetrahydro-6H-dibenz(c,g)azonine.

Synthesis and pharmacological properties of N-derivatives of 5,6-dihydro-7H,12H-dibenz[c,f]azocine, a new tricyclic system.

Terpene compounds as drugs. 11. Anabolic 19-nortestosterone terpenoates.

Terpene compounds as drugs. X. 4-prenyl-1,2-diphenyl-3,5-pyrazolidinedione (DA 2370): a new anti-inflammatory drug, with low ulcerogenic effects, derived from a series of terpenyl pyrazolidinediones.

Gianfranco Pala

Papers

Synthesis and pharmacological properties of N-derivatives of 5,7,12,13-tetrahydro-6H-dibenz(c,g)azonine.

Synthesis and pharmacological properties of N-derivatives of 5,6-dihydro-7H,12H-dibenz[c,f]azocine, a new tricyclic system.

Terpene compounds as drugs. 11. Anabolic 19-nortestosterone terpenoates.

Terpene compounds as drugs. X. 4-prenyl-1,2-diphenyl-3,5-pyrazolidinedione (DA 2370): a new anti-inflammatory drug, with low ulcerogenic effects, derived from a series of terpenyl pyrazolidinediones.

Terpene compounds as drugs. VI. Acyclic mono- and sesquiterpene thiocyanates and isothiocyanates.