Structure-toxicity relationship studies

Rekker, R.F. 1985. The principles of congenericity, a frequently overlooked prerequisite in quantitative structure-activity and structure-toxicity relationship studies. In QSAR in Toxicology and Xenobiochemistry, Tichy, M. (Ed.), Elsevier, Amsterdam, pp. 3-24. 

Previous syntheses An example of this point can be recognized by examination of one known synthesis of thienobenzazepines (Scheme 6.1). This synthetic route involves a key palladinm-catalyzed cross-conpling of stannyl intermediate 3, prepared by method of Gronowitz et al., with 2-nitrobenzyl bromide. Acetal deprotection and reductive cyclization afforded the desired thienobenzazepine tricycle 4. In support of structure activity relationship studies, this intermediate was conveniently acylated with varions acyl chlorides to yield several biologically active componnds of structure type 5. While this synthetic approach does access intermediate 4 in relatively few synthetic transformations for stractnre activity relationship studies, this route is seemingly nnattractive for preparative scale requiring stoichiometric amounts of potentially toxic metals that are generally difficult to remove and present costly purification problems at the end of the synthesis. 

Quantitative Structure-Activity Relationship studies search for a relationship between the activity/toxicity of chemicals and the numerical representation of their structure and/or features. The overall task is not easy. For instance, several environmental properties are relatively easy to model, but some toxicity endpoints are quite difficult, because the toxicity is the result of many processes, involving different mechanisms. Toxicity data are also affected by experimental errors and their availability is limited because experiments are expensive. A 3D-QSAR model reflects the characteristics of... 

Anthracyclines are antitumor quinone containing antibiotics produced by different strains of Streptomyces. Some of them, such as adriamycin doxorubicin), and daunorubicin are broad spectrum antitumor compounds. They act by binding to DNA and interfering with DNA replication and gene transcription. Their limitations for clinical use are cardiac toxicity and drug resistance phenomena. Consequently, intense structure-activity relationship studies have been performed to improve the pharmacological profile as well as to enhance the affinity for DNA. In particular, a number of fluorinated anthracyclines have been prepared with introduction of fluorine atoms into D or A cycles, and into the aglycone side chain linked atC-14. ... 

A relatively recent development in QSAR research is molecular reference (MOLREF). This molecular modelling technique is a method that compares the structures of any number of test molecules with a reference molecule, in a quantitative structure-activity relationship study (27). Partial least squares regression analysis was used in molecular reference to analyse the relation between X- and Y-matrices. In this paper, forty-two disubstituted benzene compounds were tested for toxicity to Daphnia... 

Clearly, extensive whole-animal toxicity studies have not been warranted in the development of structure-toxicity relationships. Accordingly, Wesche et al.11 and Edwards and colleagues12,13 have developed in vitro methods for assessing neurotoxicity in neuronal cells. Based on these studies, dihydroartemisinin has been found to be the most neurotoxic artemisinin analog (Figure 9.2). 

Soltan MK, Ghonaim HM, El Sadek M et al (2009) Design and synthesis of N-4, N-9-disubstituted spermines for non-viral siRNA delivery - structure-activity relationship studies of transfection efficiency versus toxicity. Pharm Res 26 286-295... 

Numerous studies have examined the structure-toxicity relationships for CDDs. For example, examination of lethality data in guinea pigs revealed that the fully lateral-substituted tetra- to hexachloro-substituted isomers were the most toxic congeners, and the structure-activity relationships were comparable to those observed for their AHH-induction and receptor-binding activities (Eadon et al. 

R. L. Lipnick and W. J. Dunn, in Quantitative Approaches to Drug Design, J. C. Dearden, Ed., Elsevier, Amsterdam, 1983, pp. 265—266. A MLAB Study of Aquatic Structure-Toxicity Relationships. 

G. W. Adamson, D. Bawden, and D. T. Saggers, Pestic. Sci., 15, 31 (1984). Quantitative Structure-Activity Relationship Studies of Acute Toxicity LDJ0 in a Large Series of Herbici-dal Benzimidazoles. 

Gombar VK. 1987. Quantitative structure-activity relationship studies Acute toxicity of environmental contaminants. QSAR in Environmental Toxicology, Proceedings of the International Workshop 2 125-133. 

Laurence, W.H., Bas, G.E., Purcell, W.P., Autian, J. (1972) Use of mathematical models in the study of structure-toxicity relationships of dental compounds I. Esters of acrylic and methylacrylic acids. J. Dent. Res. 51, 526-535. 

The total synthesis of ZK-EPO (1) is an example of a highly convergent synthesis which contains the construction and combination of three segments. The segments are built up by reactions that allow and tolerate the introduction of different substituents and are suitable for the construction of substance libraries. This was necessary both for toxicity and structure-response relationship studies. Note that 1 was developed via this library synthesis. 

Di Paolo, T. (1978a). Molecular Connectivity in Quantitative Structure-Activity Relationship Study of Anesthetic and Toxic Activity of Aliphatic Hydrocarbons, Ethers, and Ketones. J.Pharm.ScL, 67, 566-568. 

Panaye A, Fan BT, Doucet JP, Yao XJ, Zhang RS, et al. Quantitative structure-toxicity relationships (QSTRs) A comparative study of various nonlinear methods. General regression neural network, radial basis function neural network and support vector machine in predicting toxicity of nitro- and cyano- aromatics to Tetrahymena pyriformis. SAR QSAR Environ Res 2006 17 75-91. 

Hall LH, Kier LB. Structure-activity relationship studies on the toxicides of benzene derivatives II. An analysis of benzene substituent effects on toxicity. Environ Toxicol Chem 1986 5 333-7. 

The above results show that quite a few classes of compounds can become toxic upon conjugation by the various pathways discussed. Since the mechanism of toxicity may be both a reversible Interaction with a receptor, and irreversible binding due to the formation of a reactive Intermediate, it is difficult to predict toxicity, even within a series of structural analogues as demonstrated with the dlhalogenated alkanes. Unless, of course the exact mechanism of action at the molecular level is known and there is a firmer base for structure activity relationship studies. 

Quantum-chemical molecular descriptors have been actively used in the quantitative structure-activity relationship studies of biological activities [1,2,72]. In the following, examples of QSARs involving quantum-chemical descriptors and applied on the enzymatic reactivity, pharmacological activity, and toxicity of compounds are discussed. 

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