Influence of chlorine substituents on biological activity of chemicals: a review (Reprinted from J Prakt Chem, vol 341, pg 417-435, 1999)

A number of well known polychlorinated chemicals are toxicologically and en vironmentally unsafe. Because of their persistence they are in the focus of public discussions against chlorine chemistry. However, chlorinated organi c chemicals in the molecular weight range between 200 and 600 constitute an important and indispensable segment in the arsenal of existing biologicall y active chemicals used as pharmaceuticals or crop-protection agents. Over the course of time it has been found empirically that the introduction of a chlorine atom into one or more specific positions of a biologically active molecule may substantially improve the intrinsic biological activity. In s ome cases the presence of a chlorine atom is crucial for significant activi ty in compounds derived both from nature and chemical synthesis. But in oth er cases chlorination diminishes or abolishes biological activity, as shown for chlordane homologues. Thus a chlorine atom, like any other substituent , is a modulator of activity. Almost all non-reactive chlorinated chemicals and chlorine-free chemicals are devoid of any biological activity at the h ighest concentration typically used in primary screening tests for discover y of useful biological properties. The influence of a substituent such as c hlorine on the biological activity of a potential drug on, crop protection agent still has to be established empirically in biological experiments des igned to detect desired activity or toxicological properties. Sometimes chl orine does prove to be the optimum for improvement of activity. Long-term r igorous investigations of several hundred chlorinated compounds, registered by the authorities as pharmaceutical drugs or crop-protection agents, show that the generalisation 'all chlorinated chemicals are dangerous', deduced from the negative toxicological properties of a hundred chlorinated and re active compounds of low molecular weight that are relevant in terms of safe working conditions in the chemical industry and for ecological safety, is not justified. Chlorinated compounds are not necessarily toxic or dangerous . Highly reactive chemicals or polychlorinated compounds cannot be compared with regard to toxicological properties with unreactive compounds having a low degree of chlorination. The chlorine atom, as one of many possible sub stituents used in synthetic organic chemistry, will remain in the future on e of the important tools for probing structure-activity relationships in li fe science research and as a molecular component in commercialised compound s, in order to provide safer, more selective and more environmentally compa tible products with higher activity for medicine and agriculture. (C) 1999 WILEY-VCH Verlag GmbH.