Davis, Walter (1951)
Syntheses and reactions of some possible growth inhibiting compounds.
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The developments in the use of the nitrogen "mustards" as chemotherapeutic agents are discussed against the back-ground or the general chemotherapy of cancer. Their cytotoxic activity, for which different mechanisms have been advanced, presents the possibility of using the nitrogen "mustards" to Inhibit the growth of tumours and the development of the various lymphadenopathies the aromatic series of chloroalkylmines was prepared in the search for active growth inhibitors of lower toxicity than the original aliphatic nitrogen "mustards" and the syntheses described in this thesis extend that series. The attempts to elucidate the mode of action of these compounds by seeking correlation between chemical reactivity and physiological activity underlies the sections that deal with the reactions of the halogenoalkylamines. The mode of hydrolysis of the chloroethylamines and the evidence supporting an SN1 mechanism are discussed, Their hydrolysis rates are compared with their structures and the effects of substituents of the aromatic nucleus are interpreted in terms of the electron-attracting or -releasing character of those substituents. the differing rates of hydrolysisresulting from the exchange of one halogen by another were investigated by following reactions in the presence of thiosulphate, when it became apparent that la the case of the iodo-compounds hydrolysis is of a complex nature, the experimental results being accounted for by assuming simultaneous SN1 and SN2 machanisms. The reactions of the nitrogen "mustards" with primary amines to give 1:4-dioubstituted piperazines is demonstrated and the biological significance of this reaction is discussed. In the third section on the reactions of the aryl-2-halogonolkylamies, the stability of the derived esters to alkaline hydrolysis is measured and comparison made with simple esters and esters derived from other radiomimetic agents - epoxides and sulphur "mustards". The results of biological tests of the compounds whose syntheses were described are recorded in the final chapter and the degree of correlation between activity and chemical properties is discussed.
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Institution: University of London, Royal Holloway College (United Kingdom).