Aromatic Nitrogen Mustards

Pamplona, Maria Teresa Troina (1994). Aromatic Nitrogen Mustards. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000fdd8

Abstract

This work was stimulated by the search for more potent drug/prodrug combinations in the field of the aromatic nitrogen mustards, for potential used in antibody directed enzyme prodrug therapy.

4-Acyl prodrugs of N,N-bis(2-chloroethyl)-4-amino-aniline, possible substrates for the bacterial enzyme acylarylamidase E.C. 3.5.1.13, were synthesised. Attention was focus on 4-N'-acetyl and 4-N'-trifluoroacety 1 compounds. The relative reactivity towards hydrolysis of the prodrug and drug was examined at pH 7.4 and 37°C by HPLC. The hydrolysis of the prodrugs at different pH (2, and 12/13) was also examined and the products identified and quantitated.

The leaving group effect on stability and reactivity was also investigated for a series of simple aniline mustards of the type C6H4-N(CH2CH2X)2 with X-groups other than chloro, by comparing their hydrolysis behaviour in aqueous DMSO at 37°C and pH 7 - 9.

To advance the search for new prodrug structures, the N'-acyl derivative of N-(4-nitrophenyl)-4'-aminobenzyl carbamate was synthesised and evaluated as a possible substrate for the acylarylamidase enzyme. The hydrolysis of the 4-N'-acyl compound to its 4-amino parent was briefly examined at pH 2-12 and 25°C. The 4-N’-acyl compound proved to be relatively stable whereas the N-(4-nitrophenyl)-4'-aminobenzyl carbamate proved to be very reactive spontaneously decomposing to 4-nitro aniline and other identified products. Synthesis of the 4-amino parent was difficult but it was obtained from the protected 4'-amino carbamate of general formula 4-(G-NH)-C6H4-CH2-O-C(O)-NH-C6H4-Z [Z=nitro instead of 4-(N,N-bis-2-chloroethylamino)phenyl] by chemical removal of the protecting group G. Several protection groups G were investigated and the best conditions to remove them established.

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