Drug design: nitrosoureas
Eisenbrand, G.; Müller, N.; Schreiber, J.; Stahl, W.; Sterzel, W.; Berger, M.R.; Zeller, W.J.; Fiebig, H.
Iarc Scientific Publications 78: 281-294
1986
ISSN/ISBN: 0300-5038 PMID: 3583393 Document Number: 272169
Attempts to develop more effective and less toxic antineoplastic nitrosoureas are summarized. Previous research resulted in the synthesis and extensive preclinical testing of new, short-chain, water-soluble, but lipophilic compounds--1-(2-chloroethyl)-1-nitroso-3-(2-hydroxyethyl)urea (HECNU) and 1-(2-chloroethyl)-1-nitroso-3-(methylene carboxamido)urea. Molecular mechanisms of reactions with biomolecules are discussed with regard to DNA alkylation and cross-linking, carbamoylation of glutathione and glutathione reductase inhibition. Results of a clinical phase-II study show that HECNU, as predicted from preclinical tests, exhibits outstanding activity in brain tumours. Future development concentrates on the use of carrier molecules for nitrosoureas. Results of an extensive structure-activity study with oestradiol-linked analogues show that an oestradiol-17 ester derivative is much more active than other analogues.