The effect of 1,4-dihydropyridine and 1,4-dihydroindeno[1,2-b]pyridine derivatives on glutathione S-transferase activity in vitro.

The 1,4-dihydropyridine (1,4-DHP) and 1,4-dihydroindeno[1,2-b]pyridine (1,4-DHIP) derivatives were investigated as glutathione S-transferase (GT) inhibitors. The obtained results indicate that some of the 1,4-DHP's containing lipophylic and bulky substituents have inhibitory effects on GT in vitro. The derivatives of 1,4-DHIP are more pronounced inhibitors.

Plasma stability and cytotoxicity of lipophilic daunorubicin derivatives incorporated into low density lipoproteins.

The selective targeting of antineoplastic drugs to tumours by incorporation in low density lipoproteins (LDL) is an attractive possibility if the drug-LDL complex remains stable in the circulation and is taken up by the tumour. In previous studies we have shown that vincristine- and N-trifluoroacetyladriamycin-14-valerate-LDL complexes were unstable in vivo. We synthesized five N-substituted lipophilic derivatives of daunorubicin and studied their incorporation into LDL. Three out of five daunorubicin derivatives incorporated successfully into LDL. In vitro these complexes were more cytotoxic towards LDL receptor positive Chinese hamster ovary cells than LDL receptor negative cells. Non-specific cytotoxicity was explained by slow dissociation of the drug-LDL complex in plasma. Our results underline the importance of careful studies of plasma stability when investigating lipoproteins and other carriers in drug targeting.

The use of taurine analogues to investigate taurine functions and their potential therapeutic applications.

Despite the multitude of evidence for the beneficial effects of taurine supplementation in a variety of disease, the underlying modifying action of taurine with respect to either molecular or biochemical mechanisms is almost totally unknown. We have assessed the development of taurine analogues, particularly where there has been substitution at the suphonate or amine group. Such substitutions allow the investigator to probe the relationship between structure and function of the taurine molecule. In addition such studies should help to ascertain taurine's point of interaction with the effector molecule. These results will prepare the way for the development of the second generation of taurine analogues.