title: Adriamycin analogues. Preparation and biological evaluation of some thio ester analogues of adriamycin and N-(trifluoroacetyl)adriamycin 14-valerate.
abstract: On the consideration that the highly active DNA-nonbinding adriamycin analogues N-(trifluoroacetyl)adriamycin 14-valerate and N-(trifluoroacetyl)adriamycin 14-O-hemiadipate undergo initial metabolic conversion to N-(trifluoroacetyl)adriamycin by the action of nonspecific serum and tissue esterases, a number of N-(trifluoroacetyl)adriamycin 14-thio esters have been prepared and studied for in vitro growth inhibition, vs. human-derived CCRF-CEM leukemic lymphocytes, and in vivo antitumor activity, vs. murine P388 leukemia, relative to the rate of thio ester deacylation induced by esterases present in mouse serum. Products were obtained by reaction of N-(trifluoroacetyl)-14-bromodaunorubicin with thioacetic, thiopropionic, thiobutyric, thiovaleric, and thiobenzoic acids in ethanol, in the presence of potassium carbonate. Because little is known about similar thio ester derivatives of adriamycin itself, the corresponding adriamycin 14-thio esters were also prepared and evaluated for antitumor activity; with these products, determination of their extent of interaction with calf thymus DNA was also performed. For the adriamycin thio ester products, significant in vivo anti-P388 activity was seen with the thioacetate, thiovalerate, and thiobenzoate derivatives, although no compound matched the curative effects of N-(trifluoroacetyl)adriamycin 14-valerate in this system. With respect to the N-(trifluoroacetyl)adriamycin 14-thio ester products, although the corresponding oxo ester analogues are all significantly biologically active, none of the thio ester derivatives showed activity in vitro or in vivo.
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D004247:DNA / Q000378:metabolism; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D007202:Indicators and Reagents; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D007202:Indicators and Reagents; D004317:Doxorubicin; D004247:DNA