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Structure-activity relationship of anthracycline-induced genotoxicity in vitro
Abstract:
Anthracycline antitumor antibiotics, such as Adriamycin and daunomycin, are potent genotoxic agents and carcinogens. A variety of anthracycline derivatives was investigated in various in vitro short-term tests, i.e., mutagenesis in Salmonella typhimurium and V79 Chinese hamster cells and induction of unscheduled DNA synthesis in primary rat hepatocytes. Compounds containing a daunosamine sugar moiety (Adriamycin, daunomycin, 4-demethoxydaunomycin, 4-demethoxyadriamycin, and carminomycin) were highly active in both mutagenesis assays. Addition of S9 to the bacteria and cocultivation of V79 cells with rat hepatocytes, in general, decreased the mutagenicity of these compounds. In contrast, anthracyclines with N-alkylated sugar moieties (aclacinomycin A, marcellomycin, musettamycin, pyrromycin, rudolfomycin, N,N-dimethyladriamycin, N,N-dimethyldaunomycin, N-benzyldaunomycin, N,N-dibenzyldaunomycin, 3'-deamino-3'-methoxypiperidinodaunomycin, morpholinodaunomycin, cyanomorpholinodaunomycin, and cyanomorpholinoadriamycin) were weakly mutagenic or not mutagenic at all in both bacterial and mammalian cells. The two latter compounds were weakly active in the Salmonella/microsome assay only after addition of S9. Results obtained in the DNA repair studies did not correlate to these mutagenicity data; while most compounds, including Adriamycin and daunomycin, were either weakly active or inactive at inducing unscheduled DNA synthesis in primary rat hepatocytes, morpholinodaunomycin, cyanomorpholinodaunomycin, and cyanomorpholinoadriamycin were extremely active. The results indicate that the mutagenicity of anthracyclines is related more to differences in their sugar moiety than to differences in the chemical structure of their aglycones; N-alkylation of the sugar moiety can abolish or greatly reduce their mutagenic activity. Moreover, induction of unscheduled DNA synthesis, although considered to be due to DNA damage, is not correlated to anthracycline-induced mutations but may possibly indicate covalent DNA interaction.
Insights
Anthracycline antibiotics are genotoxic; modifications to their sugar moiety significantly impact mutagenicity. N-alkylation of the sugar greatly reduces mutagenic activity, while DNA repair induction doesn't always correlate with mutations.
Area of Science:
- Biochemistry
- Toxicology
- Pharmacology
Background:
- Anthracyclines like Adriamycin are potent genotoxic agents and carcinogens.
- Understanding structure-activity relationships is crucial for developing safer analogs.
Purpose of the Study:
- To investigate the mutagenicity and DNA repair induction of various anthracycline derivatives.
- To correlate structural modifications, particularly in the sugar moiety, with genotoxic potential.
Main Methods:
- In vitro short-term tests including bacterial mutagenesis (Salmonella typhimurium) and mammalian cell mutagenesis (V79 Chinese hamster cells).
- Induction of unscheduled DNA synthesis (UDS) in primary rat hepatocytes.
- Evaluation of anthracycline derivatives with varying sugar moieties and N-alkylated structures.
Main Results:
- Anthracyclines with a daunosamine sugar moiety were highly mutagenic in both bacterial and mammalian cells.
- N-alkylation of the sugar moiety significantly reduced or abolished mutagenicity.
- Induction of unscheduled DNA synthesis (UDS) did not correlate with mutagenicity; some non-mutagenic compounds showed high UDS activity.
Conclusions:
- The sugar moiety, not the aglycone, is the primary determinant of anthracycline mutagenicity.
- N-alkylation of the sugar moiety is an effective strategy to reduce anthracycline mutagenicity.
- Unscheduled DNA synthesis (UDS) induction may indicate DNA interaction but not necessarily mutagenicity.