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Synthesis and biological activity of some further cyclopenta[a]phenanthrenes
1Joint Academic Unit of Obstetrics, Gynaecology and Reproductive Physiology, London Hospital Medical College, UK.
Abstract:
16,17-Dihydro-11-methoxy-15H-cyclopenta[a]phenanthrene was synthesized by two different routes and tested for carcinogenicity in Tylers Original (TO) and SENCAR strain of mice by repeated application and initiation/promotion regime. 16,17-Dihydro-11-hydroxy-15H-cyclopenta[alpha]phenanthrene was also tested for carcinogenicity in the TO strain by repeated application. Surprisingly with both of these compounds, which lack conjugation in ring D, one of the ingredients essential for biological activity appears to be carcinogenic. It is tempting to speculate whether these compounds undergo metabolic oxidation in the skin at the benzylic C-17 position.
Insights
Two novel cyclopenta[a]phenanthrene derivatives were found to be carcinogenic in mice, despite lacking typical structural features for biological activity. This suggests potential metabolic activation in the skin.
Area of Science:
- Chemical carcinogenesis
- Dermatology
- Toxicology
Background:
- Cyclopenta[a]phenanthrenes are polycyclic aromatic hydrocarbons known for their carcinogenic potential.
- Biological activity of these compounds is often linked to conjugation in ring D.
- The role of non-conjugated derivatives in carcinogenesis is less understood.
Purpose of the Study:
- To synthesize and evaluate the carcinogenicity of two novel cyclopenta[a]phenanthrene derivatives: 16,17-Dihydro-11-methoxy-15H-cyclopenta[a]phenanthrene and 16,17-Dihydro-11-hydroxy-15H-cyclopenta[alpha]phenanthrene.
- To investigate the carcinogenic potential of these compounds in different mouse strains and experimental models.
Main Methods:
- Synthesis of two novel cyclopenta[a]phenanthrene derivatives via two distinct synthetic routes.
- Carcinogenicity testing in Tylers Original (TO) and SENCAR mice.
- Application methods included repeated topical application and an initiation/promotion regime.
Main Results:
- Both synthesized compounds, 16,17-Dihydro-11-methoxy-15H-cyclopenta[a]phenanthrene and 16,17-Dihydro-11-hydroxy-15H-cyclopenta[alpha]phenanthrene, exhibited carcinogenic activity in mice.
- Carcinogenicity was observed in both TO and SENCAR strains, and across different application protocols.
- The observed carcinogenicity occurred despite the absence of conjugation in ring D, a feature typically considered essential for biological activity.
Conclusions:
- The tested cyclopenta[a]phenanthrene derivatives are carcinogenic in mice.
- These findings challenge the established structure-activity relationships for this class of compounds.
- Metabolic oxidation at the benzylic C-17 position is a plausible mechanism for the observed carcinogenicity.