While studying the environmental fate of potent endocrine-active steroid hormones, we observed the formation of an intramolecular [2+2] photocycloaddition product with a novel hexacyclic ring system following photolysis of altrenogest. The structure and absolute configuration were established by X-ray diffraction analysis. Theoretical computations identified a barrierless two-step cyclization mechanism for the formation of the photoproduct upon photoexcitation. The product exhibited progesterone, estrogen, androgen, and pregnane X receptor activity, albeit generally with reduced potency relative to parent altrenogest. The retained bioactivity is expected to maintain ecosystem and human health risks associated with the inevitable release of altrenogest to the environment or incidental exposure during handling and administration to animals. Collectively, our results underscore the need for more comprehensive fate and risk assessment profiling, including prioritization of environmental transformation products for high-potency pollutant classes such as endocrine-disrupting steroids.
Intramolecular [2+2] Photocycloaddition of Altrenogest: Confirmation of Product Structure, Theoretical Mechanistic Insight, and Bioactivity Assessment
Nicholas C. Pflug,* Eric V. Patterson, Dalma Martinović-Weigelt,Edward P. Kolodziej, James B. Gloer, Kristopher McNeill, David M. Cwiertny, and Kristine H. Wammer
J. Org. Chem. 2019 https://doi.org/10.1021/acs.joc.9b02070