Structural Determinants Responsible for the Biological Activity of (-)-Emetine, (-)-Cryptopleurine, and (-)-Tylocrebrine: Structure-Activity Relationship among Related Compounds

The structural basis for the cross-resistance and the common site of action of the benzoiosoquinoline alkaloids, (-)-emetine, (-)-tubulosine, (-)-cephaeline, and (-)-dehydroemetine, and of the phenanthroquinolizidine-type alkaloids, (-)-cryptopleurine, and the phenanthroindolizidine type, (-)-tylocrebrine, has been investigated by examining the cross-resistance of emetine-resistant mutants of Chinese hamster ovary cells to a large number of related compounds. On the basis of our results, we suggest that the aforementioned compounds possess common structural determinants which are responsible for their biological activity and that the requirement for biological activity is a planar molecule with two aromatic rings (rendered slightly electron richer, i.e., electronegative by methoxyl or hydroxyl groups) and the presence of a nucleophilic element such as nitrogen at a certain distance from the aromatic rings. The structure-activity relationship between the compounds indicates that the distance between the two aromatic rings, the angle between the nitrogen atom and the rings, and the electronegative character of the rings and planarity of the structure are critical features in determining the biological activity. Based on a comparison between the structures of compounds of the emetine type and those that are phenanthrene based, we have proposed the absolute sterochemistry of (-)-cryptopoeurine and (-)-tylocrebnne. ACKNOWLEDGMENTS The authors wish to thank Mr. David H. Chan for skillful technical assistance and Dr. B. Bosnich ofthe Chemistry Department (University of Toronto) for the circular dichroism measurements. We are also grateful to various investigators for providing us with the compounds employed here.