Molecular Pharmacology, Vol 14, 693-703, Copyright © 1978 by the American Society for Pharmacology and Experimental Therapeutics

Structure-Activity Relationships in the Ansamycins: the Crystal Structure of Tolypomycinone

¹ University of Siena, University of Rome, and National Research Council Laboratory of Structural Chemistry, C.P. 10, 00016 Monterotondo Stazione, Rome, Italy

The structure of tolypomycinone, C₃₇H₄₃NO₁₃, obtained by mild hydrolysis from the antibiotic tolypomycin Y, was studied by X-ray methods in order to carry out further investigations on structure-activity relationships in the ansamycins. Accurate examination of the conformation of tolypomycinone led to the hypothesis that its low activity may be related to the spatial disposition of the hydroxyls on C(21) and C(23), unfavorable to the formation of hydrogen bonds with bacterial RNA polymerase. The results confirm that the activity of ansamycins is strongly influenced by the ansa chain conformation. Furthermore, we suggest that substituents introduced at position 3 in the aromatic nucleus of this class of antibiotics influence the ansa chain conformation.

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ACKNOWLEDGMENTS The technical assistance of Mr. A. Amorese and Mr. B. Paoluzzi is gratefully acknowledged.