Semisynthetic Derivatives of Concanamycin A and C, as Inhibitors of V- and P-Type ATPases: Structure-Activity Investigations and Developments of Photoaffinity Probes

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• 作者：Stefan Drö ; se ; Claudia Boddien ; Michael Gassel ; Gudrun Ingenhorst ; Axel Zeeck ; and Karlheinz Altendorf
• 刊名：Biochemistry
• 出版年：2001
• 出版时间：March 6, 2001
• 年：2001
• 卷：40
• 期：9
• 页码：2816 - 2825
• 全文大小：187K
• 年卷期：v.40,no.9(March 6, 2001)
• ISSN：1520-4995

文摘

V-type ATPases are inhibited by the plecomacrolides bafilomycin and concanamycin, whichexert their inhibitory potential at nanomolar concentrations. In addition, some P-type ATPases are inhibitedat micromolar concentrations. We initiated intensive structure-activity investigations with semisyntheticconcanamycin derivatives to approach the following two questions: (i) What is the pharmacophor, thestructural key element, of the plecomacrolides that leads to their inhibitory potential against V- and P-typeATPases? (ii) Where is the binding site within these two different types of ATPases? In a first step, weexamined where chemical modifications (O-acylations, substitutions, eliminations) could be placed withoutseriously affecting the inhibitory potential of the macrolides. In a second step, we used the knowledge ofthese structure-activity investigations to introduce traceable elements (fluorescent or radioactive) or nitrene-generating azido or carbene-generating diazirine-groups able to bind the inhibitors to their target covalently.These studies led finally to the synthesis of two photoaffinity probes that were used in labeling experimentswith the purified plasma membrane V-type ATPase of Manduca sexta (described in a following paper,Huss, M., Gassel, M., Ingenhorst, G., Dröse, S., Zeeck, A., Altendorf, K., Wieczorek, H., manuscriptsubmitted).