Semisynthetic derivatives of concanamycin A and C, as inhibitors of V- andP-type ATPases: Structure-activity investigations and developments of photoaffinity probes

V-type ATPases are inhibited by the plecomacrolides bafilomycin and concana mycin, which exert their inhibitory potential at nanomolar concentrations. In addition, some P-type ATPases are inhibited at micromolar concentrations . We initiated intensive structure-activity investigations with semisynthet ic concanamycin derivatives to approach the following two questions: (i) Wh at is the pharmacophor, the structural key element, of the plecomacrolides that leads to their inhibitory potential against V- and P-type ATPases? (ii ) Where is the binding site within these two different types of ATPases? In a first step, we examined where chemical modifications (O-acylations, subs titutions, eliminations) could be placed without seriously affecting the in hibitory potential of the macrolides. In a second step, we used the knowled ge of these structure-activity investigations to introduce traceable elemen ts (fluorescent or radioactive) or nitrene-generating azido or carbene-gene rating diazirine-groups able to bind the inhibitors to their target covalen tly. These studies led finally to the synthesis of two photoaffinity probes that were used in labeling experiments with the purified plasma membrane V -type ATPase of Manduca sexta (described in a following paper, Huss, M., Ga ssel, M., Ingenhorst, G., Drose, S., Zeeck, A., Altendorf, K., Wieczorek, H ., manuscript submitted).