P-glycoprotein functions as an ATP-driven active efflux pump for many cytotoxic drugs. We now show that hydrophobic peptides and ionophores also interact with the multidrug transporter. Multidrug-resistant cells are cross-resistant to several hydrophobic peptides and ionophores, but not to some other membrane-active species. Linear peptides, cyclic peptides, and ionophores stimulated the ATPase activity of P-glycoprotein in plasma membrane vesicles by up to 2.5-fold. Drugs and chemosensitizers were able to block P-glycoprotein ATPase stimulation by verapamil, however, peptides and ionophores (with the exception of cyclosporine A) were unable to do so. Peptides and ionophores also effectively inhibited ATP-dependent drug transport by P-glycoprotein in plasma membrane vesicles. The median effect analysis was used to extract quantitative parameters from the drug transport inhibition data. Unlike drug substrates and cyclic peptides, linear peptides did not inhibit photoaffinity labeling of P-glycoprotein by [3H]azidopine. Taken together, these results indicate that certain hydrophobic peptides and ionophores are P-glycoprotein substrates, however, they affect the transporter in a different manner from drugs. Linear peptides interact with P-glycoprotein at a site distinct from those for verapamil and azidopine, whereas the interaction site for cyclic peptides and ionophores appears to be linked to these sites to varying degrees. Export of hydrophobic peptides may be an important physiological function of P-glycoprotein.

Synthesis of Fused-Ring Cyclobutenones via a Tandem (2 + 2) Cycloadditionβ-Elimination Sequence.-Photoreaction of the enol acetates (I) of 1,3-cyclohexanediones with the cycloalkenes (II) gives the fused cyclobutanes (III). These are converted into the corresponding cyclobutenes (IV) by base-induced . beta.-elimination of acetic acid. -(GALATSIS, P.; ASH-BOURNE, K. J.; MANWELL, J. J.; WENDLING, P.; DUFAULT, R.; HATT, K. L.; FERGUSON, G.; GALLAGHER, J. F.; J.

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