Abstract
A series of structurally related diphenol aldimines (DPAs) were synthesized. These aldimines involve different substitution patterns of their phenolic groups, for the purpose of optimizing their ability to inhibit ATP synthase. The inhibitory effects of these DPA compounds were evaluated using purified F1 and membrane-bound F1F0 E. coli ATP synthase. Structure-activity relationship studies of these di-phenol compounds showed that maximum inhibition was achieved when both phenolic groups are either in the meta-positions (DPA-7, IC50 = 2.0 μM), or in the ortho-positions (DPA-9, IC50 = 5.0 μM). The lowest ATP synthase inhibition was found to be when the phenolic groups are both in the para-positions (DPA-2, IC50 = 100.0 μM). Results also show that the inhibitory effects of these compounds on ATPase are completely reversible. Identical inhibition patterns of both the purified F1 and the membrane bound F1F0 enzyme were observed. Study of E. coli cell growth showed that these diphenol aldimines effectively inhibit both ATP synthesis and cell growth.
Highlights
ATP synthase, the last enzyme of the oxidative phosphorylation in the respiratory chain, catalyzes the synthesis of ATP by oxidative phosphorylation of ADP
Study of E. coli cell growth showed that these diphenol aldimines effectively inhibit both ATP synthesis and cell growth
It has been reported that elevated expression of ATP synthase on endothelial cell surfaces plays a critical role in cellular processes during angiogenesis; the action of the angiogenesis inhibitor angiostatin can be in part attributed to inhibition of ATP synthase [10]
Summary
ATP synthase, the last enzyme of the oxidative phosphorylation in the respiratory chain, catalyzes the synthesis of ATP by oxidative phosphorylation of ADP. It is described as a “molecular motor” that is driven by the electrochemical gradient of protons and sodium ions across the mitochondrial membrane. It has been shown that ATP synthase or its components, found on the outer surface of plasma membrane, can function as a receptor for various ligands and plays an important role in the immune response of tumor cells [5,6,7,8,9]. Abnormalities in the function of this enzyme have been associated with a number of human diseases that are linked to mitochondrial myopathy, such as diabetes, heart disease, and cancer
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