Synthesis and mechanism of biological action of morpholinyl-bearing arylsquaramides as small-molecule lysosomal pH modulators.

Lysosomal pH is an important modulator for many cellular processes. An agent that is capable of regulating lysosomal pH may find a wide range of potential applications in the field of biomedicine. In this study, we describe the synthesis of a family of morpholinyl-bearing arylsquaramides as small-molecule lysosomal pH modulators. These compounds are able to efficiently facilitate the transmembrane transport of chloride anions as mobile carriers across vesicular and cellular phospholipid membranes. They are capable of specifically alkalizing liposomes, disrupting the homeostasis of lysosomal pH and inactivivating lysosomal Cathepsin B enzyme. Anion transport is considered as the probable mechanism of action for the high efficiency of these compounds to modulate lysosomal pH. The present findings present a novel means to efficiently regulate lysosomal pH, which is in contrast to the methods shown by conventional lysosomal pH modulators that generally function by either acting as a weak base/acid, or releasing a basic/acidic component in lysosomal environments to change lysosomal pH.