Development of Selective and Soluble Mitochondrial Complex 1 Inhibitors Derived from Papaverine for...

The efficacy of radiation therapy is limited by low oxygen tension within solid tumors. Papaverine and some derivatives were previously shown to inhibit mitochondrial complex 1 and decrease oxygen consumption, reversing hypoxia and radiosensitizing model tumors. Papaverine is typically used as a vasorelaxant due to its ability to inhibit phosphodiesterase 10A (PDE10A), which can lead to unwanted side effects when used clinically as a radiosensitizer. We have therefore generated additional derivatives which have improved mitochondrial complex 1 inhibition and reduced PDE10A inhibition. Two of these compounds were tested in vivo for radiosensitization of murine EO771 mammary gland tumors and found to be as effective as papaverine with an improved safety profile.