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

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.