Synthesis of improved lysomotropic autophagy inhibitors

Journal of Medicinal Chemistry
Tong WangJeffrey P MacKeigan

Abstract

Autophagy is a conserved cellular pathway used to recycle nutrients through lysosomal breakdown basally and under times of stress (e.g., nutrient deprivation, chemotherapeutic treatment). Oncogenes are known to induce autophagy, which may be exploited by cancers for cell survival. To identify autophagy inhibitors with potential therapeutic value for cancer, we screened a panel of antimalarial agents and found that quinacrine (QN) had 60-fold higher potency of autophagy inhibition than chloroquine (CQ), a well-known autophagy inhibitor that functions by disrupting lysosomal activity. Despite desirable autophagy inhibiting properties, QN showed considerable cytotoxicity. Therefore, we designed and synthesized a novel series of QN analogs and investigated their effects on autophagy inhibition and cell viability. Notably, we found two compounds (33 and 34), bearing a backbone of 1,2,3,4-tetrahydroacridine, had limited cytotoxicity yet strong autophagy inhibition properties. In conclusion, these improved lysomotropic autophagy inhibitors may have use as anticancer agents in combination with conventional therapies.

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Citations

Dec 23, 2015·Future Medicinal Chemistry·Abigail R Solitro, Jeffrey P MacKeigan
Dec 8, 2015·Acta Biochimica Et Biophysica Sinica·Yuting ZhouBinhua P Zhou
Nov 26, 2015·Annals of the New York Academy of Sciences·Shengfu Piao, Ravi K Amaravadi
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Dec 7, 2017·Journal of Medicinal Chemistry·Siyu HeHaopeng Sun

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