Mitochondrial respiratory complex II (CII) is also known as succinate dehydrogenase. It is a potential target for a multitude of human diseases, including myocardial infarction, stroke and cancer. It has a significant role in the generation of reactive oxygen species and inhibition impairs glutaminolysis, the major source of energy for cancer cells. Complex II inhibition leads to the activation of autophagy and apoptosis in tumor cells. Many low potency CII inhibitors are selectively cytotoxic to cancer cells with negligible effects on non-malignant cells. The natural product Atpenin A5 is the most potent CII inhibitor known to date, with an IC50 value in the range of 3.6–10 nM. However, its physicochemical properties prohibit its use as a potential therapeutic. Conversely, the clinically available vasodilator Diazoxide possesses excellent ‘drug-like’ properties but weak CII inhibition with an IC50 = 32 µM. Aided by molecular modeling and Quantitative Structure-Activity Relationship (QSAR) studies, we have designed, synthesized and characterized a library of Atpenin A5 and Diazoxide analogues with enhanced ‘drug-likeness’ and evaluated their antineoplastic activity. Several of these derivatives show greater CII inhibition and significant antineoplastic activity in in vitro cellular models. Design aspects of lead derivatives include optimum ligand lipophilicity efficiency (LLE) of &gt;5, low clearance, a half-life of &gt;3 hours and a six-carbon side chain which forms part of the auxophore and is suitable for further derivatization yet still maintains the cell proliferation inhibition activity in low nanomolar range. Complex II inhibitors with nanomolar potency and selective anti-cancer activity are reported. The lead Atpenin A5 derivative was &gt;150-fold selective towards CII over mitochondrial complex I (CI). This derivative displayed potent and selective inhibition of multiple human prostate cancer cell lines and reactive stromal cells in a dose-dependent manner with a seven-fold greater anti-proliferative activity to cancer and reactive stromal cells than in non-malignant cells. Selectively inhibiting proliferation of both cancer cells and reactive stromal cells in conjunction, maybe a novel therapeutic strategy which can confer significant benefit to patients.

Design and synthesis of mitochondrial respiratory complex II inhibitors and evaluation of anticancer activity

Macromolecular Chemistry: The Second Century

[Author Benefits](https://scimeetings.acs.org/?utm_source=pubs_content_marketing&utm_medium=website&utm_campaign=0320_MCF_NPI_Launch_Spring_Homepage&ref=pubs_content_marketing)

[How to use SciMeetings](https://storage.googleapis.com/dl.morressier.com/acs/SciMeetings-ACSSpring2020-HowToGuide_M3020-Final.pdf)

[Frequently Asked Questions](https://storage.googleapis.com/dl.morressier.com/acs/SciMtng_ACSNMSp2020_FAQ_M3120_Final.pdf)

ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.