Sara is a medicinal chemistry graduate student at the University of Minnesota in Gunda Georg’s lab, where she is working towards the total synthesis of natural product analogs with improved metabolic stability for the treatment of resistant ovarian cancers. She received dual degrees in chemistry and biochemistry from the University of Colorado at Boulder in 2013. While at Boulder, she worked in Hubert Yin’s lab on the synthesis and evaluation of probes for the detection of cancer metastasis, and also at Amgen as an intern in the Peptide Therapeutics Discovery Department. When not in lab, Sara enjoys biking, cooking, and brewing beer.
The National Cancer Institute estimates that over 80% of ovarian epithelial cancer patients will relapse following first-line platinum- and taxane-based chemotherapies. Microtubule targeting agents represent some of the most successful chemotherapeutics due to the role of microtubules in cell division and mitosis, however cancer cells frequently acquire resistance to these drugs through a variety of mechanisms. Additionally, current anti-tubulin drugs display significant bone-marrow toxicity and neuropathy. The natural product pironetin displays potent cytotoxic activity against ovarian cancer cells both sensitive and resistant to first-line chemotherapeutics such as paclitaxel and cisplatin. A recently published crystal structure shows that pironetin covalently binds with alpha-tubulin, whereas all tubulin-binding agents currently approved by the FDA target beta-tubulin. Furthermore, Nikas and coworkers studied the gene expression of ovarian cancer patients and found that TUBA3C, the gene encoding the alpha-tubulin subtype TUBA3C, is associated with short-term survival and resistance to first-line chemotherapeutics. Alpha-tubulin is therefore an attractive, alternative drug target that would address the critical need for new treatments for drug-resistant ovarian cancers. Despite the potent in vitro activity, pironetin was only marginally effective in the single reported in vivo study, which resulted in severe weight loss in the mice, indicating poor pharmacokinetic/pharmacodynamic properties as well as off target toxicities.
We have demonstrated that pironetin has a very short half-life in liver microsomes and hypothesized that rapid metabolism could lead to a less-active agent. We identified the major and minor metabolites in human liver microsomes and confirmed the identity through semi-synthesis. With this knowledge, we designed a small library of pironetin analogs with predicted improved metabolic stability Herein, we will show the complete total synthesis of a pironetin analog with predicted improved metabolic stability.