News & Events

When

Date - June 28, 2019
1:00 pm - 2:00 pm

What

PhD Dissertation Seminar – 752
Title: Studies on Epipolythiodioxopiperazine Alkaloids”
Advisor: Dr. Nicholas Oberlies

Abstract:

Verticillins are members of the epipolythiodioxopiperazine (ETP) alkaloid class of fungal metabolites and are known as potent cytotoxic agents with IC₅₀ values lower than 10 nM. Studies showed that verticillin A has activity as a selective histone methyl transferases inhibitor with important anticancer properties. However, major challenges slow down moving this class forward. Initially, the supply was the first challenge to provide amounts required for preclinical advancement of these leads. Thus, having a reliable way to probe a suite of fermentation conditions was desired, so as to optimize the biosynthesis of the ETPs resulting in the selection of the best fungal strain, the best medium for growth and the optimum growth time. Another challenge, like many natural products, these analogues are poorly soluble, which makes their administration a challenging process. Encapsulating verticillin A inside expansile nanoparticles (eNPs) enhanced greatly their solubility in physiologic conditions, thereby facilitating in vivo studies. eNPs were prepared in a 5% loading, within a range of 70-80% of the initial amount encapsulated. The verticillin A loaded eNPs showed promising results in vitro and in vivo against ovarian cancer in murine models. Expanding the chemical space of verticillins is also of great importance. This goal was achieved by two main approaches; a synthetic biology approach and a semisynthetic approach. Seven fluorinated epipolythiodioxopiperazine alkaloids were generated by incorporating fluorinated tryptophan into verticillin analogues using the precursor-directed biosynthesis. in situ analysis via the dropletProbe, NMR and HRESIMS/MS/MS data were used to characterize the new compounds. The new derivatives and their parent compounds were tested in three types of human cancer cell lines, demonstrating nanomolar IC₅₀ values. Semisynthetic approaches on verticillin H as a scaffold resulted in the production of a couple of derivatives such as carbonates, carbamates and sulfonate that are believed to be a good way to enhance the half-life and the solubility of the parent compound. The new semisynthetic compounds were characterized using NMR and HRESIMS/MS/MS data and showed IC₅₀ values in the order of the nanomolar against three different human cancer cell lines.