The Need

Verticillins, which are epipolythiodioxopiperazine (ETP) alkaloids, have shown promising anticancer qualities; these fungal metabolites have exhibited high potency against a variety of tumor cell types, with IC50 values typically in the 10-500 nanomolar range. However, these compounds suffer from poor drug-like properties, including low solubility and stability, which make difficult application for in vivo experimentation and administration. Efforts to synthesize ETPs have resulted in compounds lacking key –OH moieties. Thus, an efficient and reproducible process for fluorinating or otherwise modifying ETP alkaloids is necessary to harness the promising anticancer properties of verticillins and to overcome their poor pharmacological qualities. Analogs that have increased pharmacological qualities, such as increased potency, membrane permeability, and metabolism are needed.

The Technology

Dr. James Fuchs and his colleagues have developed novel ETP alkaloid analogues. The resulting compounds are more stable, have increased aqueous solubility, and do not require metabolic activation. Treatment using the analogues inhibited cell growth of melanoma, ovarian, and breast cancers in cell culture, retaining IC50 values in the nanomolar range, comparable to, and in some cases more potent than, the parent compounds.

Commercial Applications

• Oncology and other disease indications
• Therapeutics
• Biomedical research

Benefits/Advantages

• Increased solubility
• Increased stability
• Retained anticancer potency
• Possible superior safety and efficacy profiles than existing FDA-approved treatments and synergy with FDA-approved agents

Patent Filing(s)

Pending applications in U.S. and Europe

Research Interests

Dr. Fuchs’s lab uses synthetic chemistry as a tool to probe biological problems. The lab uses synthetic methods to prepare bioactive compounds and natural product analogues, gain insight into the structure–activity relationships of ligand/receptor systems, and investigates biosynthetic pathways.

Publications

Engineering Fluorine into Verticillins (Epipolythiodioxopiperazine Alkaloids) via Precursor-Directed Biosynthesis https://pubs.acs.org/doi/abs/10.1021/acs.jnatprod.9b00711