Analogues of the Epipolythiodioxopiperazine Alkaloids
T2019-372 Analogues of verticillin which have more useful drug-like properties than the verticillin parent compounds alone, including increased solubility, absorption, and stability, all while maintaining similar anticancer potency to the original compounds.
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.
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. The nature of the substituted group can have profound effect on the pharmacological properties of the molecule, including increased solubility and stability, and this flexibility allows for the fine-tuning of in vivo characteristics with similar potency to the parent verticillin molecules.
- Biomedical research
- Increased solubility
- Increased stability
- Retained anticancer potency
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.