Anticancer Natural Products Article is Monthly Publication Highlight for September
October 11, 2015
A collaborative research project that will help provide investigators a greater understanding of anticancer properties of natural products is the UK College of Pharmacy Monthly Publication Highlight for September 2015.
The article was published in Angewandte Chemie International Edition, “A Divergent Enantioselective Strategy for the Synthesis of Griseusins,” and was a collaborative effort between investigators in the Markey Cancer Center and the Center for Pharmaceutical Research and Innovation (CPRI), a UK research center focused on advancing translational research, drug discovery, and drug development that is supported by the UK College of Pharmacy, the UK Center for Clinical and Translational Science (CCTS) and the Markey Cancer Center.
The project was co-directed by Jon Thorson, Professor of Pharmaceutical Sciences and Director of the CPRI, and Qing-Bai She, Professor of Pharmacology and Nutritional Sciences at the UK College of Medicine. Yinan Zhang is the study’s lead author and was assisted by Qing Ye and Xiachang Wang, postdoctoral fellows in the Thorson and She laboratories, respectively.
The manuscript reports a new method for synthesizing griseusins, a class of cyclic compounds made by a common soil bacterium, Streptomyces griseus, with antibiotic, antifungal, and anticancer properties - an architectural signature of which is their fused tetrahydro-spiropyran ring system. The team recently discovered these metabolites to function in a mechanistically distinct manner and the new synthetic method allows the investigators to explore the structural elements of these molecules that confer their bioactivity and better understand their mechanism of action. While griseusin members were first reported nearly three decades ago, their total synthesis has remained elusive. The strategy reported by Zhang and coworkers solves a number of important issues that plagued prior synthetic approaches and is highly divergent and practical, meaning that this methodology enables the ability to generate many analogs for hit to lead optimization, structure-activity relationships, and mechanistic studies. As a proof of concept, this study also highlighted certain modifications of the core griseusin scaffold to modulate cytotoxicity in colorectal cancer cells. In collaboration with Dr. Mark Leggas (Professor of Pharmaceutical Sciences and CPRI Translational Studies core leader), this team is currently assessing the maximal tolerated dose, pharmacokinetics, biodistribution and in vivo anticancer efficacy of a structurally and mechanistically-related family of natural products.
“The results of these initial tests reveal structural elements that are essential for activity and unlock the door to our understanding of the anticancer properties of griseusins, a key step that may allow UK investigators to generate new anticancer drugs,” said Greg Graf, Assistant Dean for Translational Research.