The winding road of the uvaretin class of natural products: from total synthesis to bioactive agent discovery

Herein, we disclose the development of a synthetic route to gain access to the uvaretin class of chalcone natural products. In this, the construction of a small library was achieved, and the collection was evaluated for cytotoxicity and other biological properties. Uvaretin (1) was accessed via a seven-step route in an overall yield of 15.1%. Within this route, the unsaturated enone variant of uvaretin (2), also a natural product, was accessed in a 16.7% yield over six steps. This route provides a nearly three-fold increase in yields of 1 and 2 in comparison to the previous synthetic route accessing them in 5.8% and 3.0% overall yields, respectively. Evaluation of 1 and 2 revealed IC50 values between 2.0 and 5.1 mu M in the cancerous cell lines HeLa, U937, A549, and MIA PaCa-2. Screening of the whole chalcone library set led to the discovery of over 30 compounds, within six cancerous cell lines, possessing single digit mu M IC50 activity as sole agents. Furthermore, multiple library members were found to possess promising potentiating properties with known chemotherapeutic agents.