Combinatorial Synthesis of Tetrasubstituted Alkenes and Related Compounds with Potential Anticancer Activity

In search of efficient anticancer agents, we aimed at the design and synthesis of a library of tetrasubstituted alkenes. These are structural analogues of tamoxifen, one of the widely used anticancer therapeutics.

Our small organic compound library was prepared via a chemical synthesis in the solution using the Larock three-component coupling reaction, which is known to tolerate diverse functional groups. Further, we have integrated this synthetic approach to four- and fivecomponent alkene assembly by using Sonogashira coupling, A3 and AHA reactions. The final products were isolated through preparative LC/MS station and characterized by NMR, MS, and X-ray crystallography. The biological activity of all novel compounds was tested by luciferase reporter assays against estrogen receptor (ER) and androgen receptor (AR).

Our combinatorial synthetic approach was based on structurally diverse internal alkynes, arylboronic acids and aryl halides. After experiment optimization a "one-pot" single synthetic procedure was developed. This allowed us to prepare a small-sized screening library of novel tetrasubstituted alkenes quickly and efficiently without laborious intermediate isolation. In most cases, we isolated the final product as a single isomer, and in selected cases, we confirmed their chemical structure via X-ray crystallography. High throughput screening of the novel tetrasubstituted alkenes revealed a dozen hits with predominant agonistic ERα- and antagonistic AR-activity in the micromolar range.

The proposed combinatorial approach is applicable for the synthesis of diversified organic compound libraries and for the discovery of new tamoxifen analogues with an improved therapeutic profile.