Short Total Synthesis of Δ¹²-Prostaglandin J₂ and Related Prostaglandins. Design, Synthesis, and Biological Evaluation of Macrocyclic Δ¹²-Prostaglandin J₂ Analogues

Abstract

Comprised of a large collection of structurally diverse molecules, the prostaglandins exhibit a wide range of biological properties. Among them are Δ¹²-prostaglandin J₂ (Δ¹²-PGJ₂) and Δ¹²-prostaglandin J₃ (Δ¹²-PGJ₃), whose unusual structural motifs and potent cytotoxicities present unique opportunities for chemical and biological investigations. Herein, we report a short olefin-metathesis-based total synthesis of Δ¹²-PGJ₂ and its application to the construction of a series of designed analogues possessing monomeric, dimeric, trimeric, and tetrameric macrocyclic lactones consisting of units of this prostaglandin. Biological evaluation of these analogues led to interesting structure-activity relationships and trends and the discovery of a number of more potent antitumor agents than their parent naturally occurring molecules.