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.