Short Total Synthesis of Delta(12)-Prostaglandin J(2) and Related Prostaglandins. Design, Synthesis, and Biological Evaluation of Macrocyclic Delta(12)-Prostaglandin J(2) Analogues

摘要

Comprised of a large collection of structurally diverse molecules, the prostaglandins exhibit a wide range of biological properties. Among them are Delta(12)-prostaglandin J(2) (Delta(12)-PGJ(2)) and Delta(12)-prostaglandin J(3) (Delta(12)-PGJ(3)), 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 Delta(12)-PGJ(2) 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.