Synthesis and Biological Investigation of Δ12-Prostaglandin J3 (Δ12-PGJ3) Analogues and Related Compounds
K.C. Nicolaou, K.K. Pulukuri, S. Rigol, P. Heretsch, R. Yu, C.I. Grove, C.R.H. Hale, A.E. Marrouni, V. Fetz, M. Brönstrup, M. Aujay, J. Sandoval, J. Gavrilyuk – 2016
A series of Δ12-prostaglandin J3 (Δ12-PGJ3) analogues and derivatives were synthesized employing an array of synthetic strategies developed specifically to render them readily available for biological investigations. The synthesized compounds were evaluated for their cytotoxicity against a number of cancer cell lines, revealing nanomolar potencies for a number of them against certain cancer cell lines. Four analogues (2, 11, 21, and 27) demonstrated inhibition of nuclear export through a covalent addition at Cys528 of the export receptor Crm1. One of these compounds (i.e., 11) is currently under evaluation as a potential drug candidate for the treatment of certain types of cancer. These studies culminated in useful and path-pointing structure activity relationships (SARs) that provide guidance for further improvements in the biological/pharmacological profiles of compounds within this class.