ja6b02075_si_001.pdf (40.83 MB)
Synthesis and Biological Investigation of Δ12-Prostaglandin J3 (Δ12-PGJ3) Analogues and Related Compounds
journal contribution
posted on 2016-05-12, 14:51 authored by K. C. Nicolaou, Kiran Kumar Pulukuri, Stephan Rigol, Philipp Heretsch, Ruocheng Yu, Charles I. Grove, Christopher
R. H. Hale, Abdelatif ElMarrouni, Verena Fetz, Mark Brönstrup, Monette Aujay, Joseph Sandoval, Julia GavrilyukA 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.