posted on 2019-03-04, 19:51authored byShengxin Cai, April L. Risinger, Cora L. Petersen, Tanja Grkovic, Barry R. O’Keefe, Susan L. Mooberry, Robert H. Cichewicz
An extract of the plant Anacolosa
clarkii was
obtained from the NCI Natural Products Repository, and it showed cytotoxic
activity toward several types of pediatric solid tumor cell lines.
Bioassay-guided fractionation led to the purification of eight new
clerodane diterpenes [anacolosins A–F (1–6) and corymbulosins X and Y (7 and 8)] and two known compounds (9 and 10) that
contained an isozuelanin skeleton. The structures of the new natural
products were determined using 1D and 2D NMR and HRESIMS data, while
the relative and absolute configurations of the compounds were assessed
using a combination of 1H NMR coupling constant data, ROESY
experiments, ECD (electronic circular dichroism) and VCD (vibrational
circular dichroism) spectroscopy, chemical methods (including Mosher
and 2-naphthacyl esterification), and chiral HPLC analyses. The purified
natural products exhibited a range of cytotoxic activities against
cell lines representing four pediatric cancer types (i.e., rhabdomyosarcoma,
Ewing sarcoma, medulloblastoma, and hepatoblastoma) with total growth
inhibitory (TGI) values in the range 0.2–4.1 μM. The
rhabdomyosarcoma and medulloblastoma cell lines showed higher sensitivity
to compounds 1–4, which are the first
compounds reported to contain an isozuelanin skeleton and feature
keto carbonyl groups at the C-6 positions. In contrast, the hepatoblastoma
cell line was modestly more sensitive to 7–10, which contained a C-6 hydroxy group moiety.