TY - JOUR
T1 - Anacolosins A-F and Corymbulosins X and Y, Clerodane Diterpenes from Anacolosa clarkii Exhibiting Cytotoxicity toward Pediatric Cancer Cell Lines
AU - Cai, Shengxin
AU - Risinger, April L.
AU - Petersen, Cora L.
AU - Grkovic, Tanja
AU - O'Keefe, Barry R.
AU - Mooberry, Susan L.
AU - Cichewicz, Robert H.
N1 - Funding Information:
Support for this project was provided by NIH grant R01GM107490 to R.H.C. and S.L.M. and the Greehey Endowment (S.L.M.). The LC-MS instrument used for this project was provided in part by a Challenge Grant from the Office of the Vice President for Research, University of Oklahoma, Norman Campus, and an award through the Shimadzu Equipment Grant Program (R.H.C.). Computational data for ECD and VCD experiments were obtained through the University of Oklahoma Supercomputing Center for Education & Research (OSCER). This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.
Funding Information:
†Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, and ‡Natural Products Discovery Group and Institute for Natural Products Applications and Research Technologies, University of Oklahoma, Norman, Oklahoma 73019, United States §Department of Pharmacology and ⊥Mays Cancer Center, University of Texas Health Science Center, San Antonio, Texas 78229, United States ∥Natural Products Support Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, United States #Natural Products Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Frederick, Maryland 21702, United States ¶Molecular Targets Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, United States
PY - 2019/4/26
Y1 - 2019/4/26
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jnatprod.8b01015
DO - 10.1021/acs.jnatprod.8b01015
M3 - Article
C2 - 30830773
AN - SCOPUS:85062884940
VL - 82
SP - 928
EP - 936
JO - Journal of Natural Products
JF - Journal of Natural Products
SN - 0163-3864
IS - 4
ER -