Tricyclic guanidine alkaloids from the marine sponge Acanthella cavernosa that stabilize the tumor suppressor PDCD4

Tanja Grkovic; Johanna S Blees; Magdalena M Bayer; Nancy H Colburn; Cheryl L Thomas; Curtis J Henrich; Megan L Peach; James B McMahon; Tobias Schmid; Kirk R Gustafson

doi:10.3390/md12084593

Tricyclic guanidine alkaloids from the marine sponge Acanthella cavernosa that stabilize the tumor suppressor PDCD4

Mar Drugs. 2014 Aug 21;12(8):4593-601. doi: 10.3390/md12084593.

Authors

Affiliations

¹ Molecular Targets Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA. t.grkovic@griffith.edu.au.
² Molecular Targets Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA. M_Bajer@gmx.de.
³ Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany. M_Bajer@gmx.de.
⁴ Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA. colburna@mail.nih.gov.
⁵ Molecular Targets Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA. cltterry@mail.nih.gov.
⁶ Molecular Targets Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA. henrichcj@mail.nih.gov.
⁷ Basic Science Program, Leidos Biomedical Research, Inc., Chemical Biology Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA. mpeach@helix.nih.gov.
⁸ Molecular Targets Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA. mcmahoja@mail.nih.gov.
⁹ Molecular Targets Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA. gustafki@mail.nih.gov.

Abstract

A cell-based high-throughput screen that assessed the cellular stability of a tumor suppressor protein PDCD4 (Programmed cell death 4) was used to identify a new guanidine-containing marine alkaloid mirabilin K (3), as well as the known compounds mirabilin G (1) and netamine M (2). The structures of these tricyclic guanidine alkaloids were established from extensive spectroscopic analyses. Compounds 1 and 2 inhibited cellular degradation of PDCD4 with EC50 values of 1.8 μg/mL and 2.8 μg/mL, respectively. Mirabilin G (1) and netamine M (2) are the first marine natural products reported to stabilize PDCD4 under tumor promoting conditions.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Alkaloids / chemistry*
Alkaloids / pharmacology*
Animals
Apoptosis Regulatory Proteins / metabolism*
Guanidine / chemistry*
Guanidine / pharmacology*
HEK293 Cells
Humans
Oleanolic Acid / analogs & derivatives
Oleanolic Acid / chemistry
Porifera / chemistry*
RNA-Binding Proteins / metabolism*
Saponins / chemistry
Tumor Suppressor Proteins / metabolism*

Substances

Alkaloids
Apoptosis Regulatory Proteins
PDCD4 protein, human
RNA-Binding Proteins
Saponins
Tumor Suppressor Proteins
mirabilin
Oleanolic Acid
Guanidine

Abstract

Publication types

MeSH terms

Substances

Grants and funding