Search for Hsp90 inhibitors with potential anticancer activity: isolation and SAR studies of radicicol and monocillin I from two plant-associated fungi of the Sonoran desert.
In an effort to discover small molecule inhibitors of Hsp90, we have screened over 500 EtOAc extracts of Sonoran desert plant-associated fungi using a two-stage strategy consisting of a primary cell-based heat shock induction assay (HSIA) followed by a secondary biochemical luciferase refolding assay (LRA). Bioassay-guided fractionation of extracts active in these assays derived from Chaetomium chiversii and Paraphaeosphaeria quadriseptata furnished the Hsp90 inhibitors radicicol (1) and monocillin I (2), respectively. In SAR studies, 1, 2, and their analogues, 3-16, were evaluated in these assays, and the antiproliferative activity of compounds active in both assays was determined using the breast cancer cell line MCF-7. Radicicol and monocillin I were also evaluated in a solid-phase competition assay for their ability to bind Hsp90 and to deplete cellular levels of two known Hsp90 client proteins with relevance to breast cancer, estrogen receptor (ER), and the type 1 insulin-like growth factor receptor (IGF-1R). Some inferences on SAR were made considering the crystal structure of the N-terminus of yeast Hsp90 bound to 1 and the observed biological activities of 1-16. Isolation of radicicol and monocillin I in this study provides evidence that we have developed an effective strategy for discovering natural product-based Hsp90 inhibitors with potential anticancer activity.
Turbyville
Thomas J
TJ
SW Center for Natural Products Research and Commercialization, University of Arizona, Tucson, Arizona 85706-6800, USA.
Wijeratne
E M Kithsiri
EM
Liu
Manping X
MX
Burns
Anna M
AM
Seliga
Christopher J
CJ
Luevano
Libia A
LA
David
Cynthia L
CL
Faeth
Stanley H
SH
Whitesell
Luke
L
Gunatilaka
A A Leslie
AA
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001203:Ascomycota / Q000737:chemistry*; D001943:Breast Neoplasms / Q000188:drug therapy; D003889:Desert Climate; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000187:drug effects; D007783:Lactones / Q000494:pharmacology*; D008156:Luciferases / Q000378:metabolism; D018942:Macrolides; D015394:Molecular Structure; D010944:Plants; D011817:Rabbits; D011960:Receptors, Estrogen / Q000187:drug effects; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D007783:Lactones; D018942:Macrolides; D011960:Receptors, Estrogen; C444505:monocillin I; D007334:Insulin-Like Growth Factor I; D008156:Luciferases; C035359:monorden