Design, Synthesis and Biological Evaluation of Novel Deguelin-Based Heat Shock Protein 90 (HSP90) Inhibitors Targeting Proliferation and Angiogenesis
- Authors
- Chang, D.J., An, H., Kim, K.S., Kim, H.H., Jung, J., Lee, J.M., Kim, N.J., Han, Y.T., Yun, H., Lee, S., Lee, G., Lee, S., Lee, J.S., Cha, J.H., Park, J.H., Park, J.W., Lee, S.C., Kim, S.G., Kim, J.H., Lee, H.Y., Kim, K.W., and Suh, Y.G.
- ID
- ZDB-PUB-121206-9
- Date
- 2012
- Source
- Journal of medicinal chemistry 55(24): 10863-10884 (Journal)
- Registered Authors
- Kim, Nam-Jung
- Keywords
- none
- MeSH Terms
-
- Angiogenesis Inhibitors/chemical synthesis*
- Angiogenesis Inhibitors/chemistry
- Angiogenesis Inhibitors/pharmacology
- Animals
- Antineoplastic Agents/chemical synthesis*
- Antineoplastic Agents/chemistry
- Antineoplastic Agents/pharmacology
- Benzopyrans/chemical synthesis*
- Benzopyrans/chemistry
- Benzopyrans/pharmacology
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Drug Design
- Drug Screening Assays, Antitumor
- Embryo, Nonmammalian/blood supply
- Embryo, Nonmammalian/drug effects
- HSP90 Heat-Shock Proteins/antagonists & inhibitors*
- Humans
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
- Neovascularization, Physiologic/drug effects
- Protein Binding
- Rotenone/analogs & derivatives*
- Rotenone/chemical synthesis
- Rotenone/chemistry
- Rotenone/pharmacology
- Stereoisomerism
- Structure-Activity Relationship
- Zebrafish
- PubMed
- 23186287 Full text @ J. Med. Chem.
Deguelin exhibits potent apoptotic and anti-angiogenic activities in a variety of transformed cells and cancer cells. Deguelin also exhibits potent tumor suppressive effects in xenograft tumor models for many human cancers. Our initial studies confirmed that deguelin disrupts ATP binding to HSP90 and consequently induces destabilization of its client proteins such as HIF-1α. Interestingly, a fluorescence probe assay revealed that deguelin and its analogs do not compete with ATP binding to the N-terminus of HSP90, unlike most HSP90 inhibitors. To determine the key parts of deguelin that contribute to its potent HSP90 inhibition, as well as its anti-proliferative and anti-angiogenic activities, we have established a structure-activity relationship (SAR) of deguelin. In the course of these studies, we identified a series of novel and potent HSP90 inhibitors. In particular, analogs 54 and 69, the B- and C-ring-truncated compounds, exhibited excellent anti-proliferative activities with IC50s of 140 and 490 nM in the H1299 cell line, respectively and anti-angiogenic activities in zebrafish embryos in a dose dependent manner (0.25~1.25 μM).