2-(3-4-dimethoxyphenyl)-1-(5-methoxy-2-2-dimethyl-2h-chromen-6-yl)ethanone and deguelin

A series of novel B and C-rings truncated deguelin derivatives have been designed and synthesized in the present study as heat shock protein 90 (Hsp90) inhibitors. The synthesized compounds exhibited micromolar antiproliferative potency toward a panel of human cancer cell lines. Their structure-activity relationships (SARs) were investigated in a systematic manner. Compound 21c was identified to have high Hsp90 binding potency (60 nM) and caused degradation of client proteins through ubiquitin proteasome system. Further biological studies showed that compound 21c induced a dose-dependent S and G2-phase cell cycle arrest on human breast cancer MCF-7 cells. Flow cytometry and Western blot analyses confirmed that compound 21c caused apoptosis of MCF-7 cells. In addition, compound 21c showed much potent inhibition on the migration and invasion of MCF-7 cells. Taken together, these results suggest that 21c might be a promising lead compound for further development of Hsp90 inhibitors.

Topics: Antineoplastic Agents; Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Drug Design; Drug Screening Assays, Antitumor; HSP90 Heat-Shock Proteins; Humans; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Proteasome Endopeptidase Complex; Rotenone; Structure-Activity Relationship

Based on the lead compound L-80 (compound 2), a potent heat shock protein 90 (HSP90) inhibitor, a series of C-ring truncated deguelin analogs were designed, synthesized and evaluated for Hypoxia Inducible Factor-1α (HIF-1α) inhibition as a primary screening method. Their structure-activity relationship was investigated in a systematic manner by varying the A/B ring, linker and D/E ring, respectively. Among the synthesized inhibitors, compound 5 exhibited potent HIF-1α inhibition in a dose-dependent manner and significant antitumor activity in human non-small cell lung carcinoma (H1299), with better activities than L-80. It also inhibited in vitro hypoxia-mediated angiogenic processes in human retinal microvascular endothelial cells (HRMEC). The docking study of 5 showed a similar binding mode as L-80: it occupied the C-terminal ATP-binding pocket of HSP90, indicating that the anticancer and antiangiogenic activities of 5 were derived from HIF-1α destabilization by inhibiting the C-terminal ATP-binding site of hHSP90.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; HSP90 Heat-Shock Proteins; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Models, Molecular; Molecular Structure; Neovascularization, Pathologic; Rotenone; Structure-Activity Relationship

A series of fluorophenyl and pyridine analogues of 1 and 2 were synthesized as ring-truncated deguelin surrogates and evaluated for their HIF-1α inhibition. Their structure-activity relationship was systematically investigated based on the variation of the linker B-region moiety. Among the inhibitors, compound 25 exhibited potent HIF-1α inhibition in a dose-dependent manner and significant antitumor activity in H1299 with less toxicity than deguelin. It also inhibited in vitro hypoxia-mediated angiogenic processes in HRMECs. The docking study indicates that 25 occupied the C-terminal ATP-binding pocket of HSP90 in a similar mode as 1, which implies that the anticancer and antiangiogenic activities of 25 are derived from HIF-1α destabilization by binding to the C-terminal ATP-binding site of hHSP90.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Endothelial Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Molecular Structure; Retinal Vessels; Rotenone; Structure-Activity Relationship

Deguelin exhibits potent apoptotic and antiangiogenic 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 analogues 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 antiproliferative and antiangiogenic 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, analogues 54 and 69, the B- and C-ring-truncated compounds, exhibited excellent antiproliferative activities with IC(50) of 140 and 490 nM in the H1299 cell line, respectively, and antiangiogenic activities in zebrafish embryos in a dose dependent manner (0.25-1.25 μM).

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Benzopyrans; Cell Line, Tumor; Cell Proliferation; Drug Design; Drug Screening Assays, Antitumor; Embryo, Nonmammalian; HSP90 Heat-Shock Proteins; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Neovascularization, Physiologic; Protein Binding; Rotenone; Stereoisomerism; Structure-Activity Relationship; Zebrafish