A novel derivative of the natural agent deguelin for cancer chemoprevention and therapy

Cancer Prev Res (Phila). 2008 Dec;1(7):577-87. doi: 10.1158/1940-6207.CAPR-08-0184.


The natural compound deguelin has promising preventive and therapeutic activity against diverse cancers by directly binding to heat shock protein-90 and thus suppressing its function. Potential side effects of deguelin over a certain dose, however, could be a substantial obstacle to its clinical use. To develop a derivative(s) of deguelin with reduced potential side effects, we synthesized five deguelin analogues (SH-02, SH-03, SH-09, SH-14, and SH-15) and compared them with the parent compound and each other for structural and biochemical features; solubility; and antiproliferative effects on normal, premalignant, and malignant human bronchial epithelial (HBE) and non-small-cell lung cancer (NSCLC) cell lines. Four derivatives destabilized hypoxia-inducible factor-1alpha as potently as did deguelin. Reverse-phase protein array (RPPA) analysis in H460 NSCLC cells revealed that deguelin and the derivatives suppressed expression of a number of proteins including heat shock protein-90 clients and proteins involved in the phosphoinositide 3-kinase/Akt pathway. One derivative, SH-14, showed several features of potential superiority for clinical use: the highest apoptotic activity; no detectable influence on Src/signal transducer and activator of transcription signaling, which can promote cancer progression and is closely related to pathogenesis of Parkinson's disease (deguelin, SH-02 and SH-03 strongly activated this signaling); better aqueous solubility; and less cytotoxicity to immortalized HBE cells (versus deguelin) at a dose (1 micromol/L) that induced apoptotic activity in most premalignant and malignant HBE and NSCLC cell lines. These collective results suggest that the novel derivative SH-14 has strong potential for cancer chemoprevention and therapy, with equivalent efficacy and lesser toxicity (versus deguelin).

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Carcinoma, Non-Small-Cell Lung / prevention & control*
  • Cell Line, Tumor
  • Chemoprevention / methods
  • Gene Expression / drug effects
  • Humans
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Lung Neoplasms / prevention & control*
  • Rotenone / analogs & derivatives*
  • Rotenone / chemical synthesis
  • Rotenone / chemistry
  • Rotenone / pharmacology
  • Signal Transduction / drug effects


  • 9,10-dimethoxy-3,3-dimethyl-7,7a,13,13atetrahydro-3H-chromeno(3,4-b)pyrano(2,3-h)chromen-7-ol
  • Antineoplastic Agents
  • Rotenone
  • deguelin