Orally active purine-based inhibitors of the heat shock protein 90
| Autor: | Marco A. Biamonte, Jiandong Shi, Kevin Hong, David C. Hurst, Lin Zhang, Junhua Fan, David J. Busch, Patricia L. Karjian, Angelica A. Maldonado, John L. Sensintaffar, Yong-Ching Yang, Adeela Kamal, Rachel E. Lough, Karen Lundgren, Francis J. Burrows, Gregg A. Timony, Marcus F. Boehm, Srinivas R. Kasibhatla |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Purine
Administration Oral Biological Availability Mice Nude Antineoplastic Agents Chemical synthesis chemistry.chemical_compound Mice Structure-Activity Relationship Heat shock protein Drug Discovery Structure–activity relationship Animals HSP90 Heat-Shock Proteins biology Chemistry Adenine Biological activity Hsp90 Tautomer Xenograft Model Antitumor Assays Biochemistry Solubility Enzyme inhibitor Purines biology.protein Molecular Medicine Female |
| Zdroj: | Journal of medicinal chemistry. 49(2) |
| ISSN: | 0022-2623 |
| Popis: | Orally active Hsp90 inhibitors are of interest as potential chemotherapeutic agents. Recently, fully synthetic 8-benzyladenines and 8-sulfanyladenines such as 4 were disclosed as Hsp90 inhibitors, but these compounds are not water soluble and consequently have unacceptably low oral bioavailabilities. We now report that water-solubility can be achieved by inserting an amino functionality in the N(9) side chain. This results in compounds that are potent, soluble in aqueous media, and orally bioavailable. In an HER-2 degradation assay, the highest potency was achieved with the neopentylamine 42 (HER-2 IC(50) = 90 nM). In a murine tumor xenograft model (using the gastric cancer cell line N87), the H(3)PO(4) salts of the amines 38, 39, and 42 induced tumor growth inhibition when administered orally at 200 mg/kg/day. The amines 38, 39, and 42 are the first Hsp90 inhibitors shown to inhibit tumor growth upon oral dosage. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|