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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.

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By indirect inimunofluorcscenec, 13 different p?-oleins were studied in 2-hour, acquired pellicles collected from four subjects over LI 5-day period. The 300 specimens were coded, and the intensity of fluorescence spceific for each protein was scored by two independent observers.Statistical analyses indicated that the mean score values differed significantly when a comparison was made between individual proteins or between subject-donors of the pellicles. Also, the scores for eaeh protein were highly dependent on the subjeet. Despite daily l'luetuations, the pellicles from eaeh subject presented a eharactcristic protein profile.Frequently, high fluorescenee seores were noted for proteins of generally low salivary concentration, e.g., iglVt ajid tgG. The third component of complement was diseovered in several peUicles and, by subsequent testing, in whole saliva but not in parotid fluid. Its presence in pellicles of an edentulous subject suggests that this protein may be transferred across the oral epithelium. f;