Preparation and evaluation of novel derivatives of geldanamycin

1121 Background: Geldanamycin (GA) is a potent inhibitor of Hsp90. Its derivative, 17-AAG is in Phase II clinical trials for the treatment of several cancers. However, due to its hydrophobicity, 17-AAG is administered in cremophor. Both GA and 17-AAG contain a quinone group that is well known to have redox-active properties that may be linked to potential toxicity. Herein we describe the preparation and biological evaluation of novel geldanamycin derivatives. Methods: The new derivatives of GA were prepared from GA or 17-substituted GA Purity and authenticity of new compounds were confirmed with NMR, MS and HPLC. The new derivatives of GA were evaluated for invitro cytotoxicity against MX-1 (human mammary carcinoma), HT29 (colon), HepG2 (hepatoma), HCT116 (colon), and 3T3 (fibroblast). Hsp90 binding affinity of the new GA derivatives was evaluated using a competitive Hsp90α fluorescence polarization binding assay. Nanoparticle albumin bound (nab) forms of 17AAG and the novel compounds were prepared for further invivo studies. Results: More than forty new derivatives of GA were prepared from either GA or 17-substituted GA in 50-80% yield. All of derivatives were obtained in single E isomers. Some of the prepared derivatives showed significantly increased cytotoxicity compared to 17-AAG. For example, ABI328 (IC50 = 0.11 μM and 0.13 μM) exhibited more potent activity than 17-AAG (IC50 = 1.7 μM and 9.4 μM ) on MX-1 and HCT116 respectively; ABI287 (IC50=1.66 μM) was more active than 17-AAG (IC50 = 142 μM) against HT29. Some of the new derivatives of GA retained similar binding affinities to Hsp90 in comparison to 17-AAG. Nanoparticle nab-17AAG and nab-ABI328 were successfully prepared. . Conclusion: We have successfully prepared a series of geldanamycin derivatives, some of which exhibit higher cytotoxic activities and comparable Hsp90 affinities in comparison to 17-AAG. Nanoparticle (nab) versions of 17AAG and the novel compounds were successfully prepared. The evaluation of antitumor activity of ABI328 and ABI287 in xenograft models is in progress.