P114: Generation of Glycosylated Non-Benzoquinone Geldanamycin Analogs using in vitro Enzymatic Reaction

Heat shock protein 90 (Hsp90) is emerging as an important target in cancer therapeutics and several other diseases. Hsp90 is effectively inhibited by benzoquinone ansamycins such as geldanamycin (GM) and its C17-aminated derivatives, which bind to the ATP binding site in the N-terminal domain. However, its potential clinical utility is hampered by its severe toxicity and poor water solubility. These first-generation Hsp90 inhibitors all share a common unfavorable structural feature: the benzoquinone toxicophore. Recently, we reported the development of non-benzoquinone GM analogs using a mutasynthetic approach and rational biosynthetic method. However, these non-benzoquinone GM analogs still have formulation problems that predominantly result from their extremely low solubility and, to a lesser extent, their cancer selectivity. Our hypothesis is that the bulky glucose structure might be able to enhance the drug solubility for formulation of clinical applications. Glycosyltransferases are an important class of enzyme and are essential for the biosynthesis of glycosylated natural products because they catalyze the attachment of a sugar to an aglycon. Here, we report the facile production of glucose conjugated non-benzoquinone GM analogs using Bacillus glycosyltransferase BL-C. Putative glucoside compounds were evidenced through the presence of product peak(s) via in vitro glycosylation reaction and were also verified using LC/MS analyses. These glucoside compounds exhibited dramatic improvement of the solubility compared with the original aglycon, non-benzoquinone GM. (Supported by grants from KRIBB Research Initiative Program, Global Frontier Project (NRF) and Next-Generation BioGreen 21 Program (RDA, Republic of Korea))