1. ω-Hydroxy isoprenoid bisphosphonates as linkable GGDPS inhibitors.
- Author
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Bhuiyan NH, Varney ML, Bhattacharya DS, Payne WM, Mohs AM, Holstein SA, and Wiemer DF
- Subjects
- Antineoplastic Agents chemistry, Apoptosis, Cell Proliferation, Enzyme Inhibitors chemistry, Humans, Models, Molecular, Molecular Structure, Multiple Myeloma enzymology, Multiple Myeloma pathology, Protein Prenylation, Structure-Activity Relationship, Tumor Cells, Cultured, Antineoplastic Agents pharmacology, Diphosphonates chemistry, Enzyme Inhibitors pharmacology, Farnesyltranstransferase chemistry, Multiple Myeloma drug therapy, Terpenes chemistry
- Abstract
The enzyme geranylgeranyl diphosphate synthase (GGDPS) is a potential therapeutic target for multiple myeloma. Malignant plasma cells produce and secrete large amounts of monoclonal protein, and inhibition of GGDPS results in disruption of protein geranylgeranylation which in turn impairs intracellular protein trafficking. Our previous work has demonstrated that some isoprenoid triazole bisphosphonates are potent and selective inhibitors of GGDPS. To explore the possibility of selective delivery of such compounds to plasma cells, new analogues with an ω-hydroxy group have been synthesized and examined for their enzymatic and cellular activity. These studies demonstrate that incorporation of the ω-hydroxy group minimally impairs GGDPS inhibitory activity. Furthermore conjugation of one of the novel ω-hydroxy GGDPS inhibitors to hyaluronic acid resulted in enhanced cellular activity. These results will allow future studies to focus on the in vivo biodistribution of HA-conjugated GGDPS inhibitors., (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- Published
- 2019
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