Journal article
Impact of fixed phosphorus position on activity of triazole bisphosphonates as geranylgeranyl diphosphate synthase inhibitors
Bioorganic & medicinal chemistry, Vol.122, 118140
02/26/2025
DOI: 10.1016/j.bmc.2025.118140
PMCID: PMC12090098
PMID: 40043324
Abstract
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•Complex structure–function relationship of isoprenoid triazole-based GGDPS inhibitors.•Fixed phosphorus position impacts both enzymatic and cellular potency.•Studies suggest specific membrane transporters mediate inhibitor uptake.
Geranylgeranyl diphosphate synthase (GGDPS) produces the 20-carbon isoprenoid species used in protein geranylgeranylation reactions. Inhibition of GGDPS has emerged as a novel means of disrupting the activity of geranylgeranylated proteins in cancers such as myeloma and osteosarcoma. We have focused on developing a series of isoprenoid triazole bisphosphonate-based GGDPS inhibitors, demonstrating a complex structure–activity relationship (SAR), not only at the enzymatic level, but also at the cellular and whole organism levels. To further investigate this SAR, we have prepared a family of novel derivatives that have a fixed phosphorus position by virtue of vinyl, epoxide or cyclopropyl groups that incorporate the α-carbon position. Additional modifications include compounds with citronellyl chains instead of homogeranyl or homoneryl chains. All new compounds were evaluated in GGDPS enzyme assays and in cellular assays involving a panel of human myeloma and osteosarcoma cell lines. The homocitronellyl derivatives displayed markedly reduced activity in both enzymatic and cellular assays. While all of the homogeranyl/homoneryl vinyl/epoxide/cyclopropyl compounds had relatively similar activity in the enzyme assay (IC50’s 0.37–2.87 μM), the cellular potencies varied more dramatically (ranging from 10 nM to no activity at 100 μM), depending on the olefin stereochemistry, the specific α-carbon modification and the tumor cell type. These findings, coupled with POM-prodrug and membrane permeability studies, support the hypothesis that there are specific membrane transporters mediating cellular uptake of these GGDPS inhibitors. Future studies focused on the identification of the membrane transporters responsible for the cellular uptake will enable further understanding of this complex SAR.
Details
- Title: Subtitle
- Impact of fixed phosphorus position on activity of triazole bisphosphonates as geranylgeranyl diphosphate synthase inhibitors
- Creators
- Md Ayub Ali - University of Iowa, ChemistryMona A. Maalouf - University of IowaDan Feng - University of Nebraska Medical CenterMamunur Rashid - University of Nebraska Medical CenterNathaniel R. Gehrke - University of IowaYashpal S. Chhonker - University of Nebraska Medical CenterDaryl J. Murry - University of Nebraska Medical CenterDavid F. Wiemer - University of IowaSarah A. Holstein - University of Nebraska Medical Center
- Resource Type
- Journal article
- Publication Details
- Bioorganic & medicinal chemistry, Vol.122, 118140
- DOI
- 10.1016/j.bmc.2025.118140
- PMID
- 40043324
- PMCID
- PMC12090098
- NLM abbreviation
- Bioorg Med Chem
- ISSN
- 0968-0896
- eISSN
- 1464-3391
- Publisher
- Elsevier Ltd
- Grant note
- National Institutes of Health: R01 CA258621, P30 CA036727
Funding This work was supported by the National Institutes of Health (R01 CA258621 and P30 CA036727) .
- Language
- English
- Date published
- 02/26/2025
- Academic Unit
- General University College; Chemistry; Holden Comprehensive Cancer Center
- Record Identifier
- 9984797929902771
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