Synthesis of fluorescently tagged isoprenoid bisphosphonates that inhibit protein geranylgeranylation

Geminal bisphosphonates can be used for a variety of purposes in human disease including reduction of bone resorption in osteoporosis, treatment of fractures associated with malignancies of the prostate, breast, and lung, and direct anticancer activity against bone marrow derived malignancies. Previ...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2007-03, Vol.15 (5), p.1959-1966
Main Authors: Maalouf, Mona A., Wiemer, Andrew J., Kuder, Craig H., Hohl, Raymond J., Wiemer, David F.
Format: Article
Language:English
Subjects:
Anthranilate
Biological and medical sciences
Bisphosphonate
Blotting, Western
Diphosphonates - chemical synthesis
Diphosphonates - chemistry
Diterpenes - chemistry
Fluorescence
Fluorescent Dyes - chemistry
Humans
Isoprenoid
K562 Cells
Magnetic Resonance Spectroscopy
Medical sciences
Microscopy, Fluorescence
Miscellaneous
Pharmacology. Drug treatments
Polyisoprenyl Phosphates - chemistry
Protein prenylation
Proteins - chemistry
Spectrometry, Mass, Electrospray Ionization
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Summary:Geminal bisphosphonates can be used for a variety of purposes in human disease including reduction of bone resorption in osteoporosis, treatment of fractures associated with malignancies of the prostate, breast, and lung, and direct anticancer activity against bone marrow derived malignancies. Previous research led to identification of some novel isoprenoid bisphosphonates that inhibit geranylgeranyl pyrophosphate (GGPP) synthesis and diminish protein geranylgeranylation. Described here is the synthesis of fluorescent anthranilate analogues of the most active isoprenoid bisphosphonates and examine their ability to impact post-translational processing of the small GTPases Ras, Rap1a, and Rab6. Similar to their non-fluorescent counterparts, some of these fluorescent isoprenoid bisphosphonates diminish protein geranylgeranylation. Their biological activity and fluorescent character suggest that they may be useful in studies of bisphosphonate localization both in cultured cells and in whole organisms.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2007.01.002