Synthesis of fluorescently tagged isoprenoid bisphosphonates that inhibit protein geranylgeranylation

• 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
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2007.01.002

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.