Stable propylphosphonic acid analogues of geranylgeranyl diphosphate possessing inhibitory activity on geranylgeranyl protein transferase

Minutolo, Filippo; Asso, Valentina; Bertini, Simone; Betti, Laura; Gervasi, G.B.; Ghilardi, Elisa; Giannaccini, Gino; Placanica, Giorgio; Prota, Giovanni; Rapposelli, Simona; Macchia, Marco

doi:10.1016/j.farmac.2004.06.003

Cited by 4 publications

(2 citation statements)

References 16 publications

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“…To prepare the PtdIns(4)P-MP analogues (Figure 1, top panel), the Bz group was then removed to provide the 1- O -( tert -butyldiphenylsilyl)-2,3,5,6- O-tetrakis -(methoxymethylene)- myo -inositol ( 3 ). Installation of the methylenephosphonate group started with the synthesis of dimethyl phosphonomethyltriflate (Hamilton and Roberts, 1999; Phillion and Andrew, 1986), which was coupled with compound 3 using n -BuLi (Minutolo, et al, 2004). The TBDPS group was removed by treating intermediate 4 with Bu 4 NF·H 2 O, and compound 5 was produced in high yield (95%).…”

Section: Resultsmentioning

confidence: 99%

Metabolically Stabilized Derivatives of Phosphatidylinositol 4-Phosphate: Synthesis and Applications

He¹,

Gajewiak²,

Scott³

et al. 2011

Chemistry & Biology

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Summary Phosphatidylinositol-4-phosphate (PtdIns(4)P) is an essential component of eukaryotic membranes and a marker of the Golgi complex. The pivotal role of PtdIns(4)P in signaling and trafficking necessitates the development of synthetic derivatives of this lipid that are resistant to hydrolysis and therefore can be used in biochemical, structural and functional assays to monitor time-dependent processes at the Golgi membranes. Here, we developed novel metabolically stabilized (ms) analogues of the PtdIns(4)P lipid and the inositol 1,4-bisphosphate (IP2) head group derivative suitable for outfitting with a reporter tag and demonstrated that these compounds can substitute the natural lipid in peripheral protein recruitment and membrane deformation. The methylenephosphonate (MP) and phosphorothioate (PT) analogues of PtdIns(4)P and the aminohexyl (AH)-IP2 probe are recognized by the PtdIns(4)P-specific PH domain of four phosphate adaptor protein 1 (FAPP1). Binding of FAPP1 to the PtdIns(4)P derivatives stimulates insertion of the PH domain into the lipid layers and induces tubulation of membranes. Both ms-analogues and IP2-probes could be invaluable for identifying novel protein effectors and characterizing and monitoring PtdIns(4)P-dependent signaling cascades within the trans-Golgi network (TGN).

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Section: Resultsmentioning

confidence: 99%

Metabolically Stabilized Derivatives of Phosphatidylinositol 4-Phosphate: Synthesis and Applications

He¹,

Gajewiak²,

Scott³

et al. 2011

Chemistry & Biology

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“…Phosphorus-containing cyclopropanes are an important class of compounds with great potential for both medicinal chemistry and organic synthesis. Thus, derivatives of cyclopropylphosphonic acid make attractive targets for drug discovery, as they are omnipresent among biologically active compounds including antiproliferative, antiviral, and antimalarial agents. Phosphorylated cyclopropanes also hold great promise as potential selective herbicides .…”

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confidence: 99%