title: Variously substituted (phosphonoacetamido)oxy analogues of geranylgeranyl diphosphate (GGdP) as GGdP-transferase (GGTase) inhibitors and antiproliferative agents.
abstract: Aberrant signalling through the pathways of small GTP-binding proteins, belonging to the Ras superfamily (Ras, Rho, Rac, Cdc42 etc.), occurs in several types of cancer, where mutated Ras accumulates in its GTP-bound active form and causes uncontrolled cell proliferation. For these reasons, molecules able to target the Ras pathway in any of its stages are potentially useful in anti-cancer therapies. Inhibition of farnesyl-protein transferase (FTase), the enzyme that post-translationally activates Ras, has been pursued for the obvious role of the Ras oncoprotein in human malignancies. It was later found that some mutated forms of Ras (K- and N-Ras) can also be geranylgeranylated by geranylgeranyl-protein transferase (GGTase) when FTase is blocked, circumventing the antiproliferative effects of FTase inhibitors. Therefore, a new task has been the search for new GGTase inhibitors, which can also interfere on cell proliferation by blocking the isoprenylation of other Ras superfamily proteins (i.e. Rho, Rac, Cdc42) involved in the regulation of cell cycle progression. We have recently described a series of phosphonoacetamido- and phosphonoacetamidoxy-stable analogues of geranylgeranyl-diphosphate (GGdP) possessing good GGTase inhibitory properties and, some of them, also remarkable GGTase/FTase selectivity levels. We have now extended this series to a larger number of variously substituted phosphonoacetamidoxy-analogues of GGdP in order to establish the effect on GGTase inhibitory activity and selectivity due to the presence of different substituents in the polar portion of these GGdP mimics. We have also measured the cytotoxicity of these compounds on tumour cell lines with the aim of evaluating their potential anti-proliferative effects.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Minutolo
authors.forename: Valentina
authors.initials: V
authors.lastname: Asso
authors.forename: Simone
authors.initials: S
authors.lastname: Bertini
authors.forename: Laura
authors.initials: L
authors.lastname: Betti
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Ciriaco
authors.forename: Romano
authors.initials: R
authors.lastname: Danesi
authors.forename: Gianbattista
authors.initials: G
authors.lastname: Gervasi
authors.forename: Elisa
authors.initials: E
authors.lastname: Ghilardi
authors.forename: Elisa
authors.initials: E
authors.lastname: Giovanetti
authors.forename: Gino
authors.initials: G
authors.lastname: Giannaccini
authors.forename: Giorgio
authors.initials: G
authors.lastname: Placanica
authors.forename: Giovanni
authors.initials: G
authors.lastname: Prota
authors.forename: Simona
authors.initials: S
authors.lastname: Rapposelli
authors.forename: Marco
authors.initials: M
authors.lastname: Macchia
mesh_terms: D000081:Acetamides / Q000737:chemistry; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004224:Diterpenes / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D009943:Organophosphorus Compounds / Q000737:chemistry; D011106:Polyisoprenyl Phosphates / Q000737:chemistry*
chemical_list: D000081:Acetamides; D000970:Antineoplastic Agents; D004224:Diterpenes; D004791:Enzyme Inhibitors; D009943:Organophosphorus Compounds; D011106:Polyisoprenyl Phosphates; C008887:phosphon; C030686:acetamide; D051231:Farnesyltranstransferase; C002963:geranylgeranyl pyrophosphate