title: Farnesyltransferase inhibitors: CAAX mimetics based on different biaryl scaffolds.
abstract: Mimetics of the C-terminal CAAX tetrapeptide of Ras protein were designed as farnesyltransferase (FTase) inhibitors (FTIs) by replacing AA with o-aryl or o-heteroaryl substituted p-hydroxy- or p-aminobenzoic acid, while maintaining the replacement of C with 1,4-benzodioxan-2-ylmethyl or 2-amino-4-thiazolylacetyl residue as in previous CAAX mimetics. Both FTase inhibition and antiproliferative effect were showed by two thiazole derivatives, namely those with 1-naphthyl (10 and 10a) or 3-furanyl (15 and 15a) in the central spacer, and by the benzodioxane derivative with 2-thienyl (6 and 6a) in the same position. Accumulation of unprenylated RAS was demonstrated in cells incubated with 15a. Consistently with FTIs literature, such results delineate the biaryl scaffold not only as a spacer but also as a sensible area of these mimetic molecules, where modifications at the branching aromatic ring are not indifferent and should be matter of further investigation.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Milano, via Mangiagalli 25, I-20133 Milano, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Straniero
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Milano, via Mangiagalli 25, I-20133 Milano, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Pallavicini
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Milano, via Mangiagalli 25, I-20133 Milano, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Chiodini
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Milano, via Mangiagalli 25, I-20133 Milano, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Ruggeri
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Milano, via Mangiagalli 25, I-20133 Milano, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Fumagalli
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Milano, via Mangiagalli 25, I-20133 Milano, Italy.
authors.forename: Cristiano
authors.initials: C
authors.lastname: Bolchi
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, via Balzaretti 9, I-20133 Milano, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Corsini
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, via Balzaretti 9, I-20133 Milano, Italy; Multimedica IRCCS, Milano, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Ferri
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, via Balzaretti 9, I-20133 Milano, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Ricci
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Milano, via Mangiagalli 25, I-20133 Milano, Italy. Electronic address: ermanno.valoti@unimi.it.
authors.forename: Ermanno
authors.initials: E
authors.lastname: Valoti
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D018716:Molecular Mimicry; D015394:Molecular Structure; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D009842:Oligopeptides; D013844:Thiazoles; D051231:Farnesyltranstransferase
keywords: 2-Aminothiazole; Benzodioxane; FTase inhibitor; Mimetic; RAS protein