title: Novel route to chaetomellic acid A and analogues: serendipitous discovery of a more competent FTase inhibitor.
abstract: A new practical route to chaetomellic acid A (ACA), based on the copper catalysed radical cyclization (RC) of (Z)-3-(2,2-dichloropropanoyl)-2-pentadecylidene-1,3-thiazinane, is described. Remarkably, the process entailed: (i) a one-pot preparation of the intermediate N-α-perchloroacyl-2-(Z)-alkyliden-1,3-thiazinanes starting from N-(3-hydroxypropyl)palmitamide, (ii) a two step smooth transformation of the RC products into ACA and (iii) only one intermediate chromatographic purification step. The method offers a versatile approach to the preparation of ACA analogues, through the synthesis of an intermediate maleic anhydride with a vinylic group at the end of the aliphatic tail, a function that can be transformed through a thiol-ene coupling. Serendipitously, the disodium salt of 2-(9-(butylthio)nonyl)-3-methylmaleic acid, that we prepared as a representative sulfurated ACA analogue, was a more competent FTase inhibitor than ACA. This behaviour was analysed by a molecular docking study.
authors.affiliation: Dipartimento di Scienze Chimiche e Geologiche, Università degli Studi di Modena, Via Campi 183, I-40125 Modena, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Bellesia
authors.forename: Seoung-ryoung
authors.initials: SR
authors.lastname: Choi
authors.forename: Fulvia
authors.initials: F
authors.lastname: Felluga
authors.forename: Giuliano
authors.initials: G
authors.lastname: Fiscaletti
authors.forename: Franco
authors.initials: F
authors.lastname: Ghelfi
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Menziani
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Parsons
authors.forename: C Dale
authors.initials: CD
authors.lastname: Poulter
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Roncaglia
authors.forename: Massimo
authors.initials: M
authors.lastname: Sabbatini
authors.forename: Domenico
authors.initials: D
authors.lastname: Spinelli
mesh_terms: D000818:Animals; D002384:Catalysis; D003300:Copper / Q000737:chemistry; D003500:Cyclization; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008298:Maleates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D051381:Rats; D015003:Yeasts / Q000201:enzymology
chemical_list: D004791:Enzyme Inhibitors; D008298:Maleates; C080569:chaetomellic acid A; D003300:Copper; D051231:Farnesyltranstransferase