title: Umbelliferone aminoalkyl derivatives, a new class of squalene-hopene cyclase inhibitors.
abstract: The synthesis is described of several aminoalkyl derivatives of coumarin, obtained in good yields under microwave or high-intensity ultrasound irradiation. These compounds proved uniformly active as inhibitors of squalene-hopene cyclase (SHC) from Alicyclobacillus acidocaldarius. Their design stemmed from our recent finding that the umbelliferone nucleus acquires inhibitory properties towards SHC when functionalized with a suitable chain such as the omega-epoxyfarnesyl group. Under our experimental conditions the most active ones, such as 7-(4'-allylmethylamino-but-2-ynyloxy)chromen-2-one (IC(50) 0.75 mM), approached the potency of anticholesteremic drug Ro 48-8071 (IC(50) 0.35 mM), an effective inhibitor of both squalene- and oxidosqualene-cyclases (OSC). Tests are in progress to determine their efficacy on different eukaryotic OSCs.
authors.affiliation: Dip. to di Scienza e Tecnologia del Farmaco, Università di Torino, via Giuria 9, 10125 Turin, Italy. giancarlo.cravotto@unito.it
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Cravotto
authors.forename: Gianni
authors.initials: G
authors.lastname: Balliano
authors.forename: Silvia
authors.initials: S
authors.lastname: Tagliapietra
authors.forename: Giovanni
authors.initials: G
authors.lastname: Palmisano
authors.forename: Andrea
authors.initials: A
authors.lastname: Penoni
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents; D001406:Bacillaceae / Q000201:enzymology; D001577:Benzophenones / Q000494:pharmacology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D019751:Intramolecular Transferases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008099:Liver; D013185:Squalene / Q000378:metabolism; D013552:Swine; D014468:Umbelliferones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000924:Anticholesteremic Agents; D001577:Benzophenones; D004791:Enzyme Inhibitors; D014468:Umbelliferones; C105726:Ro 48-8071; D013185:Squalene; D019751:Intramolecular Transferases; C066630:squalene-hopene cyclase; C021924:lanosterol synthase