title: Discovery and preliminary structure-activity relationship studies on tecomaquinone I and tectol as novel farnesyltransferase and plasmodial inhibitors.
abstract: Biological screening of a library of synthesized benzo[c]chromene-7,10-dione natural products against human farnesyltransferase (FTase) has identified tecomaquinone I (IC50 of 0.065±0.004μM) as being one of the more potent natural product inhibitors identified to date. Anti-plasmodial screening of the same library against a drug-resistant strain of Plasmodium falciparum identified the structurally-related dichromenol tectol as a moderately active growth inhibitor with an IC50 3.44±0.20μM. Two novel series of analogues, based on the benzo[c]chromene-7,10-dione scaffold, were subsequently synthesized, with one analogue exhibiting farnesyltransferase inhibitory activity in the low micromolar range. A preliminary structure-activity relationship (SAR) study has identified different structural requirements for anti-malarial activity in comparison to FTase activities for these classes of natural products. Our results identify tecomaquinone I as a novel scaffold from which more potent inhibitors of human and parasitic FTase could be developed.
authors.affiliation: School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Cadelis
authors.affiliation: Laboratoire Molécules de Communication et Adaptation des Micro-organismes, UMR 7245 CNRS, Muséum National d'Histoire Naturelle, 57 rue Cuvier (C.P. 54), 75005 Paris, France.
authors.forename: Marie-Lise
authors.initials: ML
authors.lastname: Bourguet-Kondracki
authors.affiliation: Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Centre de Recherche de Gif, Avenue de la Terrasse, 91198 Gif sur Yvette Cedex, France.
authors.forename: Joëlle
authors.initials: J
authors.lastname: Dubois
authors.affiliation: Université de Toulouse, PHARMA-DEV, UMR 152 IRD-UPS, UPS, 118 Route de Narbonne, F-31062 Toulouse Cedex 9, France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Valentin
authors.affiliation: School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: David
authors.initials: D
authors.lastname: Barker
authors.affiliation: School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. Electronic address: b.copp@auckland.ac.nz.
authors.forename: Brent R
authors.initials: BR
authors.lastname: Copp
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology; D011714:Pyrans / Q000737:chemistry / Q000494:pharmacology*; D013057:Spectrum Analysis / Q000379:methods; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D004791:Enzyme Inhibitors; D006576:Heterocyclic Compounds, 4 or More Rings; D011714:Pyrans; C502974:tecomaquinone I; C053744:tectol; D051231:Farnesyltranstransferase
keywords: Anti-plasmodial; Dimerization; FTase inhibitor; Natural product; Tecomaquinone I