Discovery and preliminary structure–activity relationship studies on tecomaquinone I and tectol as novel farnesyltransferase and plasmodial inhibitors. Issue 14 (15th July 2016)

• Record Type: Journal Article
• Authors: Cadelis, Melissa M.; Bourguet-Kondracki, Marie-Lise; Dubois, Joëlle; Valentin, Alexis; Barker, David; Copp, Brent R.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 14(2016)
• Page Start: 3102
• Page End: 3107
• Publication Date: 2016-07-15
• Subjects: VYNGZASNGVAOMT-UHFFFAOYSA-N -- FVTJXDIACKJEPH-UHFFFAOYSA-N -- HYLGGIUWJAJQJB-UHFFFAOYSA-N -- DWAGHTAECLYWCT-WNAAXNPUSA-N -- QONRUBHKACJNHR-UHFFFAOYSA-N -- AMIIUBKFJIKNDJ-UHFFFAOYSA-N -- XCQUMLRJBMLRSM-ZXNSPXPDSA-N -- RDQOOZOSOQUKJT-JTOYJDTJSA-N -- IKBLDYRKOHGRGM-YBFXNURJSA-N -- GNKHZLCLDITUKE-UHFFFAOYSA-N -- YRLLMZGITSQOAZ-UHFFFAOYSA-N -- NQVBCGTZRWHVSY-UHFFFAOYSA-N -- CFNTYPNQFGENAH-LFVJCYFKSA-N -- SZRIUQOLPCIHRA-GKTLAHRSSA-N -- YGNPHNOMVBPITA-VCHYOVAHSA-N; Tecomaquinone I -- Natural product -- Dimerization -- FTase inhibitor -- Anti-plasmodial; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.05.024
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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 ± 0.004 μM) 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 ± 0.20 μM. 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.