title: A-ring oxygenation modulates the chemistry and bioactivity of caged Garcinia xanthones.
abstract: Natural products of the caged Garcinia xanthones (CGX) family are characterized by a unique chemical structure, potent bioactivities and promising pharmacological profiles. We have developed a Claisen/Diels-Alder reaction cascade that, in combination with a Pd(0)-catalyzed reverse prenylation, provides rapid and efficient access to the CGX pharmacophore, represented by the structure of cluvenone. To further explore this pharmacophore, we have synthesized various A-ring oxygenated analogues of cluvenone and have evaluated their bioactivities in terms of growth inhibition, mitochondrial fragmentation, induction of mitochondrial-dependent cell death and Hsp90 client inhibition. We found that installation of an oxygen functionality at various positions of the A-ring influences significantly both the site-selectivity of the Claisen/Diels-Alder reaction and the bioactivity of these compounds, due to remote electronic effects.
authors.affiliation: Department of Chemistry & Biochemistry, University of California, San Diego, La Jolla, CA 92093-0358, USA.
authors.forename: Kristyna M
authors.initials: KM
authors.lastname: Elbel
authors.forename: Gianni
authors.initials: G
authors.lastname: Guizzunti
authors.forename: Maria A
authors.initials: MA
authors.lastname: Theodoraki
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.forename: Ayse
authors.initials: A
authors.lastname: Batova
authors.forename: Marianna
authors.initials: M
authors.lastname: Dakanali
authors.forename: Emmanuel A
authors.initials: EA
authors.lastname: Theodorakis
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D029760:Garcinia / Q000737:chemistry*; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000187:drug effects; D015394:Molecular Structure; D010100:Oxygen / Q000737:chemistry*; D013329:Structure-Activity Relationship; D044004:Xanthones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D044004:Xanthones; C052659:gambogic acid; D010100:Oxygen
references.citation: Nature. 2011 Jul 20;475(7356):324-32
references.pmid: 21776078
references.citation: Invest New Drugs. 2012 Oct;30(5):1841-8
references.pmid: 21898184
references.citation: Chemistry. 2010 Sep 3;16(33):9944-62
references.pmid: 20648491
references.citation: Mol Cancer Ther. 2008 Jun;7(6):1639-46
references.pmid: 18566235
references.citation: Bioessays. 2004 Aug;26(8):882-93
references.pmid: 15273990
references.citation: Nature. 2003 Sep 25;425(6956):407-10
references.pmid: 14508491
references.citation: Angew Chem Int Ed Engl. 2001 Nov 19;40(22):4264-4268
references.pmid: 29712093
references.citation: Org Biomol Chem. 2007 Feb 7;5(3):494-500
references.pmid: 17252132
references.citation: J Nat Prod. 2011 Mar 25;74(3):460-3
references.pmid: 21067206
references.citation: Cancer Discov. 2012 Dec;2(12):1134-49
references.pmid: 22993403
references.citation: Drug Discov Today. 2012 Mar;17(5-6):242-52
references.pmid: 22245656
references.citation: J Am Chem Soc. 2004 May 5;126(17):5493-501
references.pmid: 15113221
references.citation: Nat Rev Cancer. 2005 Oct;5(10):761-72
references.pmid: 16175177
references.citation: Org Lett. 2006 Jul 6;8(14):2989-92
references.pmid: 16805534
references.citation: J Nat Prod. 2011 May 27;74(5):1085-92
references.pmid: 21486005
references.citation: Annu Rev Biochem. 2006;75:271-94
references.pmid: 16756493
references.citation: Bioorg Med Chem. 2008 Apr 15;16(8):4233-41
references.pmid: 18337106
references.citation: J Ethnopharmacol. 2008 May 22;117(3):433-8
references.pmid: 18384990
references.citation: Biochem Pharmacol. 2008 Mar 1;75(5):1083-92
references.pmid: 18070617
references.citation: World J Gastroenterol. 2005 Jun 28;11(24):3655-9
references.pmid: 15968715
references.citation: Curr Med Chem. 2009;16(28):3775-96
references.pmid: 19747141
references.citation: Int J Dermatol. 2009 Feb;48(2):186-92
references.pmid: 19200201
references.citation: Cancer Lett. 2007 Oct 28;256(2):259-66
references.pmid: 17693016
references.citation: Drug Chem Toxicol. 2010;33(1):88-96
references.pmid: 20001662
references.citation: Angew Chem Int Ed Engl. 2003 Sep 15;42(35):4225-9
references.pmid: 14502742
references.citation: J Proteomics. 2012 Jun 6;75(10):2790-802
references.pmid: 22236519
references.citation: Basic Clin Pharmacol Toxicol. 2006 Aug;99(2):178-84
references.pmid: 16918721
references.citation: Chembiochem. 2012 May 29;13(8):1191-8
references.pmid: 22532297
references.citation: Cell Death Differ. 1999 Feb;6(2):99-104
references.pmid: 10200555
references.citation: Pharmacol Ther. 2004 Mar;101(3):227-57
references.pmid: 15031001
references.citation: Planta Med. 2002 Mar;68(3):198-203
references.pmid: 11914953
references.citation: Drug Discov Today. 2008 Jan;13(1-2):38-43
references.pmid: 18190862
references.citation: Bioorg Med Chem. 2004 Jan 15;12(2):309-17
references.pmid: 14723951
references.citation: Proc Natl Acad Sci U S A. 2004 Aug 17;101(33):12030-5
references.pmid: 15210986
references.citation: Int Immunopharmacol. 2008 Nov;8(11):1493-502
references.pmid: 18573352
references.citation: Org Biomol Chem. 2009 Dec 7;7(23):4886-94
references.pmid: 19907779
references.citation: Biochem Biophys Res Commun. 2010 Dec 17;403(3-4):282-7
references.pmid: 21074517
references.citation: Exp Cell Res. 2012 Jul 1;318(11):1213-20
references.pmid: 22406265
references.citation: Angew Chem Int Ed Engl. 2005 Jan 21;44(5):756-61
references.pmid: 15657969
references.citation: Org Lett. 2003 May 1;5(9):1491-4
references.pmid: 12713306
references.citation: Cell. 2007 Oct 5;131(1):121-35
references.pmid: 17923092
references.citation: Annu Rev Biochem. 2011;80:1055-87
references.pmid: 21456965
references.citation: Eur J Med Chem. 2009 Jun;44(6):2611-20
references.pmid: 18996626
references.citation: Biochim Biophys Acta. 2012 Mar;1823(3):742-55
references.pmid: 22062686
references.citation: Anticancer Agents Med Chem. 2009 Jan;9(1):77-98
references.pmid: 19149484
references.citation: Org Biomol Chem. 2003 Dec 21;1(24):4418-22
references.pmid: 14727628
references.citation: Nat Rev Mol Cell Biol. 2010 Jul;11(7):515-28
references.pmid: 20531426
references.citation: Org Lett. 2002 Mar 21;4(6):909-12
references.pmid: 11893183