title: Synthesis and evaluation of Apogossypol atropisomers as potential Bcl-xL antagonists.
abstract: Anti-apoptotic Bcl-2 family proteins such as Bcl-2 and Bcl-X(L) have been recently validated as targets for the discovery of novel anti-cancer agents. We previously reported that racemic (+/-) Apogossypol, a semi-synthetic compound derived from the natural product Gossypol, binds and inhibits Bcl-2 and Bcl-X(L)in vitro and in cell. Given that (+) and (-) Gossypol display different proapoptotic activities, here we report on the synthesis of (+) and (-) Apogossypol and the evaluation of their in vitro and cellular activity.
authors.affiliation: Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Wei
authors.forename: Michele F
authors.initials: MF
authors.lastname: Rega
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kitada
authors.forename: Hongbin
authors.initials: H
authors.lastname: Yuan
authors.forename: Dayong
authors.initials: D
authors.lastname: Zhai
authors.forename: Prabhakar
authors.initials: P
authors.lastname: Risbood
authors.forename: Herbert H
authors.initials: HH
authors.lastname: Seltzman
authors.forename: Charles E
authors.initials: CE
authors.lastname: Twine
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pellecchia
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005454:Fluorescence Polarization; D006072:Gossypol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D013237:Stereoisomerism; D051020:bcl-X Protein / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; C492806:apogossypol; D051020:bcl-X Protein; D006072:Gossypol
references.citation: Oncogene. 1998 Dec 24;17(25):3225-36
references.pmid: 9916985
references.citation: Cancer Lett. 1999 Jan 29;135(2):171-80
references.pmid: 10096426
references.citation: Cell. 2002 Jan 25;108(2):153-64
references.pmid: 11832206
references.citation: J Clin Oncol. 1999 Sep;17(9):2941-53
references.pmid: 10561374
references.citation: Biochem Pharmacol. 2003 Jul 1;66(1):93-103
references.pmid: 12818369
references.citation: Nat Cell Biol. 2001 Feb;3(2):173-82
references.pmid: 11175750
references.citation: Chem Biol. 2004 Mar;11(3):389-95
references.pmid: 15123268
references.citation: Adv Pharmacol. 1997;41:501-32
references.pmid: 9204157
references.citation: J Pharm Biomed Anal. 2006 Nov 16;42(5):581-6
references.pmid: 16859853
references.citation: Proc Natl Acad Sci U S A. 2000 Jun 20;97(13):7124-9
references.pmid: 10860979
references.citation: J Mol Graph. 1994 Jun;12(2):98-105
references.pmid: 7918258
references.citation: J Med Chem. 2003 Sep 25;46(20):4259-64
references.pmid: 13678404
references.citation: Nat Rev Drug Discov. 2002 Feb;1(2):111-21
references.pmid: 12120092
references.citation: Science. 1998 Aug 28;281(5381):1322-6
references.pmid: 9735050
references.citation: J Mol Biol. 1997 Apr 4;267(3):727-48
references.pmid: 9126849
references.citation: Science. 1997 Feb 14;275(5302):983-6
references.pmid: 9020082
references.citation: J Comput Aided Mol Des. 1997 Sep;11(5):425-45
references.pmid: 9385547
references.citation: Blood. 2008 Mar 15;111(6):3211-9
references.pmid: 18202226
references.citation: J Med Chem. 2006 Oct 19;49(21):6139-42
references.pmid: 17034116
references.citation: Semin Hematol. 1998 Jul;35(3 Suppl 3):3-13
references.pmid: 9685174
references.citation: Genes Dev. 1999 Aug 1;13(15):1899-911
references.pmid: 10444588
references.citation: Exp Biol Med (Maywood). 2002 Jun;227(6):398-401
references.pmid: 12037129