Design, synthesis, and biological evaluation of a biyouyanagin compound library.
Modern drug discovery efforts rely, to a large extent, on lead compounds from two classes of small organic molecules; namely, natural products (i.e., secondary metabolites) and designed compounds (i.e., synthetic molecules). In this article, we demonstrate how these two domains of lead compounds can be merged through total synthesis and molecular design of analogs patterned after the targeted natural products, whose promising biological properties provide the motivation. Specifically, the present study targeted the naturally occurring biyouyanagins A and B and their analogs through modular chemical synthesis and led to the discovery of small organic molecules possessing anti-HIV and anti-arenavirus properties.
Department of Chemistry, Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. kcn@scripps.edu
K C
KC
Nicolaou
Silvano
S
Sanchini
David
D
Sarlah
Gang
G
Lu
T Robert
TR
Wu
Daniel K
DK
Nomura
Benjamin F
BF
Cravatt
Beatrice
B
Cubitt
Juan C
JC
de la Torre
Ann J
AJ
Hessell
Dennis R
DR
Burton
D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001117:Arenaviridae Infections / Q000188:drug therapy; D018050:Arenavirus; D002460:Cell Line; D006678:HIV; D015658:HIV Infections / Q000188:drug therapy; D006801:Humans; D015394:Molecular Structure; D012717:Sesquiterpenes / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology
D019380:Anti-HIV Agents; D012717:Sesquiterpenes; D013141:Spiro Compounds; C509583:biyouyanagin A; C544053:biyouyanagin B
Nat Rev Immunol. 2006 May;6(5):343-57
16622479
Cell. 2010 Mar 19;140(6):900-17
20303879
Cell. 2010 Mar 19;140(6):918-34
20303880
Immunol Today. 2000 Aug;21(8):403-10
10916144
J Med Chem. 2005 Sep 8;48(18):5613-38
16134928
Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3473-8
19208813
Chemistry. 2010 Jul 12;16(26):7678-82
20572192
Bioorg Med Chem. 2009 Mar 15;17(6):2290-303
19028103
Angew Chem Int Ed Engl. 2009;48(47):8952-7
19844931
Phytomedicine. 2002 Jul;9(5):468-74
12222670
Cell. 2010 Mar 19;140(6):935-50
20303881
Angew Chem Int Ed Engl. 1998 Apr 3;37(6):688-749
29711371
JAMA. 2002 May 8;287(18):2391-405
11988060
Cell. 2010 Mar 19;140(6):883-99
20303878
Chem Biol. 1996 Aug;3(8):623-39
8807895
Angew Chem Int Ed Engl. 2007;46(25):4708-11
17523208
Nat Rev Cancer. 2001 Nov;1(2):118-29
11905803
Org Lett. 2005 Jul 7;7(14):2997-9
15987189
Science. 2003 Oct 24;302(5645):613-8
14576427
Nat Biotechnol. 2005 Sep;23(9):1073-8
16151394
J Nat Prod. 2009 Aug;72(8):1447-52
19606850
J Am Chem Soc. 2009 Aug 5;131(30):10587-97
19722632
Nat Med. 2003 Mar;9(3):269-77
12612576
Nature. 2008 Jul 24;454(7203):428-35
18650913
J Nat Prod. 2007 Mar;70(3):461-77
17309302
J Nat Prod. 1997 Jan;60(1):52-60
9014353
N Engl J Med. 2006 May 25;354(21):2208-11
16723613
Science. 2000 Mar 17;287(5460):1964-9
10720315
Am J Obstet Gynecol. 2002 Dec;187(6):1715-6
12501090
Angew Chem Int Ed Engl. 1998 Aug 17;37(15):2014-2045
29711063
Nat Biotechnol. 2005 Sep;23(9):1037-9
16151384
Angew Chem Int Ed Engl. 2004 Jan;43(1):46-58
14694470
J Am Chem Soc. 2008 Aug 20;130(33):11114-21
18646750