Abstract

The principal objectives of this proposal are to develop syntheses of several marine-derived natural products that possess potent pharmacological activity, and that are currently available only in limited amounts. Specific target molecules include cylindramide A, aburatubolactam A, and the C29-C53 subunit of norhalichondrin B, and the C29-C54 subunit of halichondrin B. Cylindramide A and aburatubolactam A are structurally related tetramic acid macrolactams characterized by a substituted bicyclo[3.3.0]octane core and a tetramic acid moiety entrapped within a macrolactam. Both compounds possess potent biological activity - cylindramide inhibits the growth of B16 melanoma cells at low microgram per milliliter IC[50] values, and aburatubolactam A inhibits the growth of P388 murine leukemia cells along with the ability to inhibit superoxide anion generation. As part of synthetic studies on this class of molecules a simple scaffold that can display the tetramic acid macrolactam will be developed as a surrogate for the bicyclo[3.3.0]octane core. Norhalichondrin B and halichondrin B are complex marine-derived polyethers that display remarkably potent in vitro and in vivo anti-cancer activity (GI[50] values of

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA110246-02
Application #
6876668
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Lees, Robert G
Project Start
2004-03-24
Project End
2009-02-28
Budget Start
2005-03-01
Budget End
2006-02-28
Support Year
2
Fiscal Year
2005
Total Cost
$234,478
Indirect Cost

  Institution

Name
University of Colorado at Boulder
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
007431505
City
Boulder
State
CO
Country
United States
Zip Code
80309

  Publications

Hallside, Michal S; Brzozowski, Richard S; Wuest, William M et al. (2014) A concise synthesis of carolacton. Org Lett 16:1148-51
Cole, Kathryn E; Dowling, Daniel P; Boone, Matthew A et al. (2011) Structural basis of the antiproliferative activity of largazole, a depsipeptide inhibitor of the histone deacetylases. J Am Chem Soc 133:12474-7
Jackson, Katrina L; Henderson, James A; Motoyoshi, Hajime et al. (2009) A total synthesis of norhalichondrin B. Angew Chem Int Ed Engl 48:2346-50
Jackson, Katrina L; Henderson, James A; Phillips, Andrew J (2009) The halichondrins and E7389. Chem Rev 109:3044-79
Griggs, Nolan D; Phillips, Andrew J (2008) A concise and modular synthesis of pyranicin. Org Lett 10:4955-7
Jackson, Katrina L; Henderson, James A; Morris, Jonathan C et al. (2008) A synthesis of the C1-C15 domain of the halichondrins. Tetrahedron Lett 49:2939-2941
Nasveschuk, Christopher G; Ungermannova, Dana; Liu, Xuedong et al. (2008) A concise total synthesis of largazole, solution structure, and some preliminary structure activity relationships. Org Lett 10:3595-8
Keaton, Katie A; Phillips, Andrew J (2008) Toward the synthesis of spirastrellolide B: a synthesis of the C1-C23 subunit. Org Lett 10:1083-6
Um, Joann M; Houk, K N; Phillips, Andrew J (2008) Origin of stereoselectivity in the reduction of a planar oxacarbenium. Org Lett 10:3769-72
Henderson, James A; Phillips, Andrew J (2008) Total synthesis of aburatubolactam A. Angew Chem Int Ed Engl 47:8499-501

Showing the most recent 10 out of 16 publications