This proposal describes the continuation of a research program involving the synthesis and mode of action studies of structurally complex natural products that have demonstrated unique antitumor activity. Three major projects are described. The first project involves synthetic and biological studies on apoptolidin a macrolide antitumor agent that induces transformed cells to undergo programmed cell death. We plan to continue development of a concise synthesis of apoptolidin and structural analogs designed to probe the cellular target of apoptolidin, an interaction presumed responsible for the unique onset of cell death. A second project is directed toward the synthesis of the structurally complex natural product hibarimicin B, a specific inhibitor of tyrosine kinase and oncogenic cell transformation. A third project is directed towards the development of a general method for the rapid assembly of 2-deoxy oligosaccharides, a frequent structural feature of natural antitumor antibiotics. Overall, this program is expected to have a significant impact on the areas of chemistry, biology and medicine.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA059515-06A1
Application #
6383665
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Lees, Robert G
Project Start
1996-03-01
Project End
2005-04-30
Budget Start
2001-05-01
Budget End
2002-04-30
Support Year
6
Fiscal Year
2001
Total Cost
$264,186
Indirect Cost
Name
Texas A&M University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
047006379
City
College Station
State
TX
Country
United States
Zip Code
77845
Chong, Katherine M; Leelatian, Nalin; Deguire, Sean M et al. (2016) The use of fluorescently-tagged apoptolidins in cellular uptake and response studies. J Antibiot (Tokyo) 69:327-30
DeGuire, Sean M; Earl, David C; Du, Yu et al. (2015) Fluorescent probes of the apoptolidins and their utility in cellular localization studies. Angew Chem Int Ed Engl 54:961-4
Romaine, Ian M; Sulikowski, Gary A (2015) Studies on a biomimetic oxidative dimerization approach to the hibarimicins. Tetrahedron Lett 56:3617-3619
Baranczak, Aleksandra; Sulikowski, Gary A (2012) Synthetic studies directed toward dideoxy lomaiviticinone lead to unexpected 1,2-oxazepine and isoxazole formation. Org Lett 14:1027-9
Baranczak, Aleksandra; Sulikowski, Gary A (2012) Cascade assembly of the benzo[a]anthraquinone ring system common to the angucycline antibiotics. Tetrahedron Lett 53:1345-1346
Chau, Stephen T; Hayakawa, Yoichi; Sulikowski, Gary A (2011) 18O assisted analysis of a ?,?-epoxyketone cyclization: synthesis of the C16-C28 fragment of ammocidin D. Org Lett 13:756-9
Romaine, Ian M; Hempel, Jonathan E; Shanmugam, Ganesh et al. (2011) Assignment and stereocontrol of hibarimicin atropoisomers. Org Lett 13:4538-41
DeGuire, Sean M; Ma, Shutao; Sulikowski, Gary A (2011) Synthesis of a bicyclobutane fatty acid identified from the cyanobacterium Anabaena PCC 7120. Angew Chem Int Ed Engl 50:9940-2
Du, Yu; Derewacz, Dagmara K; Deguire, Sean M et al. (2011) Biosynthesis of the Apoptolidins in Nocardiopsis sp. FU 40. Tetrahedron 67:6568-6575
Bachmann, Brian O; McNees, Ruth; Melancon, Bruce J et al. (2010) Light-induced isomerization of apoptolidin a leads to inversion of C2-C3 double bond geometry. Org Lett 12:2944-7

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