) Salicylihalamide A is the first member of a novel class of complex macrocyclic salicylates and displays a unique differential cytotoxicity profile in the National Cancer Institute's 60-cell line human tumor assay. Since their initial discovery in 1997, a growing number of structurally related metabolites have been isolated, including lobatamides A-F, apicularen A, oximidines I-II, CJ 12,950 and SCH351448. The observation that each one of them seems to induce a unique response in mammalian cells, and as such represent unique new leads for the development of therapeutic agents, warrants the development of synthetic chemistry in this area. Building on an efficient synthesis of the salicylihalamide and apicularen macrocyclic cores, part of the proposed research is intended to provide synthetic materials, otherwise not accessible, for structure-activity and mode-of-action studies. Synthetic substitutes for their common, but labile enamide side-chain will be explored in addition to the synthesis of photoaffinity, radiolabeled, and biotinylated probes. The remainder of the proposed research deals with chemistry related to oximidine, CJ- 12,950 and SCH 351448. To achieve a total synthesis of oximidine, a variety of cross- coupling approaches will be explored to install a highly unusual conjugated E,Z,Z-triene subunit embedded within a 1 2-membered benzolactone. For the determination of the relative and absolute stereochemistry of CJ-12,950, which remains unknown, an efficient synthesis of a selected stereoisomer of the benzolactone core is proposed, serving as a platform for rapid stereoisomer interconversion via Mitsunobu chemistry. NMR spectroscopy will be the tool to correlate spectroscopic fingerprints of these advanced intermediates with CJ-12,950. Finally, a short, highly convergent synthesis of SCH351448, a macrocyclic polyketide bis-lactone composed of two identical acids, is proposed using a novel tandem inter-/intramolecular olefin metathesis strategy. Ultimately, the proposed studies will provide small-molecule probes for discovery biology in addition to new therapeutic leads.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA090349-02
Application #
6514946
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Lees, Robert G
Project Start
2001-03-01
Project End
2006-02-28
Budget Start
2002-03-01
Budget End
2003-02-28
Support Year
2
Fiscal Year
2002
Total Cost
$263,640
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
Wu, Cheng-Yang; Feng, Yu; Cardenas, Eduardo R et al. (2012) Studies toward the unique pederin family member psymberin: structure-activity relationships, biochemical studies, and genetics identify the mode-of-action of psymberin. J Am Chem Soc 134:18998-9003
Feng, Yu; Jiang, Xin; De Brabander, Jef K (2012) Studies toward the unique pederin family member psymberin: full structure elucidation, two alternative total syntheses, and analogs. J Am Chem Soc 134:17083-93
Denisova, Oxana V; Kakkola, Laura; Feng, Lin et al. (2012) Obatoclax, saliphenylhalamide, and gemcitabine inhibit influenza a virus infection. J Biol Chem 287:35324-32
Razzak, Mina; De Brabander, Jef K (2011) Lessons and revelations from biomimetic syntheses. Nat Chem Biol 7:865-75
Liang, Qiren; Qian, Mingxing; Razzak, Mina et al. (2011) Platinum-catalyzed synthesis of ýý-keto tetrahydropyrans and cyclic dienolethers. Chem Asian J 6:1958-60
Paradise, Christopher L; Sarkar, Pooja R; Razzak, Mina et al. (2011) Gold-catalysed synthesis of amino acid-derived 2,5-disubstituted oxazoles. Org Biomol Chem 9:4017-20
Liang, Qiren; De Brabander, Jef K (2011) Heterocycles via intramolecular platinum-catalyzed propargylic substitution. Tetrahedron 67:5046-5053
Bender, Christopher F; Yoshimoto, Francis K; Paradise, Christopher L et al. (2009) A concise synthesis of berkelic acid inspired by combining the natural products spicifernin and pulvilloric acid. J Am Chem Soc 131:11350-2
Liu, Jun; De Brabander, Jef K (2009) A concise total synthesis of saliniketal B. J Am Chem Soc 131:12562-3
Lebreton, Sylvain; Jaunbergs, Janis; Roth, Michael G et al. (2008) Evaluating the potential of vacuolar ATPase inhibitors as anticancer agents and multigram synthesis of the potent salicylihalamide analog saliphenylhalamide. Bioorg Med Chem Lett 18:5879-83

Showing the most recent 10 out of 19 publications