The medicinal chemistry and synthetic organic chemistry efforts provided on this component of the program project will provide both natural product syntheses as well as the design, synthesis, and development of novel analogs of the chemopreventive agents isolated in connection with the other components of the project. For natural products that are isolated in trace amounts that do not permit testing in the desired battery of in vitro biological assays, practical syntheses are required that will provide quantities in the 100 mg to 1 g range. In addition, it can be expected that the potential therepeutic utilities of the naturally occurring chemopreventive assays will be limited by the usual factors including lack of sufficient potency, chemical instability, inadequate solubility to permit formulation, and limitations of absorption, distribution, metabolism, and excretion, and well as toxicity. It can be expected that each individual agent will present its own array of limitations, and these will be addressed on a case-by-case basis as the need arises. For example, lack of chemical stability will be overcome by substitution of the unstable moieties with functional groups that possess enhanced chemical stability with retention of the desired biological activity. Lack of intrinsic activity (potency) will be handled through the investiaton of structure-activity relationships as well as by rational design based on the target structure, using computer graphics molecular modeling approaches. Inadequate solubility will be overcome through incorporation or elimination of acidic and basic functionalities that permit salt formation. Metabolic instability will be remedied through in replacement of the metabilized groups with biologically active moieties having enhanced metabolic stabilities. Problems with toxicity will be solved through prodrug approaches in which the original compound is transformed into a non-toxic precursor that is metabolized back to the parent, biologically active compound in the target tissue. Lack of absorption can be solved either by manipulation of lipophilicity or by the attachment of carrier moieties that are actively transported. If the drug does not reach the target tissue in adequate concentrations to produce the desired biological effects, it can be converted to a prodrug form having more favorable distribution characteristics, or it can be converted to an analog that will allow appropriate formulation for administration by a different route. If the drug is eliminated too rapidly, it will be transforrmed into an analog that has altered properties with regard to reabsorption and excretion mechanisms in the renal tubules. This can often be addressed through a change in polarity. It can be anticipated that the chemopreventive agents that will be under investigation at any particular time will change as the emerging isolation, structure elucidation, and biological investigation activities progress in the other parts of the program project. Our intial investigations will focus on the polyhydroxylated stilbenes related to resveratrol and piceatannol, as well as the chemopreventive agents in the flavone, isoflavone, and alkaloid families.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA048112-17
Application #
7864135
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
17
Fiscal Year
2009
Total Cost
$176,290
Indirect Cost
Name
Purdue University
Department
Type
DUNS #
072051394
City
West Lafayette
State
IN
Country
United States
Zip Code
47907
Youn, Ui Joung; Sripisut, Tawanun; Park, Eun-Jung et al. (2015) Determination of the absolute configuration of chaetoviridins and other bioactive azaphilones from the endophytic fungus Chaetomium globosum. Bioorg Med Chem Lett 25:4719-23
Chai, Xingyun; Youn, Ui Joung; Sun, Dianqing et al. (2014) Herbicidin congeners, undecose nucleosides from an organic extract of Streptomyces sp. L-9-10. J Nat Prod 77:227-33
Ihsan-ul-Haq; Mirza, Bushra; Kondratyuk, Tamara P et al. (2013) Preliminary evaluation for cancer chemopreventive and cytotoxic potential of naturally growing ethnobotanically selected plants of Pakistan. Pharm Biol 51:316-28
Ihsan-ul-Haq; Youn, Ui Joung; Chai, Xingyun et al. (2013) Biologically active withanolides from Withania coagulans. J Nat Prod 76:22-8
St John, Sarah E; Jensen, Katherine C; Kang, Soosung et al. (2013) Design, synthesis, biological and structural evaluation of functionalized resveratrol analogues as inhibitors of quinone reductase 2. Bioorg Med Chem 21:6022-37
Conda-Sheridan, Martin; Park, Eun-Jung; Beck, Daniel E et al. (2013) Design, synthesis, and biological evaluation of indenoisoquinoline rexinoids with chemopreventive potential. J Med Chem 56:2581-605
Park, Eun-Jung; Pezzuto, John M; Jang, Kyoung Hwa et al. (2012) Suppression of nitric oxide synthase by thienodolin in lipopolysaccharide-stimulated RAW 264.7 murine macrophage cells. Nat Prod Commun 7:789-94
Kondratyuk, Tamara P; Park, Eun-Jung; Yu, Rui et al. (2012) Novel marine phenazines as potential cancer chemopreventive and anti-inflammatory agents. Mar Drugs 10:451-64
Reddy, P V Narasimha; Jensen, Katherine C; Mesecar, Andrew D et al. (2012) Design, synthesis, and biological evaluation of potent quinoline and pyrroloquinoline ammosamide analogues as inhibitors of quinone reductase 2. J Med Chem 55:367-77
Mayhoub, Abdelrahman S; Marler, Laura; Kondratyuk, Tamara P et al. (2012) Optimizing thiadiazole analogues of resveratrol versus three chemopreventive targets. Bioorg Med Chem 20:510-20

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