An extensive body of work supports a fundamental link between inflammation and a number of diseases, particularly cancer. Synthetic oleanane triterpenoids have been shown in preclinical models to be potent in the prevention of cancer driven by chronic inflammation. A central premise of the proposed work is that the oleanane triterpenoids are representative of a much larger class of anti-inflammatory/anti-cancer triterpenoids. We hypothesize that exploration of diverse triterpenoids, will allow a careful dissection of the molecular pathways behind triterpenoid chemoprevention, and will define novel classes of potent and effective cancer chemopreventive agents. To study the chemical space around the triterpenoids we will use two approaches including: 1) a novel oxidative cleavage and skeletal rearrangement;and 2) an innovative natural product isolation strategy to identify novel triterpenoids. These molecules will then be evaluated in vitro for their ability to suppress expression of key inflammatory mediators, and in vivo for their ability to suppress progression of gastrointestinal carcinogenesis in a system that couples immune mediated induction of oncogenic signaling intermediates with loss of expression of important tumor suppressor pathways.

Public Health Relevance

This project represents a collaborative endeavor between a two investigators interested in triterpenoids as cancer chemopreventives. The described aims will synthesize and isolate known and novel triterpenoids from traditional medicine sources to be tested as chemopreventives in inflammation driven models of carcinogenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA157735-04
Application #
8596802
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Perloff, Marjorie
Project Start
2011-03-01
Project End
2015-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Kiser, Philip D; Zhang, Jianye; Badiee, Mohsen et al. (2017) Rational Tuning of Visual Cycle Modulator Pharmacodynamics. J Pharmacol Exp Ther 362:131-145
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Gatbonton-Schwager, Tonibelle N; Sadhukhan, Sushabhan; Zhang, Guo-Fang et al. (2014) Identification of a negative feedback loop in biological oxidant formation fegulated by 4-hydroxy-2-(E)-nonenal. Redox Biol 2:755-63
Ignatenko, Vasily A; Han, Yong; Tochtrop, Gregory P (2013) Direct access to 6/5/7/5- and 6/7/5/5-fused tetracyclic triterpenoids via divergent transannular aldol reaction of lanosterol-derived diketone. J Org Chem 78:12229-35

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