The major goal of this project is to design and synthesize vitamin D3 analogs (deltanoids) having high cancer chemoprotective activities without causing hypercalcemia. These deltanoids are expected to maintain the differentiating ability of cells and thus to prevent them from adopting a proliferative phenotype. To accomplish this goal, first a series of hybrid deltanoids will be prepared combining structural modifications on the A- ring with structural modifications on the side-chain (Aim 4.1). Based on literature precedent, it is expected that the effects of these structural changes on biological activity will be synergistic. Preliminary results indicate that modifications of the A ring will contribute to low calcemic activity, and, based on literature precedent, modifications of the side chain will contribute to high antiproliferative, differentiation-inducing, and cancer chemoprotective activities. The specific side-chain modifications have been chosen to represent the most potent inducers of cell differentiation and of cancer prevention. Preliminary biological evaluation of one example of such analogs in vitro shows that, in murine keratinocytes as well as in human leukemic cell, this compound has antiproliferative potency greater than that of calcitriol, and, significantly, it is essentially non-calcemic. These findings provide strong support for examination of SAR in other structurally modified deltanoids, as proposed here. Second, a series of non-classical deltanoids lacking the natural ring A or D will be prepared (Aim 4.2). A-ring aromatic analogs are targeted because of their rigid structural similarity to natural calcitriol and because of their inability to undergo undesirable previtamin equilibrium. Synthesis of a variety of related A-ring heteroaromatic deltanoids is proposed. These deltanoids will be relatively easy to synthesize. The results of in vitro testing will lead in Years 4 and 5, to larger-scale syntheses to prepare enough material for evaluation of the most promising new deltanoids for protection of animals against cancer (Aim 4.3). Collectively, these studies should provide important structure-activity and mechanistic insights into chemoprotective actions of vitamin D3 analogs.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA044530-12
Application #
6102354
Study Section
Project Start
1999-01-01
Project End
1999-12-31
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
12
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Cho, Hye-Youn; Reddy, Sekhar P; Debiase, Andrea et al. (2005) Gene expression profiling of NRF2-mediated protection against oxidative injury. Free Radic Biol Med 38:325-43
Guyton, Kathryn Z; Kensler, Thomas W; Posner, Gary H (2003) Vitamin D and vitamin D analogs as cancer chemopreventive agents. Nutr Rev 61:227-38
Peleg, Sara; Posner, Gary H (2003) Vitamin D analogs as modulators of vitamin D receptor action. Curr Top Med Chem 3:1555-72
Kensler, Thomas W; Egner, Patricia A; Wang, Jin-Bing et al. (2002) Strategies for chemoprevention of liver cancer. Eur J Cancer Prev 11 Suppl 2:S58-64
Dinkova-Kostova, A T (2002) Protection against cancer by plant phenylpropenoids: induction of mammalian anticarcinogenic enzymes. Mini Rev Med Chem 2:595-610
Posner, Gary H; Halford, Bethany A; Peleg, Sara et al. (2002) Conceptually new low-calcemic oxime analogues of the hormone 1 alpha,25-dihydroxyvitamin D(3): synthesis and biological testing. J Med Chem 45:1723-30
Cho, Hye-Youn; Jedlicka, Anne E; Reddy, Sekhar P M et al. (2002) Role of NRF2 in protection against hyperoxic lung injury in mice. Am J Respir Cell Mol Biol 26:175-82
Cho, Hye-Youn; Jedlicka, Anne E; Reddy, Sekhar P M et al. (2002) Linkage analysis of susceptibility to hyperoxia. Nrf2 is a candidate gene. Am J Respir Cell Mol Biol 26:42-51
Posner, Gary H; Northrop, John; Paik, Ik-Hyeon et al. (2002) New chemical and biological aspects of artemisinin-derived trioxane dimers. Bioorg Med Chem 10:227-32
Pereira, Fernanda Maria Valente; Rosa, Eduardo; Fahey, Jed W et al. (2002) Influence of temperature and ontogeny on the levels of glucosinolates in broccoli (Brassica oleracea Var. italica) sprouts and their effect on the induction of mammalian phase 2 enzymes. J Agric Food Chem 50:6239-44

Showing the most recent 10 out of 122 publications