The major goals of the Project are to rationally design and synthesize and to determine the efficacy and safety of new vitamin D3 analogs (deltanoids). The novel deltanoids proposed here are expected to have high cancer chemoprotective and chemotherapeutic activities without causing hypercalcemia.
First (Aim 1), a hybrid deltanoid will be constructed that combines the most desirable fluorine atom substitution pattern of Hoffman- LaRoche's popular and potent deltanoid Ro 24-5531 with our deltanoid QW 1624F2-2. Such a new side-chain polyfluorinated deltanoid is expected to have a therapeutic profile superior to that of either of its parent deltanoids. Because some of our conceptually new sulfone deltanoids are potent and safe (i.e. non-calcemic) at inhibiting DMBA-induced skin tumorigenesis in mice, a series of new sulfone deltanoids (Aim 2) will be prepared in which small, rational structural changes (e.g. 16- substitution) will force the deltanoid side-chain into a northwest orientation that is expected to raise chemoprotective potency without causing hypercalcemia. Also, a few sulfone deltanoid dimers (Aim 3) will be prepared as molecular probes to study the effect of such chemical inducers of receptor dimerization on intracellular signal transduction processes. Additionally, a series of A-ring 2,2-disbustituted deltanoids (Aim 4) will be prepared incorporating 2,2-dimethyland 2,2- difluoro substituents that are expected sterically and electronically to retard metabolism at the 1- and 3-OH positions, thereby increasing the biological lifetime and efficacy of these new deltanoids. The most promising of these new antiproliferative but non-calcemic deltanoids will be synthesized on 15-30 mg scale for cancer chemoprevention and chemotherapy testing in animals with focus on skin and breast cancers (Aim 5). Collectively, these studies will provide important structure- activity insights into the cancer chemoprotective and chemotherapeutic actions and molecular biology of vitamin D3 analogs.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA093547-05
Application #
7079410
Study Section
Chemical Pathology Study Section (CPA)
Program Officer
Malone, Winfred F
Project Start
2002-07-01
Project End
2008-06-30
Budget Start
2006-07-01
Budget End
2008-06-30
Support Year
5
Fiscal Year
2006
Total Cost
$313,210
Indirect Cost
Name
Johns Hopkins University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Xu, Haibo; Posner, Gary H; Stevenson, Michael et al. (2010) Apc(MIN) modulation of vitamin D secosteroid growth control. Carcinogenesis 31:1434-41
Hess, Lindsey C; Posner, Gary H (2010) Asymmetric, organocatalytic, three-step synthesis of alpha-hydroxy-(E)-beta,gamma-unsaturated esters. Org Lett 12:2120-2
Posner, Gary H; Helvig, Christian; Cuerrier, Dominic et al. (2010) Vitamin D analogues targeting CYP24 in chronic kidney disease. J Steroid Biochem Mol Biol 121:13-9
Usera, Aimee R; Dolan, Patrick; Kensler, Thomas W et al. (2009) 'Novel alkyl side chain sulfone 1alpha,25-dihydroxyvitamin D3 analogs: a comparison of in vitro antiproliferative activities and in vivo calcemic activities'. Bioorg Med Chem 17:5627-31
Xu, Haibo; McCann, Mella; Zhang, Zhiyu et al. (2009) Vitamin D receptor modulates the neoplastic phenotype through antagonistic growth regulatory signals. Mol Carcinog 48:758-72
Petersen, Kimberly S; Posner, Gary H (2008) Asymmetric, organocatalytic, three-step synthesis of gamma-hydroxy-(E)-alpha,beta-unsaturated sulfones and esters. Org Lett 10:4685-7
Zhang, Jing; Posner, Gary H; Danilenko, Michael et al. (2007) Differentiation-inducing potency of the seco-steroid JK-1624F2-2 can be increased by combination with an antioxidant and a p38MAPK inhibitor which upregulates the JNK pathway. J Steroid Biochem Mol Biol 105:140-9
Posner, Gary H; Suh, Byung Chul; Petersen, Kimberly S et al. (2007) Difluoromethyl analogs of the natural hormone 1alpha,25-dihydroxyvitamin D3: Design, synthesis, and preliminary biological evaluation. J Steroid Biochem Mol Biol 103:213-21
Usera, Aimee R; Dolan, Patrick M; Kensler, Thomas W et al. (2007) Antiproliferative, low-calcemic, fluorinated sulfone analogs of 1alpha,25-dihydroxyvitamin D3: chemical synthesis and biological evaluation. Bioorg Med Chem 15:5509-18
Petersen, Kimberly S; Dolan, Patrick M; Kensler, Thomas W et al. (2007) Low-calcemic, highly antiproliferative, 23-oxa ether analogs of the natural hormone 1 alpha,25-dihydroxyvitamin D3: design, synthesis, and preliminary biological evaluation. J Med Chem 50:5824-32

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