This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Quinones are important compounds used in antitumor therapy and to treat other human illnesses. The common feature of these compounds is that these are prone to be reduced chemically, photochemically or enzymatically in biological media to produce reactive intermediates and products. Upon reduction of these compounds, superoxide and nitrosyl production rates are enhanced in a way which depends on the quinone one-electron redox potential. In addition, alkylating quinones are also activated to covalently bind DMA upon reduction under hypoxic conditions. In our previous years we found that aziridinylquinones can be reduced by photosensitization, under anoxia, followed by DNA covalent binding. We also found that in the presence of a sacrificial electron donor such as hypoxanthine, an increase in both quinone reduction and covalent adducts to DNA were detected. Since electron donors could shift the photosensitized production of singlet oxygen to superoxide and since both superoxide and hydrogen peroxide can travel within tissues farther away than singlet oxygen to produce damage, we will deal here with a study on how the hydrophobicity/hydrophilicity of dyes and electron donors play interacting roles in the relative production of singlet oxygen and superoxide. Since many tumors overexpress folate receptors (FR), one way to reduce quinone toxicity to normal tissues, and increase toxic damage to tumor, is to deliver selectively quinones to FR-overexpressing tumors. The present research proposal is also aimed at exploring new potential pathways in quinone-enhanced toxicity initiated by quinone reduction using FR-targeted quinones. FRtargeted quinones will be synthesized and their abilities to catalyze the production of reactive oxygen species and DNA and protein alkylation will be determined.
Specific Aims : 1. To determine the effects of dyes and sacrificial electron donors hydrophobicities/hydrophilicities in lipid/buffer systems on the relative yields of superoxide and singlet oxygen. 2. To synthesize FR-targeted quinones and an FR-targeted etoposide quinone derivative. 3. To characterize the semiquinones and the rate of reactive oxygen species (ROS) production upon enzymatic and photosensitized reduction of FR-targeted quinones. 4. To determine if photosensitized FR-targeted aziridinylquinone-DNA covalent binding occurs, using red-absorbing dyes. 5. To determine if the FR-targeted etoposide quinone derivative binds to protein thiols and DNA bases. 6. To determine FR-targeted semiquinone and ROS production in HeLa and non-FRoverexpressing cells, using EPR spectroscopy, and whether or not the production of these species is related to FR binding. 7. To determine FR-targeted quinone derivative cytotoxic activity in HeLa and non-FR overexpressing cells.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
5P20RR016470-11
Application #
8360148
Study Section
Special Emphasis Panel (ZRR1-RI-4 (01))
Project Start
2011-06-01
Project End
2012-05-31
Budget Start
2011-06-01
Budget End
2012-05-31
Support Year
11
Fiscal Year
2011
Total Cost
$103,072
Indirect Cost
Name
University of Puerto Rico Rio Piedras
Department
Type
DUNS #
090051616
City
San Juan
State
PR
Country
United States
Zip Code
00926
Cantres-Rosario, Yisel M; Acevedo-Mariani, Frances M; Pérez-Laspiur, Juliana et al. (2017) Microwave & magnetic proteomics of macrophages from patients with HIV-associated cognitive impairment. PLoS One 12:e0181779
Mariño, Yobana A; Verle Rodrigues, José C; Bayman, Paul (2017) Wolbachia Affects Reproduction and Population Dynamics of the Coffee Berry Borer (Hypothenemus hampei): Implications for Biological Control. Insects 8:
Martínez-Rivera, Freddyson J; Pérez-Laspiur, Juliana; Santiago-Gascot, María E et al. (2017) Differential protein expression profile in the hypothalamic GT1-7 cell line after exposure to anabolic androgenic steroids. PLoS One 12:e0180409
Zenón, Frances; Jorge, Inmaculada; Cruz, Ailed et al. (2016) 18O proteomics reveal increased human apolipoprotein CIII in Hispanic HIV-1+ women with HAART that use cocaine. Proteomics Clin Appl 10:144-55
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Martínez-Rivera, Freddyson J; Rodriguez-Romaguera, Jose; Lloret-Torres, Mario E et al. (2016) Bidirectional Modulation of Extinction of Drug Seeking by Deep Brain Stimulation of the Ventral Striatum. Biol Psychiatry 80:682-690
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Suárez-Arroyo, Ivette J; Feliz-Mosquea, Yismeilin R; Pérez-Laspiur, Juliana et al. (2016) The proteome signature of the inflammatory breast cancer plasma membrane identifies novel molecular markers of disease. Am J Cancer Res 6:1720-40
Wang, Hai-Yang; Huang, Kun; De Jesús, Melvin et al. (2016) Synthesis of enantiopure 1,2-azido and 1,2-amino alcohols via regio- and stereoselective ring-opening of enantiopure epoxides by sodium azide in hot water. Tetrahedron Asymmetry 27:91-100
Colon, Krystal; Perez-Laspiur, Juliana; Quiles, Raymond et al. (2016) Macrophage secretome from women with HIV-associated neurocognitive disorders. Proteomics Clin Appl 10:136-43

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