The long-term objective of this research project is to develop novel types of phosphoramidate anti tumor agents directed against specific cellular targets. Chemical mechanistic information will be utilized to guide the design, synthesis and evaluation of these new mechanism-based phosphoramidates.
Specific aims i nclude: 1) Design and synthesis of phosphoramidate analogs that undergo bioreductive activation and thus are targeted to hypoxic cells; 2) Design and synthesis of nucleoside phosphoramidate analogs that can function as prodrugs for nucleotide delivery or as irreversible enzyme inhibitors; 3) Design and synthesis of phosphoramidate analogs targeted to specific DNA sequences; 4) Evaluation of new agents both in vitro and in vivo against established tumor cell lines. Experiments to date have demonstrated that cytotoxic compounds can be prepared in each of these series. Antitumor evaluation will rely on the murine B16 system using a clonogenic assay in vitro and using regrowth delay and the lung metastasis assay in vivo. Hypoxia selective compounds will be evaluated in the HT-29 colon tumor system under aerobic and hypoxic conditions in vitro. Mass spectrometry will be required primarily for structural characterization of the synthetic products and for characterization of the covalent adducts formed between the drugs and their putative targets.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
2P41RR001614-15
Application #
5223395
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
15
Fiscal Year
1996
Total Cost
Indirect Cost
MacRae, Andrew J; Mayerle, Megan; Hrabeta-Robinson, Eva et al. (2018) Prp8 positioning of U5 snRNA is linked to 5' splice site recognition. RNA 24:769-777
Katsuno, Yoko; Qin, Jian; Oses-Prieto, Juan et al. (2018) Arginine methylation of SMAD7 by PRMT1 in TGF-?-induced epithelial-mesenchymal transition and epithelial stem-cell generation. J Biol Chem 293:13059-13072
Sahoo, Pabitra K; Smith, Deanna S; Perrone-Bizzozero, Nora et al. (2018) Axonal mRNA transport and translation at a glance. J Cell Sci 131:
Tran, Vy M; Wade, Anna; McKinney, Andrew et al. (2017) Heparan Sulfate Glycosaminoglycans in Glioblastoma Promote Tumor Invasion. Mol Cancer Res 15:1623-1633
Liu, Tzu-Yu; Huang, Hector H; Wheeler, Diamond et al. (2017) Time-Resolved Proteomics Extends Ribosome Profiling-Based Measurements of Protein Synthesis Dynamics. Cell Syst 4:636-644.e9
Bikle, Daniel D (2016) Extraskeletal actions of vitamin D. Ann N Y Acad Sci 1376:29-52
Twiss, Jeffery L; Fainzilber, Mike (2016) Neuroproteomics: How Many Angels can be Identified in an Extract from the Head of a Pin? Mol Cell Proteomics 15:341-3
Cil, Onur; Phuan, Puay-Wah; Lee, Sujin et al. (2016) CFTR activator increases intestinal fluid secretion and normalizes stool output in a mouse model of constipation. Cell Mol Gastroenterol Hepatol 2:317-327
Posch, Christian; Sanlorenzo, Martina; Vujic, Igor et al. (2016) Phosphoproteomic Analyses of NRAS(G12) and NRAS(Q61) Mutant Melanocytes Reveal Increased CK2? Kinase Levels in NRAS(Q61) Mutant Cells. J Invest Dermatol 136:2041-2048
Julien, Olivier; Zhuang, Min; Wiita, Arun P et al. (2016) Quantitative MS-based enzymology of caspases reveals distinct protein substrate specificities, hierarchies, and cellular roles. Proc Natl Acad Sci U S A 113:E2001-10

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