Abstract

The objective of this project is development of new mass spectral techniques in order to provide innovative and/or more rapid solutions to problems involving (1) chemical structure determination, (2) complex mixture analysis and (3) measurement of trace components in biological systems. Electrospray ionization mass spectrometry (ESI/MS), tandem mass spectrometry (MS/MS) and combined liquid chromatography-mass spectrometry (LC/MS) are the techniques of current interest. A narrow-bore (2 mm i.d., 0.200 ml/min), reversed-phase liquid chromatography system, whose flow can be automatically diverted for sample desalting, has been developed for general ESI/MS analysis of biological samples. This LC/ESI/MS system has been used to develop a rapid method utilizing tandem mass spectrometry for measuring the Phase I anti-AIDS drug 2'-beta-fluoro-2',3'-dideoxyadenosine (F-ddA) and its anti-HIV-active deaminated metabolite 2'-beta-fluoro-2',3'-dideoxyinosine (F-ddI) in human plasma with high specificity and sensitivity. This methodology is being applied to determine the pharmacokinetics and bioavailability of oral F-ddA during the initial Phase I clinical trial of this agent in AIDS patients. Fast atom bombardment mass spectrometry (FAB/MS) is used to support the LMC synthetic effort through structural characterization of new compounds and synthetic intermediates. FAB liquid matrix reactions involving ion pairing, reduction, dehalogenation and radical cation/anion formation continue to be studied and characterized to ensure the interpretability and reliability of these analyses.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC006178-11
Application #
2463715
Study Section
Special Emphasis Panel (LMC)
Project Start
Project End
Budget Start
Budget End
Support Year
11
Fiscal Year
1996
Total Cost
Indirect Cost

  Institution

Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code

  Publications

Qian, Wen-Jian; Park, Jung-Eun; Grant, Robert et al. (2015) Neighbor-directed histidine N (?)-alkylation: A route to imidazolium-containing phosphopeptide macrocycles. Biopolymers 104:663-73
Boswell, C Andrew; Regino, Celeste A S; Baidoo, Kwamena E et al. (2009) A novel side-bridged hybrid phosphonate/acetate pendant cyclam: synthesis, characterization, and 64Cu small animal PET imaging. Bioorg Med Chem 17:548-52
Malolanarasimhan, Krishnan; Kedei, Noemi; Sigano, Dina M et al. (2007) Conformationally constrained analogues of diacylglycerol (DAG). 27. Modulation of membrane translocation of protein kinase C (PKC) isozymes alpha and delta by diacylglycerol lactones (DAG-lactones) containing rigid-rod acyl groups. J Med Chem 50:962-78
Jiang, Sheng; Li, Peng; Lai, Christopher C et al. (2006) Design and concise synthesis of fully protected analogues of l-gamma-carboxyglutamic acid. J Org Chem 71:7307-14
Hodge, David R; Peng, Benjamin; Cherry, James C et al. (2005) Interleukin 6 supports the maintenance of p53 tumor suppressor gene promoter methylation. Cancer Res 65:4673-82
Ben-Kasus, Tsipi; Ben-Zvi, Zvi; Marquez, Victor E et al. (2005) Metabolic activation of zebularine, a novel DNA methylation inhibitor, in human bladder carcinoma cells. Biochem Pharmacol 70:121-33
Malolanarasimhan, Krishnan; Lai, Christopher C; Kelley, James A et al. (2005) Synthesis and biological study of a flavone acetic acid analogue containing an azido reporting group designed as a multifunctional binding site probe. Bioorg Med Chem 13:2717-22
Marquez, Victor E; Kelley, James A; Agbaria, Riad et al. (2005) Zebularine: a unique molecule for an epigenetically based strategy in cancer chemotherapy. Ann N Y Acad Sci 1058:246-54
Milanowski, Dennis J; Gustafson, Kirk R; Kelley, James A et al. (2004) Caulibugulones A-F, novel cytotoxic isoquinoline quinones and iminoquinones from the marine bryozoan Caulibugula intermis. J Nat Prod 67:70-3
Shi, Zhen-Dan; Wei, Chang-Qing; Lee, Kyeong et al. (2004) Macrocyclization in the design of non-phosphorus-containing Grb2 SH2 domain-binding ligands. J Med Chem 47:2166-9

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