Applications of New Mass Spectral Techniques

Kelley, James A.

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), combined liquid chromatography-mass spectrometry (LC/MS) and matrix-assisted laser desorption ionization (MALDI) mass spectrometry 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 on- line sample desalting, is being employed to develop a rapid method utilizing tandem mass spectrometry for measuring the Phase II anti-AIDS drug 2-b-fluoro-2,3-dideoxyadenosine (lodenosine, F-ddA), its anti-HIV- active deaminated metabolite 2-b-fluoro-2,3-dideoxyinosine (F-ddI) and the companion antiretroviral agent stavudine (2-deoxythymidinene, d4T) in human plasma with high specificity and sensitivity. This methodology is being applied to determine the pharmacokinetics, metabolism and disposition of oral F-ddA during a Phase I clinical trial of this agent in AIDS patients receiving combination antiretroviral therapy. Fast atom bombardment mass spectrometry (FAB/MS) is used to support the LMC synthetic effort through structural characterization of new compounds and synthetic intermediates. Mass spectrometric studies to confirm the structural identity of compounds identified as HIV-1 integrase inhibitors through 3-dimensional database searching are ongoing. 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.AIDS Title: Application of New Mass Spectral Methods for the Analysis of Anti-AIDS Agents - electrospray ionization, liquid chromatography - mass spectrometry, mass spectrometry, pharmacokinetics, tandem mass spectrometry, 2'-beta- fluoro-2',3'-dideoxyadenosine, - Human Tissues, Fluids, Cells, etc.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Cancer Institute (NCI)
• Type: Intramural Research (Z01)
• Project #: 1Z01BC006178-14
• Application #: 6289179
• Study Section: Special Emphasis Panel (LMC)
• Support Year: 14
• Fiscal Year: 1999

Institution

• Name: National Cancer Institute Division of Basic Sciences
• Country: United States

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