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), combined capillary electrophoresis-mass spectrometry (CE/MS) and matrix-assisted laser desorption ionization (MALDI) mass spectrometry are the techniques of current interest. Narrow-bore, reversed-phase liquid chromatography has been combined with tandem mass spectrometry to develop a general purpose system for characterizing and measuring nucleoside-based drugs in biological samples. This methodology has been applied to determine the pharmacokinetics, metabolism, disposition and bioavailability of 2'-b-fluoro-2',3'-dideoxyadenosine (lodenosine, F-ddA) and its anti-HIV-active deaminated metabolite 2'-b-fluoro-2',3'-dideoxyinosine (F-ddI) during a Phase I-II clinical trial of oral F-ddA in advanced AIDS patients receiving combination antiretroviral therapy. On-line sample concentration techniques are being investigated as a prelude to interfacing capillary electrophoresis to nano-electrospray ionization mass spectrometry for the analysis of intracellular nucleotide metabolites. Fast atom bombardment mass spectrometry (FAB/MS) is employed 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 continue. A project to evaluate the quality of the compounds in the NCI chemical database using MS and NMR analysis for structural characterization and determination of purity is ongoing. Statistical and clustering methods are being used to select compounds representative of the structural diversity of the database for analysis. AIDS Title: Application of New Mass Spectral Methods for the Analysis of Anti-AIDS Agents

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: Division of Basic Sciences - NCI (NCI)
• Type: Intramural Research (Z01)
• Project #: 1Z01BC006178-16
• Application #: 6558984
• Study Section: (LMC)
• Support Year: 16
• Fiscal Year: 2001

Institution

• Name: 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