An Efficient Procedure for the 1-Alkylation of 2-Nitroimidazoles and the Synthesis of a Probe for Hypoxia in Solid Tumours

Long, Anthony; Parrick, J.; Hodgkiss, R.J.

doi:10.1055/s-1991-26552

Cited by 31 publications

(12 citation statements)

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“…The hypoxic probe is a 2-nitroimidazole linked to a side-chain of theophylline which acts as the immunogenic site for antibody recognition. The 7-( 4'-( 2-nitroimidazole-1-y1)-buty1)-theophylline (NITP) was originally synthesised by Long and colleagues (17). Chemicals and antiserum were obtained from Sigma Chemical Co. (Dorset, UK) except where stated.…”

Section: Hypoxic and Proliferative Probesmentioning

confidence: 99%

Simultaneous triple staining for hypoxia, proliferation, and DNA content in murine tumours

1995

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Hypoxia and proliferation rate are two important biological factors influencing the outcome of radiotherapy regimes for solid tumours. Hypoxic cells are more resistant to radiation than aerobic cells and a rapidly dividing tumour may repopulate faster during treatment. Clinical trials are underway to assess the importance of both these parameters. In this article we describe a method to simultaneously measure hypoxia and proliferation using multiparameter flow cytometry. Hypoxic cells were detected using a bioreductively bound marker with an immuno-recognisable side-chain, NITP and proliferation was measured by bromodeoxyuridine (BrdUrd) incorporation. These parameters were related to cell cycle position by measuring total DNA content with 7-aminoactinomycin D. The data were analysed using single laser excitation on a bench top flow cytometer. Simultaneous measurement of the three parameters shows the presence of cells which have incorporated BrdUrd and are also hypoxic by the criterion of NITP binding. The murine SaF tumour has a relatively constant aneuploid labelling index of 24%. However, the level of aneuploid hypoxia was variable ranging from 0.8 to 40.9% with a mean value of 15.6%. Within the BrdUrd labelled population there is a range of hypoxia from 2.8 to 28.5% (mean 15.1%); this represents 0.7 to 6.6% of the total tumour population. There are approximately twice as many oxygenated cells than hypoxic cells actively in the cell cycle. In vivo tumows contain cells with S phase DNA content which do not incorporate BrdUrd. This cell population has equivalent proportions of hypoxic and oxic cells. However, there are up to 12-fold more hypoxic cells in the unlabelled S than the BrdUrd labelled population. These data show that proliferation and hypoxia can be measured simultaneously using flow cytometry and the technique may form the basis of a predictive assay for these two important biological determinants of radiotherapy Outcome. C? 1995 Wiley-Liss, Inc.Keyterms: Three colour, flow cytometry, unlabelled S phase, solid tumours, BrdUrd, NITP Hypoxia and proliferation are two of the most important biological factors that may affect the outcome of radiotherapy treatment of solid tumours. It has been recognised for many years that hypoxia has a limiting effect on radiotherapy treatment; hypoxic cells are three times as resistant to radiation than their well-oxygenated counterparts ( 12).A number of strategies have been proposed to overcome hypoxia in solid tumours including the use of hyperbaric oxygen, radiation sensitizers, oxygen or carbogen breathing, and blood transfusions of anaemic patients. Many of the trials involving chemical radiation sensitizers gave disappointing results for several reasons which included lack of patient selection, small numbers of patients in individual trials, and poor tolerance of some of the radiation-sensitizing drugs. For these reasons the results of these trials have been conflicting, such that the importance of hypoxia has not been fully appreciated. However, Overgaard ( 19...

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Section: Hypoxic and Proliferative Probesmentioning

confidence: 99%

Simultaneous triple staining for hypoxia, proliferation, and DNA content in murine tumours

1995

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“…The most commonly used methods for measuring the oxygenation status of tumours and tissues are oxygen electrodes and, more recently, time resolved luminescence measurements for direct measurement of pO 2 . Another way to quantitate hypoxia is by using immunohistochemical staining of bioreductive chemical probes, such as the 2-nitroimidazoles (29,30). After injection and staining they can be analysed by flow cytometry (31) or visualized in tissue sections (32).…”

Section: Tumour Oxygenationmentioning

confidence: 99%

Clinical Outcome and Tumour Microenvironmental Effects of Accelerated Radiotherapy with Carbogen and Nicotinamide

Bussink¹

1999

Acta Oncologica

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“…3 (7.08 g, 27.9 mmol), and K2C03 (3.85 g, 27.9 mmol) in DMF (75 mL) was heated at 110 °C for 2 h. The solvent was removed under reduced pressure, and the residue was poured into water (200 mL). The precipitate was collected, washed with water (100 mL), and dried to give 2-(2-nitro-lff-imidazolyl)ethylphthalimide (22) (5.28 g, 78%): mp 208.5-209 °C (lit.39 mp 208-210 °C); NMR ((CD3)2SO) 7.82-7.84 (m, 4 H, ArH), 7.60 (s, 1 , H-50, 7.07 (s, 1 , H-40, 4.64 (br t, 2 , H-2), 4.06 (br t, 2 H, H-l); 13C NMR 167.3 (2CO), 144.7 (C-20,134.5 (2C"om), 131.2 (C-50,128.4 (2Carom), 127.9 (C-40,123.1 (2C, rom), 48.3 (C-l), 37.1 (C-2). A stirred solution of this phthalimide (3.65 g, 12.8 mmol) and hydrazine monohydrate (1.24 mL, 25.5 mmol) in EtOH (70 mL) was heated under reflux for 2 h. The resulting suspension was cooled to 0 °C and filtered, and the filtrate was evaporated to dryness under reduced pressure.…”

Section: -(Lü-imidazolyl)ethylamine Dihydrochloride (2v2hc1)mentioning

confidence: 99%

“…Further gains in hypoxic selectivity might, in principle, be achieved by replacing this oxygen-insensitive DNA alkylating moiety with a bioreductive electrophile, thus restricting activation of the electrophilic center to hypoxic cells. Such a compound could be termed a "bis-bioreductive" agent, in that oxygen-© 1994 American Chemical Society 25:R = N02; = 3 0 (i) MsC1/CH2CW20 °C; (ii) NaN3/DMF/100 °C; (iii) Ph3P; concentrated HC1/100 °C.6 (i) NaH/DMF (20) or K2CO3/DMF (22,24); (ii) NH2NH2.…”

mentioning

confidence: 99%

Hypoxia-selective antitumor agents. 8. Bis(nitroimidazolyl)alkanecarboxamides: a new class of hypoxia-selective cytotoxins and hypoxic cell radiosensitizers

Hay

Wilson²,

Moselen³

et al. 1994

J. Med. Chem.

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A series of novel bis(nitroimidazolyl)alkanecarboxamides has been prepared and evaluated for hypoxia-selective cytotoxicity and hypoxic cell radiosensitisation in vitro and in vivo. The compounds were prepared by direct coupling of preformed side chain acid and amine components, using diethyl phosphorocyanidate at room temperature. Although designed to be bis-bioreductive prodrugs of DNA cross-linking agents, none of the compounds showed evidence of DNA cross-linking activity, being equally potent against cell lines deficient and proficient in repair of cross-links. However, one of these compounds, N-[2-(2-methyl-5-nitro-1H-imidazolyl)ethyl]-4-(2-nitro-1H- imidazolyl)butanamide (10; SN 24699), showed high hypoxic selectivity as a cytotoxin (rising to 200-fold after exposure to the drug for several hours) in the repair-proficient Chinese hamster cell line AA8. This selectivity was greater than observed for the alkylating 2-nitroimidazole (4; RB 6145) (40-fold) or simple mononitroimidazoles (5-25-fold). Investigation of structure-activity relationships for hypoxic selectivity of bis(nitroimidazoles) was restricted by their low aqueous solubility, but a certain minimum separation of the two nitroimidazole units (by more than five atoms) appears desirable. All the compounds radiosensitized hypoxic cells in vitro but were little more potent as radiosensitizers than the corresponding monomeric nitroimidazoles. Compound 10 caused additional cell killing in the KHT tumor when multiple drug doses were administered in combination with a single dose of radiation. It is not yet clear whether this activity reflects hypoxic cell radiosensitization or cytotoxicity toward hypoxic cells, but this new class of bis-bioreductive agent clearly warrants further investigation.

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An Efficient Procedure for the 1-Alkylation of 2-Nitroimidazoles and the Synthesis of a Probe for Hypoxia in Solid Tumours

Cited by 31 publications

References 0 publications

Simultaneous triple staining for hypoxia, proliferation, and DNA content in murine tumours

Simultaneous triple staining for hypoxia, proliferation, and DNA content in murine tumours

Clinical Outcome and Tumour Microenvironmental Effects of Accelerated Radiotherapy with Carbogen and Nicotinamide

Hypoxia-selective antitumor agents. 8. Bis(nitroimidazolyl)alkanecarboxamides: a new class of hypoxia-selective cytotoxins and hypoxic cell radiosensitizers

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