The Chemotherapy of Amoebiasis Part Iii. Variants of Bis(diamylamino)decane

Goodson, John Augustus; Goodwin, L. G.; Gorvin, John H.; Goss, M. D.; Kirby, K.S.; Lock, J. A.; Neal, R. A.; Sharp, Thomas M.; Solomon, William

doi:10.1111/j.1476-5381.1948.tb00353.x

Cited by 2 publications

(1 citation statement)

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“…The synthesis of MN58b has been reported in two papers where it was referred to as Compound 41 (43, 44). In this paper, we include a detailed description of the synthesis of the intermediate 1,4-bis(4-bromomethylphenyl)butane (Figure 3B), which was not provided in the original papers (45, 46) or in either of the papers describing the synthesis of MN58b (43, 44). In addition, we have improved upon the synthesis of MN58b (Figure 3B) by employing an autoclave method following the phase transfer catalyzed bromomethylation (47).…”

Section: Resultsmentioning

confidence: 99%

Direct Inhibition of Choline Kinase by a Near-Infrared Fluorescent Carbocyanine

Arlauckas

Popov

Delikatny

2014

Molecular Cancer Therapeutics

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Choline kinase alpha (ChoK) expression is increasingly being recognized as an important indicator of breast cancer prognosis, however previous efforts to non-invasively measure ChoK status have been complicated by the spectral limitations of in vivo magnetic resonance spectroscopy (MRS) and the complex network of enzymes involved in choline metabolism. The most effective ChoK inhibitors are symmetric and contain quaternary ammonium groups within heterocyclic head groups connected by an aliphatic spacer. Characterization of these bis-pyridinium and bis-quinolinium compounds has led to Phase I clinical trials to assess small molecule inhibitors of ChoK for solid tumor treatment. We report the development of a novel carbocyanine dye, JAS239, whose bis-indolium structure conforms to the parameters established for ChoK specificity and whose spacer length confers fluorescence in the near-infrared window. Fluorimetry and confocal microscopy were used to demonstrate that JAS239 rapidly enters breast cancer cells independent of the choline transporters, with accumulation in the cytosolic space where ChoK is active. Radio-tracing and 1H MRS techniques were used to determine that JAS239 binds and competitively inhibits ChoK intracellularly preventing choline phosphorylation while inducing cell death in breast cancer cell lines with similar efficacy to known ChoK inhibitors. Fluorescent molecules that report on ChoK status have potential use as companion diagnostics for non-invasive breast tumor staging, since NIR fluorescence allows for detection of real time probe accumulation in vivo. Furthermore, their ability as novel ChoK inhibitors may prove effective against aggressive, therapy-resistant tumors.

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