- Design, synthesis, and in vitro activity of catamphiphilic reverters of multidrug resistance: Discovery of a selective, highly efficacious chemosensitizer with potency in the nanomolar range
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On the basis of the results obtained in previous research, three series of compounds (A-C), derived from verapamil, were designed and synthesized to obtain drugs able to revert multidrug resistance (MDR), an acquired resistance that frequently impairs cancer chemotherapy. The ability of the obtained compounds to revert MDR was evaluated on anthracycline-resistant erythroleukemia K 562 cells, measuring the uptake of THP-adriamycin (pirarubicin) by continuous spectrofluorometric monitoring of the decrease of the fluorescence signal of the anthracycline at 590 nm (λ(ex) = 480 nm), after incubation with cells. Cardiovascular activity, which is responsible for unwanted side effects, was also evaluated. The results obtained show that many of the compounds studied are potent reverters of MDR and are endowed with reduced cardiovascular activity. One of the compounds (7, MM36) presents a pharmacological profile (unprecedented nanomolar potency, high reversal of MDR, low cardiovascular activity) that makes it a promising drug candidate to treat MDR and a useful tool for studying P-glycoprotein.
- Teodori, Elisabetta,Dei, Silvia,Quidu, Patricia,Budriesi, Roberta,Chiarini, Alberto,Garnier-Suillerot, Arlette,Gualtieri, Fulvio,Manetti, Dina,Romanelli, Maria Novella,Scapecchi, Serena
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p. 1687 - 1697
(2007/10/03)
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- Oxygen Sensitization of Electron Capture Response to Isomers of Polycyclic Aromatic Amines and Hydroxides
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The use of the oxygen-sensitized constant-current electron capture detector (ECD) with gas chromatography for analyte identification is extended by examining the responses of numerous polycyclic aromatic amines and hydroxides where an appropriate EC-enhancing chemical tag has been attached to the amino group or the hydroxy group has been methylated.For the majority of isomeric groups examined, measured response enhancements of the derivatives are sufficiently dependent on structural differences as to provide an additional means by which substitution isomers can be differentiated.The ion chemistry responsible for the EC and oxygen-sensitized responses also has been examined by the use of an atmospheric pressure ionization mass spectrometer (APIMS).
- Campbell, J. A.,Grimsrud, E. P.,Hageman, L. R.
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p. 1335 - 1340
(2007/10/02)
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