Metal complexes of the diuretic drug furosemide

New complexes of the formulaeM(fur)₂·2H₂O (M = Mn, Cu, Zn),M(fur)₂·3H₂O (M = Co, Ni, Cd), Hg₂(fur)₃Cl₂·2H₂O, Pd(fur)Cl·H₂O and Rh(fur)₃·3H₂O, wherefurH = 4-chloro-N-(2-furfuryl)-5-sulfamoylanthranilic acid, have been prepared and characterized by conductivity measurements, X-ray powder patterns, thermal methods, effective magnetic moments as well as by IR, ligand field,¹H-NMR and ESR spectroscopic studies. The anionfur ^– shows a chelated bidentate O(carboxylato), N(imino)-coordinating behaviour.

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Metallkomplexe der diuretischen Droge Furosemid

Zusammenfassung Neue Komplexe der Verbindungen:M(fur)₂·2H₂O (M = Mn, Cu, Zn),M(fur)₂·3H₂O (M = Co, Ni, Cd), Hg₂(fur)₃Cl₂·2H₂O, Pd(fur)Cl·H₂O und Rh(fur)₃·3H₂O, wobeifurH 4-chlor-N-(2-furfuryl)-5-sulfamoylanthanilsäure ist, wurden dargestellt. Die Komplexe wurden durch Leitfähigkeitsmessungen, Röntgen-Pulver-Aufnahmen, thermogravimetrische Analysen, Messungen des effektiven magnetischen Dipolemomentes sowie durch spektroskopische Untersuchungen (IR,¹H-NMR und ESR) charakterisiert. Das Anionfur ^– zeigt das Verhalten einer Chelat-bidentat-O(carboxylato),N(imino)-Koordination.

     

Coordination compounds of N-(2-aminophenyl)- and N-(3-aminophenyl)pyridine-2′-carboxamide with cobalt(II) and cobalt(III). The nature of amide deprotonation induced by cobalt(III) in acidicpH

New complexes of the general formulae CoL ₂ X·nH₂O (X=Cl, Br, I, NCS, NO₃ andn=0, 1, 2 or 3), Co₂ L ₂ X ₃·EtOH (X=Cl, Br, I, NCS), Co(DH)X ₂ (X=NCS, NO₃) and Co(DH)₂ X ₂ (X=NCS, I) have been prepared, whereLH=N-(2-aminophenyl)pyridine-2-carboxamide andDH=N-(3-aminophenyl)pyridine-2-carboxamide. The compounds were characterized by X-ray powder patterns, conductivity measurements, thermogravimetric analysis, magnetic properties as well as by IR, ligand field and¹H-NMR spectroscopy. In the presence of oxygen,LH undergoes a cobalt(III) ion promoted amide hydrogen ionization in thepH region 4–6.

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Koordinationsverbindungen von N-(2-aminophenyl)- und N-(3-aminophenyl)pyridin-2-carboxamid mit Cobalt(II) und Cobalt(III). Die Natur der Deprotonierung von Amiden induziert von Cobalt(III) in saurem Medium

Zusammenfassung Neue Komplexe der allgemeinen Formeln CoL ₂ X·nH₂O (X=Cl, Br, I, NCS, NO₃ undn=0, 1, 2, 3), Co₂ L ₂ X ₃·EtOH (X=Cl, Br, I, NCS), Co(DH)X ₂ (X=NCS, NO₃) und Co(DH)₂ X ₂ (X=NCS, I) wurden dargestellt mit LH=N-(2-aminophenyl)pyridin-2-carboxamid undDH=N-(3-aminophenyl)pyridin-2-carboxamid. Die Verbindungen wurden mittels Röntgenstrukturanalyse, Leitfähigkeitsmessungen, thermogravimetrischen Analysen, magnetischen Eigenschaften sowie mit IR-, Ligandenfeld- und¹H-NMR-Spektroskopie charakterisiert. In Gegenwart von Sauerstoff unterliegtLH einer Cobalt(III)ion-induzierten Amidwasserstoffionisierung impH-Bereich 4–6.

     

In vivo evaluation and in vitro metabolism of leuprolide in mice--mass spectrometry-based biomarker measurement for efficacy and toxicity

The study of pharmacologically active peptides is central for the understanding of cancer and the development of novel therapeutic approaches. In this context, both qualitative and quantitative determination of bioactive peptides in biological fluids/tissues and their effect on endogenous factors (e.g. hormones) are of great importance. A mass spectrometry-based approach was developed and applied towards the measurement of leuprolide, a peptide drug for the treatment of prostate cancer, in mouse plasma. High-pressure liquid chromatography coupled to a hybrid quadrupole linear ion trap (QqLIT) mass spectrometer, a platform that combines the benefits of triple QqLIT instruments, was employed for the study. Using the described methodology, we established that picomolar concentrations of leuprolide could be measured in mouse plasma (limit of quantification of 0.1 ng/ml). In order to optimize pharmacokinetic properties of analogs of leuprolide, a facile in vivo mouse model was developed and leuprolide concentrations were determined in mouse plasma following intraperitoneal administration. In the same animal model, we demonstrated the versatility of the described MS-based approach by the determination of plasma concentrations of testosterone, an established biomarker for the treatment of prostate cancer. Following dosing with leuprolide, circulating testosterone was increased significantly in comparison to vehicle-treated mice. Finally, in vitro metabolism of leuprolide was evaluated by incubation of leuprolide with mouse kidney membranes, followed by identification of major metabolites by MS. Such studies provide the framework for future evaluation of novel leuprolide analogs with potential therapeutic advantages.