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Development and validation of a liquid chromatography-tandem mass spectrometry for the determination of Kendine 91, a novel histone deacetylase inhibitor, in mice plasma and tissue

Development and validation of a liquid chromatography-tandem mass spectrometry for the determination of Kendine 91, a novel histone deacetylase inhibitor, in mice plasma and tissue. Journal of Chromatography B. 2008, vol 870, pp.109-16.

http://www.sciencedirect.com/science/article/pii/S1570023208004340

Abstract:A liquid chromatography-tandem mass spectrometric method (LC-MS/MS) has been developed and validated to determine the concentration of Kendine 91 in mice plasma and tissues. Simvastatin was employed as the internal standard. Separation was performed on a C8 column, with a mobile phase consisting of methanol and aqueous 10 mM formic acid (73:27 v/v). Both analyte and internal standard were determined using electrospray ionization and the MS data acquisition was via multiple-reaction monitoring (MRM) in positive scanning mode. Quantification was performed using the transitions m/z 444 → 169 and 441 → 325 for Kendine 91 and simvastatin, respectively. The method was validated with respect to linearity, accuracy, precision, recovery and stability. This assay has been successfully applied to a pharmacokinetic study after intravenous injection of Kendine 91 in mice in a dose of 10 mg/kg.

Development and Validation of a LC-MS assay for the Quantification of IKH12 a novel anti-tumor condidate in rat plasma and tissues and its Application in a Pharmacokinetic Study

Development and Validation of a LC-MS assay for the Quantification of IKH12 a novel anti-tumor condidate in rat plasma and tissues and its Application in a Pharmacokinetic Study. Biomedical Chromatography 2014

http://onlinelibrary.wiley.com/doi/10.1002/bmc.3414/abstract;jsessionid=607378675456311BA0AF33EDBB917445.f02t04

Abstract: IKH12 is a novel histone deacetylase 6 selective inhibitor. A rapid and sensitive liquid chromatography tandem mass spectrometry method was developed and validated for the quantification of IKH12 in rat plasma and tissue with kendine 91 as internal standard (IS). The samples were prepared by liquid-liquid extraction with tert-butyl methyl ether. The chromatographic separation was accomplished by using a Zorbax Extend C18 4.6 × 150 mm, 5 µm column, with a mobile phase consisting of methanol and 0.1% formic acid (75:25 v/v). Multiple reaction monitoring, using electrospray ionization in positive ion mode, was employed to quantitatively detect IKH12 and IS. The monitored transitions were set at m/z 418 → 252 and 444 → 169 for IKH12 and kendine 91, respectively. The calibration curve was linear over the concentration range 2-1000 ng mL-1 . The intra- and inter-assay precision and accuracy of the quality controls and the limit of quantification were satisfactory in all cases (according to European Medicines Agency guidelines). Stability studies showed that plasma samples were stable in the chromatography rack for 24 h and at -80 °C for 2 months and also after three freeze-thaw cycles. This method was successfully applied to a pharmacokinetic study of IKH12 in rat.

Biodistribution and metabolism of 11C-labeled Kendine 91 in mice and rats.

Biodistribution and metabolism of 11C-labeled Kendine 91 in mice and rats. Applied Radiation and Isotopes 2012, vol 70, pp. 2545-2551.

http://www.sciencedirect.com/science/article/pii/S0969804312003594

Abstract: The biodistribution pattern of [11C]Kendine 91 (a novel HDAC inhibitor) after IV administration has been evaluated using Positron Emission Tomography (rats) and gamma counting of dissected tissues (rats and mice) at different doses (1 μg/kg and 10.0 mg/kg). Metabolism in mice plasma has been also investigated by radio-HPLC. Obtained results (fast accumulation in lungs, heart, kidneys and liver; lower uptake in pancreas and muscle) are in concordance with previously reported results using HPLC/MS-MS. Plasma analysis studies showed a fast metabolism of the radiotracer.

Design, Synthesis and Functional Evaluation of Leukocyte- Function Associated Antigen-1 (LFA-1) Antagonists in Early and Late Stages of Cancer Development.

Design, Synthesis and Functional Evaluation of Leukocyte- Function Associated Antigen-1 (LFA-1) Antagonists in Early and Late Stages of Cancer Development. Journal of Medicinal Chemistry 2013, vol 56, pp. 735-747.

http://pubs.acs.org/doi/abs/10.1021/jm3016848

Abstract: The integrin leukocyte function associated antigen 1 (LFA-1) binds the intercellular adhesion molecule 1 (ICAM-1) by its αL-chain inserted domain (I-domain). This interaction plays a key role in cancer and other diseases. We report the structure-based design, small-scale synthesis, and biological activity evaluation of a novel family of LFA-1 antagonists. The design led to the synthesis of a family of highly substituted homochiral pyrrolidines with antiproliferative and antimetastatic activity in a murine model of colon carcinoma, as well as potent antiadhesive properties in several cancer cell lines in the low micromolar range. NMR analysis of their binding to the isolated I-domain shows that they bind to the I-domain allosteric site (IDAS), the binding site of other allosteric LFA-1 inhibitors. These results provide evidence of the potential therapeutic value of a new set of LFA-1 inhibitors, whose further development is facilitated by a synthetic strategy that is versatile and fully stereocontrolled.

Application of Stereocontrolled Stepwise [3+2] Cycloadditions to the Preparation of Inhibitors of alpha 4 beta 1-Integrin-Mediated Hepatic Melanoma Metastasis.

Application of Stereocontrolled Stepwise [3+2] Cycloadditions to the Preparation of Inhibitors of alpha 4 beta 1-Integrin-Mediated Hepatic Melanoma Metastasis. Angewandte Chemie International Edition. 2005, vol 44, pp.2903-2907.

http://onlinelibrary.wiley.com/doi/10.1002/anie.200462497/pdf

Abstract: Inhibitors of the interaction between protein VLA-4 and its natural ligand VCAM-1 have been designed, even though the structure of the protein remains unresolved. The rational design relied on the simulation of the steric and electronic properties of the active loop of VCAM-1, whose structure is known (see picture), and the inhibitors were readily prepared by stereoselective stepwise [3+2] cycloadditions.

 

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