In vitro and in vivo activity of a new small-molecule inhibitor of HDAC6 in mantle cell lymphoma

Haematologica June 2018 : haematol.2018.189241; doi:10.3324/haematol.2018.189241

Overall, our results show that the QTX125 compound obtained is a new HDAC6-specific inhibitor that causes cell-growth inhibition and programmed cell death in association with increased levels of acetylated α-tubulin, its most recognizable target. The antitumoral effect is particularly evident in MCL models, both in culture and in vivo, surpassing the efficacy of currently available HDAC6 inhibitors. Thus, QTX125 constitutes a novel candidate agent whose utility in epigenetic lymphoma therapy warrants further assessment, its efficacy in the preclinical setting having been demonstrated herein.

Analysis of apoptosis regulatory genes altered by histone deacetylase inhibitors in chronic lymphocytic leukemia cells

Pérez-Perarnau et al, Epigenetics, 2011, 6:10, 1228

Histone deacetylases (HDACs) play a key role in the regulation of acetylation status not only of histones but also of many other non-histone proteins involved in cell cycle regulation, differentiation or apoptosis. Therefore, histone deacetylase inhibitors (HDACi) have emerged as promising anticancer agents. Herein, we report the characterization of apoptosis in B-cell chronic lymphocytic leukemia (CLL) induced by two HDACi, Kendine 92 and SAHA. Both inhibitors induce dose-, time- and caspase-dependent apoptosis through the mitochondrial pathway. Interestingly, Kendine 92 and SAHA show a selective cytotoxicity for B lymphocytes and induce apoptosis in CLL cells with mutated or deleted TP53 as effectively as in tumor cells harboring wild-type TP53. The pattern of apoptosis-related gene and protein expression profile has been characterized. It has shown to be irrespective of TP53 status and highly similar between SAHA and Kendine 92 exposure. The balance between the increased BAD, BNIP3L, BNIP3, BIM, PUMA and AIF mRNA expression levels, and decreased expression of BCL-W, BCL-2, BFL-1, XIAP and FLIP indicates global changes in the apoptosis mRNA expression profile consistent with the apoptotic outcome. Protein expression analysis shows increased levels of NOXA, BIM and PUMA proteins upon Kendine 92 and SAHA treatment. Our results highlight the capability of these molecules to induce apoptosis not only in a selective manner but also in those cells frequently resistant to standard treatments. Thus, Kendine 92 is a novel HDACi with anticancer efficacy for non-proliferating CLL cells.

Synthesis of 11C-labelled Kendine 91, a histone deacetylase inhibitor.

Synthesis of 11C-labelled Kendine 91, a histone deacetylase inhibitor. Applied Radiation and Isotopes. 2012, vol 70, pp. 2552-2557.

Abstract: In the present paper, the synthesis of 11C-labeled Kendine 91 (a HDAC inhibitor which has shown in vitro and in vivo activity in HCT 116 and MOLT 4 human cancer cell lines) is described for the first time. The radiosynthesis has been approached by reaction of the non-radioactive precursor 6-((3-(4-hydroxyphenyl)-5-phenyl-1H-pyrrole-2-carboxamide))hexanehydroxamic acid with [11C]CH3I in basic media. Despite the presence of more than one reactive site in the chemical structure of the precursor, acceptable radiochemical yield (8.2±2.1%, decay corrected to the end of bombardment), specific activity (28.2±9.4 GBq/μmol) and radiochemical purity values (>95%) were obtained in reasonably short preparation times (∼40 min). Despite the moderate radiochemical yield, final radioactivity and radioactivity concentration values (1.8±0.3 GBq and 180 MBq/ml, respectively) should be sufficient for putative in vivo studies in animals.

Resonance Driven Regioselective Demethylation of Berberine. Microwave Assisted Synthesis of Berberrubine and its assesment as Fluorescent Chemosensor for Alkanes

Delgado-Camón et al, Tetrahedron. 2015, 71, 6148

Berberrubine has been synthesized by microwave assisted selective demethylation of berberine. The high selectivity observed in this reaction has been explained and justified by means of computational calculations using Density Functional Theory (DFT) and Natural Resonance Theory (NRT). The existence of two resonant structures of berberrubine is the driving force of regioselective demethylation. Berberrubine is a chemosensor of alkanes, and may have practical applications in petrochemical analysis as a ‘mass’ detector because fluorescent response of saturated hydrocarbons does not depend on hydrocarbon chain length. Berberrubine operates via dipole-induced dipole interactions. Likewise, it has two fluorescent forms in acidic and basic media, which correspond to a keto-enol tautomerism. The fluorescent signal for berberrubine and the amplification of berberrubine-alkane signals by heating can be rationalized from the predominance of enol form when berberrubine is adsorbed onto silica gel.

Stereocontrolled formation of substituted imidazolidines in the reaction between N-metallated azomethine ylides and isocyanate.

Stereocontrolled formation of substituted imidazolidines in the reaction between N-metallated azomethine ylides and isocyanate. ARKIVOC. 2005, Vol. (ix), pp 189-199.;size=150;view=text

Abstract:Substituted imidazolidines (and not imidazolidin-4-ones) are the unexpected cycloadducts obtained in the reaction between imines and isocyanates. The reaction is shown to take place via stepwise [3+2] cycloaddition between the N-metallated azomethine ylide formed in situ and the starting imine, followed by nucleophilic addition of the resulting imidazolidine on the sphybridized carbon atom of the isocyanate. Density-Functional Theory calculations provide a model for the mechanism of this unusual reaction and for the origins of the observed regio- and stereoselectivity.



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