Development of 5-benzylpaullones and paullone-9-carboxylic acid alkyl esters as selective inhibitors of mitochondrial malate dehydrogenase (mMDH)

Becker, A.; Kohfeld, Simone; Lader, Annette; Preu, Lutz; Pies, Tanja; Wieking, Karen; Ferandin, Yoan; Knockaert, Marie; Meijer, Laurent; Kunick, Conrad

doi:10.1016/j.ejmech.2009.10.018

Cited by 28 publications

(17 citation statements)

References 18 publications

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“…14,15 However, their clinical use was hampered by their limited aqueous solubility. One way to potentially overcome this problem was the coordination of these organic compounds to metal ions.…”

Section: Introductionmentioning

confidence: 99%

Effect of the Piperazine Unit and Metal-Binding Site Position on the Solubility and Anti-Proliferative Activity of Ruthenium(II)- and Osmium(II)- Arene Complexes of Isomeric Indolo[3,2-c]quinoline—Piperazine Hybrids

et al. 2014

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In this study, the indoloquinoline backbone and piperazine were combined to prepare indoloquinoline–piperazine hybrids and their ruthenium- and osmium-arene complexes in an effort to generate novel antitumor agents with improved aqueous solubility. In addition, the position of the metal-binding unit was varied, and the effect of these structural alterations on the aqueous solubility and antiproliferative activity of their ruthenium- and osmium-arene complexes was studied. The indoloquinoline–piperazine hybrids L1–3 were prepared in situ and isolated as six ruthenium and osmium complexes [(η6-p-cymene)M(L1–3)Cl]Cl, where L1 = 6-(4-methylpiperazin-1-yl)-N-(pyridin-2-yl-methylene)-11H-indolo[3,2-c]quinolin-2-N-amine, M = Ru ([1a]Cl), Os ([1b]Cl), L2 = 6-(4-methylpiperazin-1-yl)-N-(pyridin-2-yl-methylene)-11H-indolo[3,2-c]quinolin-4-N-amine, M = Ru ([2a]Cl), Os ([2b]Cl), L3 = 6-(4-methylpiperazin-1-yl)-N-(pyridin-2-yl-methylene)-11H-indolo[3,2-c]quinolin-8-N-amine, M = Ru ([3a]Cl), Os ([3b]Cl). The compounds were characterized by elemental analysis, one- and two-dimensional NMR spectroscopy, ESI mass spectrometry, IR and UV–vis spectroscopy, and single-crystal X-ray diffraction. The antiproliferative activity of the isomeric ruthenium and osmium complexes [1a,b]Cl–[3a,b]Cl was examined in vitro and showed the importance of the position of the metal-binding site for their cytotoxicity. Those complexes containing the metal-binding site located at the position 4 of the indoloquinoline scaffold ([2a]Cl and [2b]Cl) demonstrated the most potent antiproliferative activity. The results provide important insight into the structure–activity relationships of ruthenium- and osmium-arene complexes with indoloquinoline–piperazine hybrid ligands. These studies can be further utilized for the design and development of more potent chemotherapeutic agents.

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Section: Introductionmentioning

confidence: 99%

Effect of the Piperazine Unit and Metal-Binding Site Position on the Solubility and Anti-Proliferative Activity of Ruthenium(II)- and Osmium(II)- Arene Complexes of Isomeric Indolo[3,2-c]quinoline—Piperazine Hybrids

et al. 2014

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“…(12) Experiments with enzyme assays confirmed the assumption, and a larger series of paullones was evaluated for their biological activity. 13−15 …”

Section: Introductionmentioning

confidence: 99%

Ruthenium− and Osmium−Arene Complexes of 2-Substituted Indolo[3,2-c]quinolines: Synthesis, Structure, Spectroscopic Properties, and Antiproliferative Activity

et al. 2010

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The synthesis of new modified indolo[3,2-c]quinoline ligands L1−L8 with metal-binding sites is reported. By coordination to ruthenium− and osmium−arene moieties 16 complexes of the type [(η6-p-cymene)M(L)Cl]Cl (1a,b−8a,b), where M is RuII or OsII and L is L1−L8, have been prepared. All compounds were comprehensively characterized by elemental analysis, electrospray ionization mass spectrometry, IR, UV−vis, and NMR spectroscopy, thermogravimetric analysis, and single-crystal X-ray diffraction (2a, 4a, 4b, 5a, 7a, and 7b). The complexes were tested for antiproliferative activity in vitro in three human cancer cell lines, namely, CH1 (ovarian carcinoma), SW480 (colon adenocarcinoma), and A549 (non-small-cell lung cancer), yielding IC50 values in the submicromolar or low micromolar range.

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“…As a first case study for MB-OED, the homogeneous synthesis of 3,4-dihydro-1H-1-benzazepine-2,5-dione (DHBD) from the enolized 3-oxocarboxylic ester in wet dimethyl sulfoxide (DMSO) under neutral conditions and at elevated temperatures is presented; see Figure 4. DHBD and its derivatives are pharmaceutically relevant scaffolds utilized for the synthesis of various protein kinase inhibitors and anticancer agents [55][56][57][58][59][60]. In traditional reaction optimization studies, isothermal syntheses at various temperatures are carried out one by one, and the syntheses are analyzed with offline high-performance liquid chromatography (HPLC) in order to determine reaction kinetics.…”

Section: Synthesis Of An Api-scaffold (Dhbd)mentioning

confidence: 99%

The Impact of Global Sensitivities and Design Measures in Model-Based Optimal Experimental Design

et al. 2018

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In the field of chemical engineering, mathematical models have been proven to be an indispensable tool for process analysis, process design, and condition monitoring. To gain the most benefit from model-based approaches, the implemented mathematical models have to be based on sound principles, and they need to be calibrated to the process under study with suitable model parameter estimates. Often, the model parameters identified by experimental data, however, pose severe uncertainties leading to incorrect or biased inferences. This applies in particular in the field of pharmaceutical manufacturing, where usually the measurement data are limited in quantity and quality when analyzing novel active pharmaceutical ingredients.Optimally designed experiments, in turn, aim to increase the quality of the gathered data in the most efficient way. Any improvement in data quality results in more precise parameter estimates and more reliable model candidates. The applied methods for parameter sensitivity analyses and design criteria are crucial for the effectiveness of the optimal experimental design. In this work, different design measures based on global parameter sensitivities are critically compared with state-of-the-art concepts that follow simplifying linearization principles. The efficient implementation of the proposed sensitivity measures is explicitly addressed to be applicable to complex chemical engineering problems of practical relevance. As a case study, the homogeneous synthesis of 3,4-dihydro-1H-1-benzazepine-2,5-dione, a scaffold for the preparation of various protein kinase inhibitors, is analyzed followed by a more complex model of biochemical reactions. In both studies, the model-based optimal experimental design benefits from global parameter sensitivities combined with proper design measures.

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Development of 5-benzylpaullones and paullone-9-carboxylic acid alkyl esters as selective inhibitors of mitochondrial malate dehydrogenase (mMDH)

Cited by 28 publications

References 18 publications

Effect of the Piperazine Unit and Metal-Binding Site Position on the Solubility and Anti-Proliferative Activity of Ruthenium(II)- and Osmium(II)- Arene Complexes of Isomeric Indolo[3,2-c]quinoline—Piperazine Hybrids

Effect of the Piperazine Unit and Metal-Binding Site Position on the Solubility and Anti-Proliferative Activity of Ruthenium(II)- and Osmium(II)- Arene Complexes of Isomeric Indolo[3,2-c]quinoline—Piperazine Hybrids

Ruthenium− and Osmium−Arene Complexes of 2-Substituted Indolo[3,2-c]quinolines: Synthesis, Structure, Spectroscopic Properties, and Antiproliferative Activity

The Impact of Global Sensitivities and Design Measures in Model-Based Optimal Experimental Design

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