1245501-97-6Relevant academic research and scientific papers
2,3′-Bis(1′H-indole) heterocycles: New p53/MDM2/MDMX antagonists
Neochoritis, Constantinos G.,Wang, Kan,Estrada-Ortiz, Natalia,Herdtweck, Eberhardt,Kubica, Katarzyna,Twarda, Aleksandra,Zak, Krzysztof M.,Holak, Tad A.,D?mling, Alexander
, p. 5661 - 5666 (2015)
The protein-protein interaction of p53 and MDM2/X is a promising non genotoxic anticancer target. A rapid and efficient methodology was developed to synthesize the 2,3′-bis(1′H-indole) heterocyclic scaffold 2 as ester, acid and amide derivatives. Their binding affinity with MDM2 was evaluated using both fluorescence polarization (FP) assay and HSQC experiments, indicating good inhibition and a perfect starting point for further optimizations.
Rational Development of a Potent 15-Lipoxygenase-1 Inhibitor with in Vitro and ex Vivo Anti-inflammatory Properties
Eleftheriadis, Nikolaos,Neochoritis, Constantinos G.,Leus, Niek G. J.,Van Der Wouden, Petra E.,D?mling, Alexander,Dekker, Frank J.
, p. 7850 - 7862 (2015)
Human 15-lipoxygenase-1 (h-15-LOX-1) is a mammalian lipoxygenase and plays an important role in several inflammatory lung diseases such as asthma, COPD, and chronic bronchitis. Novel potent inhibitors of h-15-LOX-1 are required to explore the role of this enzyme further and to enable drug discovery efforts. In this study, we applied an approach in which we screened a fragment collection that is focused on a diverse substitution pattern of nitrogen-containing heterocycles such as indoles, quinolones, pyrazoles, and others. We denoted this approach substitution-oriented fragment screening (SOS) because it focuses on the identification of novel substitution patterns rather than on novel scaffolds. This approach enabled the identification of hits with good potency and clear structure-activity relationships (SAR) for h-1-5-LOX-1 inhibition. Molecular modeling enabled the rationalization of the observed SAR and supported structure-based design for further optimization to obtain inhibitor 14d that binds with a Ki of 36 nM to the enzyme. In vitro and ex vivo biological evaluations of our best inhibitor demonstrate a significant increase of interleukin-10 (IL-10) gene expression, which indicates its anti-inflammatory properties.
