Constantinos G. Neochoritis

1,5-Benzoxazepines vs 1,5-Benzodiazepines.One-Pot Microwave-Assisted Synthesis and Evaluation for Antioxidant Activity and Lipid Peroxidation Inhibition

Amino-1,5-benzoxazepines 2 and 5 and hydroxyl-1,5-benzodiazepines 3 and 6 have been synthesized in one-pot solvent-free conditions from 2,3-diaminophenol and ketones through microwave assisted acid catalysis, the benzoxazepine/benzodiazepine ratio depending on the R(1) and R(3) aryl substituents. The otherwise inaccessible and unknown 2,2-dimethyl-4-aryl-1,5-benzodiazepines 8 were also prepared in an analogous manner. The reaction mechanism was investigated by means of DFT calculations. Structural assignments of the new compounds as well as complete assignment of (1)H and (13)C NMR signals have been unambiguously achieved on the basis of the analysis of their (1)H and (13)C NMR (1D and 2D), IR, MS, and elemental analysis data, whereas the presence of an amino group in 5 and of a hydroxyl in 6 was confirmed by derivatization. Compounds 2, 3, 5f, 6a, 6c, 6d, 6f, 6h, 8c, and 12 were evaluated as antioxidants and lipid peroxidation inhibitors in vitro. Compound 6f was also evaluated as anti-inflammatory agent in vivo. Compounds 2 and 6f were found to be the most potent as inhibitors of lipoxygenase and of lipid peroxidation, respectively.

Versatile Multicomponent Reaction Macrocycle Synthesis Using α-Isocyano-ω-carboxylic Acids

The direct macrocycle synthesis of α-isocyano-ω-carboxylic acids via an Ugi multicomponent reaction is introduced. This multicomponent reaction (MCR) protocol differs by being especially short, convergent, and versatile, giving access to 12-22 membered rings.

How To Design a Successful p53-MDM2/X Interaction Inhibitor: A Thorough Overview Based on Crystal Structures.

A recent therapeutic strategy in oncology is based on blocking the protein–protein interaction between the murine double minute (MDM) homologues MDM2/X and the tumor‐suppressor protein p53. Inhibiting the binding between wild‐type (WT) p53 and its negative regulators MDM2 and/or MDMX has become an important target in oncology to restore the antitumor activity of p53, the so‐called guardian of our genome. Interestingly, based on the multiple disclosed compound classes and structural analysis of small‐molecule–MDM2 adducts, the p53–MDM2 complex is perhaps the best studied and most targeted protein–protein interaction. Several classes of small molecules have been identified as potent, selective, and efficient inhibitors of the p53–MDM2/X interaction, and many co‐crystal structures with the protein are available. Herein we review the properties as well as preclinical and clinical studies of these small molecules and peptides, categorized by scaffold type. A particular emphasis is made on crystallographic structures and the observed binding modes of these compounds, including conserved water molecules present.

Rational Development of a Potent 15-Lipoxygenase-1 Inhibitor with in Vitro and ex Vivo Anti-inflammatory Properties

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 14 d 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.

2,30-Bis(10H-indole) heterocycles: New p53/MDM2/MDMX antagonists.

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 2,30-bis(10H-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.

Towards a facile and convenient synthesis of highly functionalized indole derivatives based on Multi-Component Reactions

A library of potentially bioactive compounds through the novel 1H-indole-methyl-isocyanide and MCRs has been described. A flexible and efficient synthesis affording great complexity and diversity is achieved with moderate to good yields with no need for protection and deprotection steps.

Rational design and synthesis of 1,5-disubstituted tetrazoles as potent inhibitors of the MDM2-p53 interaction.

Using the computational pharmacophore-based ANCHOR.QUERY platform a new scaffold was discovered. Potent compounds evolved inhibiting the protein-protein interaction p53-MDM2. An extensive SAR study was performed based on our four-point pharmacophore model, yielding derivatives with affinity to MDM2 in the nanomolar range. Their binding affinity with MDM2 was evaluated using both fluorescence polarization (FP) assay and 2D-NMR-HSQC experiments.

Isocyanides as Influenza A Virus Subtype H5N1 Wild-Type M2 Channel Inhibitors

Basic bulky amines such as amantadine are well‐characterized M2 channel blockers, useful for treating influenza. Herein we report our surprising findings that charge‐neutral, bulky isocyanides exhibit activities similar to—or even higher than—that of amantadine. We also demonstrate that these isocyanides have potent growth inhibitory activity against the H5N1 virus. The −NH2 to −N≡C group replacement within current anti‐influenza drugs was found to give compounds with high activities at low‐micromolar concentrations. For example, a tenfold improvement in potency was observed for 1‐isocyanoadamantane (27), with an EC50 value of 0.487 μm against amantadine‐sensitive H5N1 virus as determined by both MTT and plaque‐reduction assays, without showing cytotoxicity. Furthermore, the isocyanide analogues synthesized in this study did not inhibit the V27A or S31N mutant M2 ion channels, according to electrophysiology experiments, and did not exhibit activity against amantadine‐resistant virus strains.

Leuckart-Wallach Route Toward Isocyanides and Some Applications

Isocyanide-based multicomponent reactions (IMCR) are among the most important chemical reactions to efficiently generate molecular diversity and have found widespread use in industry and academia. Generally, isocyanides are synthesized in 1-2 steps starting from primary amines. Here, we provide experimental detail on an alternative approach toward formamides and, thus, isocyanides via the Leuckart-Wallach reaction in an improved variation. The resulting >50 synthesized and characterized formamides are useful starting materials for IMCR, as well as other chemistries. The advantage of using the Leuckart-Wallach pathway to formamides and isocyanides is the lower price, on average, of the starting materials, as well as their differential and complementary structural diversity, as compared to the primary amine pathway.

Synthesis of 2-keto-imidazoles utilizing N-arylamino-substituted N-heterocyclic carbenes.

A new method for the synthesis of 2-aroyl-, 2-heteroaroyl-, and 2-cinnamoyl-substituted imidazoles in very good yields has been developed. The reaction employs novel nitrogen heterocyclic carbenes (NHCs), namely, N-arylamino-substituted NHCs, formed in situ from the corresponding imidazolium salts, and subsequent reaction with aromatic, heteroaromatic, and cinnamic aldehydes without utilizing transition metals or expensive specialized catalysts.