A Novel 3/4-Fused Indole Scaffold through Acid-Catalyzed Cascade Reaction.

3,4-bridged indoles are underrepresented among the vast number of indoles described in the literature. Attempts to access 3,4-macrocyclized indoles led to the unexpected formation of a novel tetracyclic indole through intramolecular acid-catalyzed ring contraction. The herein-established one-step synthetic route provides an excellent medicinal chemistry platform for the construction of screening libraries covering a unique chemical space of indoles.

Replacing the oxidation-sensitive triaminoaryl chemotype of problematic K 7 channel openers: Exploration of a nicotinamide scaffold.

K 7 channel openers have proven their therapeutic value in the treatment of pain as well as epilepsy and, moreover, they hold the potential to expand into additional indications with unmet medical needs. However, the clinically validated but meanwhile discontinued K 7 channel openers flupirtine and retigabine bear an oxidation-sensitive triaminoraryl scaffold, which is suspected of causing adverse drug reactions via the formation of quinoid oxidation products. Here, we report the design and synthesis of nicotinamide analogs and related compounds that remediate the liability in the chemical structure of flupirtine and retigabine.

Carba Analogues of Flupirtine and Retigabine with Improved Oxidation Resistance and Reduced Risk of Quinoid Metabolite Formation.

The K 7 potassium channel openers flupirtine and retigabine have been valuable options in the therapy of pain and epilepsy. However, as a result of adverse reactions, both drugs are currently no longer in therapeutic use. The flupirtine-induced liver injury and the retigabine linked tissue discolouration do not appear related at first glance; nevertheless, both events can be attributed to the triaminoaryl scaffold, which is affected by oxidation leading to elusive reactive quinone diimine or azaquinone diimine metabolites.

Modifications of the Triaminoaryl Metabophore of Flupirtine and Retigabine Aimed at Avoiding Quinone Diimine Formation.

The potassium channel opening drugs flupirtine and retigabine have been withdrawn from the market due to occasional drug-induced liver injury (DILI) and tissue discoloration, respectively. While the mechanism underlying DILI after prolonged flupirtine use is not entirely understood, evidence indicates that both drugs are metabolized in an initial step to reactive - and/or -azaquinone diimines or - and/or -quinone diimines, respectively. Aiming to develop safer alternatives for the treatment of pain and epilepsy, we have attempted to separate activity from toxicity by employing a drug design strategy of avoiding the detrimental oxidation of the central aromatic ring by shifting oxidation toward the formation of benign metabolites.

Azologization and repurposing of a hetero-stilbene-based kinase inhibitor: towards the design of photoswitchable sirtuin inhibitors.

The use of light as an external trigger to change ligand shape and as a result its bioactivity, allows the probing of pharmacologically relevant systems with spatiotemporal resolution. A hetero-stilbene lead resulting from the screening of a compound that was originally designed as kinase inhibitor served as a starting point for the design of photoswitchable sirtuin inhibitors. Because the original stilbenoid structure exerted unfavourable photochemical characteristics it was remodelled to its heteroarylic diazeno analogue.

Sulfide Analogues of Flupirtine and Retigabine with Nanomolar K 7.2/K 7.3 Channel Opening Activity.

The potassium channel openers flupirtine and retigabine have proven to be valuable analgesics or antiepileptics. Their recent withdrawal due to occasional hepatotoxicity and tissue discoloration, respectively, leaves a therapeutic niche unfilled. Metabolic oxidation of both drugs gives rise to the formation of electrophilic quinones.

Flupirtine Analogues: Explorative Synthesis and Influence of Chemical Structure on K7.2/K7.3 Channel Opening Activity.

Neuronal voltage-gated potassium channels K7.2/K7.3 are sensitive to small-molecule drugs such as flupirtine, even though physiological response occurs in the absence of ligands.

Synthesis and potassium K7 channel opening activity of thioether analogues of the analgesic flupirtine.

Flupirtine, an opener of neuronal voltage gated potassium channels (KV7.2/3), has been used as a therapeutic alternative for pain treatment in patients refractory to NSAIDs and opioids. Because flupirtine is associated with rare but fatal drug-induced liver injury that may result from the formation of toxic metabolites upon metabolic oxidation, we synthesized novel derivatives with the goal of identifying equally active and ultimately safer KV7.

Effects of cytotoxic cis- and trans-diammine monochlorido platinum(II) complexes on selenium-dependent redox enzymes and DNA.

Here we present the preparation of 14 pairs of cis- and trans-diammine monochlorido platinum(II) complexes, coordinated to heterocycles (i.e., imidazole, 2-methylimidazole and pyrazole) and linked to various acylhydrazones, which were designed as potential inhibitors of the selenium-dependent enzymes glutathione peroxidase 1 (GPx-1) and thioredoxin reductase 1 (TrxR-1).

Three-Component Aminoalkylations Yielding Dihydronaphthoxazine-Based Sirtuin Inhibitors: Scaffold Modification and Exploration of Space for Polar Side-Chains.

Nonpolar derivatives of heterocyclic aromatic screening hits like the non-selective sirtuin inhibitor splitomicin tend to be poorly soluble in biological fluids. Unlike sp -rich natural products, flat aromatic compounds are prone to stacking and often difficult to optimize into leads with activity in cellular systems. The aim of this work was to identify anchor points for the introduction of sp -rich fragments with polar functional groups into the newly discovered active (IC  = 5 μM) but nonpolar scaffold 1,2-dihydro-3H-naphth[1,2-e][1,3]oxazine-3-thione by a molecular modeling approach.

Substituted tetrazoles as multipurpose screening compounds.

Tetrazoles are small functional heterocycles that are suited to serve simultaneously as aromatic platform for diversity and as functional interaction motif. Furthermore, the tetrazole ring and its deprotonated tetrazolate counterpart are metal ion complexing ligands that possess a rich variety of binding and bridging modes. We recently demonstrated that fragments containing the tetrazole moiety and a metal chelating hydrazide group are well suited to discover selective screening hits with high ligand efficiency for a given protein target.

Oxidation potentials of N-modified derivatives of the analgesic flupirtine linked to potassium KV 7 channel opening activity but not hepatocyte toxicity.

Openers of neuronal voltage-gated potassium channels (KV ) are of interest as therapeutic agents for treating pain (flupirtine) and epilepsy (retigabine). In an effort to better understand the mechanisms of action and toxicity of flupirtine, we synthesized nine novel analogues with varying redox behavior. Flupirtine can be oxidatively metabolized into azaquinone diimines; thus, the oxidation potentials of flupirtine and its analogues were measured by cyclic voltammetry.

Cytotoxic saponins from the seeds of Pittosporum angustifolium.

Three new acylated R1-barrigenol triterpene glycosides, 1-3, were isolated from the seeds of Pittosporum angustifolium Lodd. together with four known glycosides, 4-7, containing R1- and A1-barrigenol backbones. On the basis of spectroscopic, spectrometric, and chemical analyses the novel compounds were named pittangretosides N-P and established as 21beta-acetoxy-22alpha-angeloyloxy- (1), 21beta-acetoxy-22alpha-(2-acetoxy-2-methylbutyroyloxy)- (2), and 21beta-(2-methylbutyroyloxy)-22alpha-acetoxy-3beta-[beta-D-glucopyranosyl- (1 --> 2)]-[alpha-L-arabinopyranosyl-(1 --> 3)]-[alpha-L-arabinofuranosyl-(1 --> 4)]-beta-D-glucuronopyranosyloxyolean-12-ene-15alpha, 6alpha, 28-triol (3).

Tractable synthesis of multipurpose screening compounds with under-represented molecular features for an open access screening platform.

The layout of multipurpose screening libraries must address criteria for the compounds such as novelty, diversity potential, innovative design, and last but not least synthetic tractability. While academic compound collections are often innovative, novel, and highly divers, synthesis of analogs or larger substance quantities is often hampered by complex multistep syntheses with low overall yields. In addition, covalently binding compounds and interaction motifs designed to bind metal ions were discriminated against by the paradigm that these interaction types must almost inevitably lead to toxic effects.

Triterpene glycosides from the leaves of Pittosporum angustifolium.

Phytochemical investigation of the leaves of Pittosporum angustifolium resulted in the isolation and structural elucidation of nine new triterpene saponins, named pittangretosides A-I (1-9), together with a known compound (10). Mainly by NMR and HRESIMS experiments, eight compounds were identified as A1-barrigenol glycosides (1-7, 10), whereas two compounds exhibited an unusual 17,22-seco-backbone of oleanolic acid (8, 9). All compounds were evaluated for their in vitro cytotoxicities against human urinary bladder carcinoma cells (5637).

Cytotoxic and antimicrobial activities of Cu(II), Co(II), Pt(II) and Zn(II) Complexes with N,O-chelating heterocyclic carboxylates.

A series of Cu(II), Co(II), Pt(II) and Zn(II) coordination compounds has been prepared by the reaction of the metal chlorides with pyrazine-2-carboxylic acid, pyridine-2-carboxylic acid, imidazole-4-carboxylic acid, benzimidazole-2-carboxylic acid and 1-methylimidazole-2-carboxylic acid. The complexes were characterized by IR, UV-VIS, elemental analysis, and some by (1) H-NMR, X-ray crystallography, HPLC and LC/MS spectroscopy. All complexes consist of a 2:1 ratio of ligand to metal ion.

Studies on the photoactivation of two cytotoxic trans,trans,trans-diazidodiaminodihydroxo-Pt(IV) complexes.

Light-activation of metal ion complexes to cytotoxic species is of interest due to the potential use in anticancer therapy. Two platinum complexes, trans,trans,trans-[Pt(IV)(N(3))(2)(OH)(2)(NH(3))(2)] (3) and trans,trans,trans-[Pt(IV)(N(3))(2)(OH)(2)(py)(NH(3))] (4) were irradiated with either UV (λ = 366 nm) or white fluorescent light and the various photochemical and photobiological phenomena were characterized. HPLC coupled to UV/Vis and MS detection was used to identify photochemical species resulting from irradiation of 4 with UV and white light.

3,5,7,9-Substituted hexaazaacridines: toward structures with nearly degenerate singlet-triplet energy separations.

Toward the goal of preparing stable, neutral open-shell systems, we synthesized a novel series of p-phenyl-substituted 3,5,7,9-hexaazaacridine and 3,5,7,9-hexaazaanthracene derivatives. The effects of substitution on the molecular electronic properties were probed both experimentally and computationally [B3LYP/6-311G(d,p)//B3LYP/6-31G(d,p)]. While the experimentally prepared structures already have small (20-25 kcal/mol) singlet-triplet energy gaps, systems with even smaller (<9 kcal/mol) singlet-triplet energy separations can be realized through systematic variation of the substituent numbers, types, and patterns.

Peroxidase catalyzed formation of azine pigments--a convenient and sensitive method for the identification of human cells with positive myeloperoxidase reactivity.

A new and efficient method for the identification of human cells with positive myeloperoxidase reactivity was developed. This method is based on the myeloperoxidase catalyzed formation of p-naphthoquinone-thiazol-2-on-azine pigments and offers a number of advantages compared to standard methods. In addition, we report the horseradish peroxidase (HRP) catalyzed oxidative coupling of 2-hydrazono-4-thiazolines with alpha-naphthol.