Heterocyclic Iminoquinones and Quinones from the National Cancer Institute (NCI, USA) COMPARE Analysis.

This review uses the National Cancer Institute (NCI) COMPARE program to establish an extensive list of heterocyclic iminoquinones and quinones with similarities in differential growth inhibition patterns across the 60-cell line panel of the NCI Developmental Therapeutics Program (DTP). Many natural products and synthetic analogues are revealed as potential NAD(P)H:quinone oxidoreductase 1 (NQO1) substrates, through correlations to dipyridoimidazo[5,4-f]benzimidazoleiminoquinone (DPIQ), and as potential thioredoxin reductase (TrxR) inhibitors, through correlations to benzo[1,2,4]triazin-7-ones and pleurotin. The strong correlation to NQO1 infers the enzyme has a major influence on the amount of the active compound with benzo[e]perimidines, phenoxazinones, benz[f]pyrido[1,2-a]indole-6,11-quinones, seriniquinones, kalasinamide, indolequinones, and furano[2,3-b]naphthoquinones, hypothesised as prodrugs. Compounds with very strong correlations to known TrxR inhibitors had inverse correlations to the expression of both reductase enzymes, NQO1 and TrxR, including naphtho[2,3-b][1,4]oxazepane-6,11-diones, benzo[a]carbazole-1,4-diones, pyranonaphthoquinones (including kalafungin, nanaomycin A, and analogues of griseusin A), and discorhabdin C. Quinoline-5,8-dione scaffolds based on streptonigrin and lavendamycin can correlate to either reductase. Inhibitors of TrxR are not necessarily (imino)quinones, e.g., parthenolides, while oxidising moieties are essential for correlations to NQO1, as with the mitosenes. Herein, an overview of synthetic methods and biological activity of each family of heterocyclic imino(quinone) is provided.

Advances in the Synthesis of Ring-Fused Benzimidazoles and Imidazobenzimidazoles.

This review article provides a perspective on the synthesis of alicyclic and heterocyclic ring-fused benzimidazoles, imidazo[4,5-f]benzimidazoles, and imidazo[5,4-f]benzimidazoles. These heterocycles have a plethora of biological activities with the iminoquinone and quinone derivatives displaying potent bioreductive antitumor activity. Synthesis is categorized according to the cyclization reaction and mechanisms are detailed. Nitrobenzene reduction, cyclization of aryl amidines, lactams and isothiocyanates are described. Protocols include condensation, cross-dehydrogenative coupling with transition metal catalysis, annulation onto benzimidazole, often using CuI-catalysis, and radical cyclization with homolytic aromatic substitution. Many oxidative transformations are under metal-free conditions, including using thermal, photochemical, and electrochemical methods. Syntheses of diazole analogues of mitomycin C derivatives are described. Traditional oxidations of o-(cycloamino)anilines using peroxides in acid via the t-amino effect remain popular.

Ring-fused dimethoxybenzimidazole-benzimidazolequinone (DMBBQ): tunable halogenation and quinone formation using NaX/Oxone.

Ring-fused benzimidazolequinones are well-known anti-tumour agents, but dimeric ring-fused adducts are new. The alicyclic [1,2-a] ring-fused dimethoxybenzimidazole-benzimidazolequinone (DMBBQ) intermediate allows late-stage functionalization of bis-p-benzimidazolequinones. DMBBQs are chlorinated and brominated at the p-dimethoxybenzene site using nontoxic sodium halide and Oxone in HFIP/water. X-ray crystallography is used to rationalize site preference in terms of the discontinuity in conjugation in the DMBBQ system. Quinone formation occurs by increasing in situ halogen generation and water. Conversely, radical trifluoromethylation occurs at the quinone of the DMBBQ.

Correction: Visible-light unmasking of heterocyclic quinone methide radicals from alkoxyamines.

Correction for 'Visible-light unmasking of heterocyclic quinone methide radicals from alkoxyamines' by Patrick Kielty et al., Chem. Commun., 2019, 55, 14665-14668, DOI: 10.1039/C9CC08261A.

Visible-light unmasking of heterocyclic quinone methide radicals from alkoxyamines.

In nature, the unmasking of heterocyclic quinones to form stabilized quinone methide radicals is achieved using reductases (bioreduction). Herein, an alternative controllable room-temperature, visible-light activated protocol using alkoxyamines and bis-alkoxyamines is provided. Selective synthetic modification of the bis-alkoxyamine, allowed chromophore deactivation to give one labile alkoxyamine moiety.

Incorporating Morpholine and Oxetane into Benzimidazolequinone Antitumor Agents: The Discovery of 1,4,6,9-Tetramethoxyphenazine from Hydrogen Peroxide and Hydroiodic Acid-Mediated Oxidative Cyclizations.

The reactivity of hydrogen peroxide and catalytic hydroiodic acid toward 3,6-dimethoxy-2-(cycloamino)anilines is tunable to give ring-fused benzimidazoles or 1,4,6,9-tetramethoxyphenazine in high yield. Mechanisms via a detected nitroso-intermediate are proposed for oxidative cyclization and the unexpected intermolecular displacement of the oxazine. An aqueous solution of molecular iodine is capable of the same transformations. Oxidative demethylation gave targeted benzimidazolequinones, including without cleavage of the incorporated oxetane.

Regioselective Fluorination of 7-Oxo-1,2,4-benzotriazines Using Selectfluor.

7-Oxo-1,2,4-benzotriazines (benzo[1,2,4]triazin-7-ones) are reversible thioredoxin reductase inhibitors that exhibit very strong correlations to pleurotin. In this article, we provide the first synthesis of fluorinated derivatives. Fluorination using Selectfluor of benzo[1,2,4]triazin-7-ones occurs regioselectively and in high yield at the enamine-activated position. This electron N-lone pair activation overrides the activation/deactivation effects of some other substituents. The reaction time was significantly reduced with the use of microwave irradiation at 120 °C and 7 bar. The cytotoxicity and cyclic voltammetry measurements for 8-fluoro-1,3-diphenylbenzo[e][1,2,4]triazin-7(1H)-one (2) are presented and compared with its synthetic precursor, 1,3-diphenylbenzo[e][1,2,4]triazin-7(1H)-one (1a).

One-Pot Synthesis of Dihalogenated Ring-Fused Benzimidazolequinones from 3,6-Dimethoxy-2-(cycloamino)anilines Using Hydrogen Peroxide and Hydrohalic Acid.

3,6-Dimethoxy-2-(cycloamino)anilines undergo 4- or 6-electron oxidations to afford novel ring-fused halogenated benzimidazoles or benzimidazolequinones using H2O2/HCl or H2O2/HBr. Cl2 and Br2 are capable of the same oxidative transformation to the benzimidazolequinones. Labeling experiments indicate that water is necessary for oxidation of the para-dimethoxybenzenes to the corresponding quinones.

Synthesis of N-[(dialkylamino)methyl]acrylamides and N-[(dialkylamino)methyl]methacrylamides from Schiff base salts: useful building blocks for smart polymers.

The traditional thermal Mannich reaction is unsuitable for preparing polymerizable N-methylene amino substituted acrylamides and methacrylamides. Herein we provide a facile multi-gram high yield synthesis of these monomeric precursors to stimuli-responsive polymers by the addition of acrylamides and methacrylamides onto in situ generated or freshly isolated methylene Schiff base (iminium) salts. The X-ray crystal structure of the hydrated iminium salt, 1-(hydroxymethyl)azocan-1-ium chloride and monomer·HCl salt (N-[(azocan-1-yl)methyl]prop-2-enamide hydrochloride) is described.

Selective Methylmagnesium Chloride Mediated Acetylations of Isosorbide: A Route to Powerful Nitric Oxide Donor Furoxans.

Isosorbide was functionalized with furoxan for the first time to give adducts that release nitric oxide up to 7.5 times faster than the commercial vasodilator, isosorbide-5-mononitrate (Is5N). The synthesis was facilitated by MeMgCl-mediated selective acetylation of isosorbide or selective deacetylation of isosorbide-2,5-diacetate, which was rationalized in terms of a more stable 5-alkoxide magnesium salt using DFT. Isosorbide-furoxans are safer to handle than Is5N due to greater thermal stability.

Anti-Cancer Activity of Phenyl and Pyrid-2-yl 1,3-Substituted Benzo[1,2,4]triazin-7-ones and Stable Free Radical Precursors.

Cell viability studies for benzo[1,2,4]triazin-7-ones and 1,2,4-benzotriazinyl (Blatter-type) radical precursors are described with comparisons made with 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO). All of the stable free radicals were several orders of magnitude less cytotoxic than the benzo[1,2,4]triazin-7-ones. The synthesis and evaluation of two new pyrid-2-yl benzo[1,2,4]triazin-7-ones are described, where altering the 1,3-substitution from phenyl to pyrid-2-yl increased cytotoxicity against most cancer cell lines, as indicated using National Cancer Institute (NCI) one-dose testing. COMPARE analysis of five-dose testing data from the NCI showed very strong correlations to the naturally occurring anti-cancer compound pleurotin. COMPARE is program, which analyzes similarities in cytotoxicity data of compounds, and enables quantitative expression as Pearson correlation coefficients. Compounds were also evaluated using the independent MTT assay, which was compared with SRB assay data generated at the NCI.

Radical Polymerization of Alkyl 2-Cyanoacrylates.

Cyanoacrylates (CAs) are well-known fast-setting adhesives, which are sold as liquids in the presence of stabilizers. Rapid anionic polymerization on exposure to surface moisture is responsible for instant adhesion. The more difficult, but synthetically more useful radical polymerization is only possible under acidic conditions. Recommendations on the handling of CAs and the resulting polymers are provided herein. In this review article, after a general description of monomer and polymer properties, radical homo- and copolymerization studies are described, along with an overview of nanoparticle preparations. A summary of our recently reported radical polymerization of CAs, using reversible addition-fragmentation chain transfer (RAFT) polymerization, is provided.

Effects of material thickness and processing method on poly(lactic-co-glycolic acid) degradation and mechanical performance.

In this study, the effects of material thickness and processing method on the degradation rate and the changes in the mechanical properties of poly(lactic-co-glycolic acid) material during simulated physiological degradation were investigated. Two types of poly(lactic-co-glycolic acid) materials were considered: 0.12 mm solvent-cast films and 1 mm compression-moulded plates. The experimental results presented in this study were compared to the experimental results of Shirazi et al. (Acta Biomaterialia 10(11):4695-703, 2014) for 0.25 mm solvent-cast films. These experimental observations were used to validate the computational modelling predictions of Shirazi et al. (J Mech Behav Biomed Mater 54: 48-59, 2016) on critical diffusion length scale and also to refine the model parameters. The specific material processing methods considered here did not have a significant effect on the degradation rate and the changes in mechanical properties during degradation; however, they influenced the initial molecular weight and they determined the stiffness and hardness of the poly(lactic-co-glycolic acid) material. The experimental observations strongly supported the computational modelling predictions that showed no significant difference in the degradation rate and the changes in the elastic modulus of poly(lactic-co-glycolic acid) films for thicknesses larger than 100 µm.

Discovery of anti-cancer activity for benzo[1,2,4]triazin-7-ones: Very strong correlation to pleurotin and thioredoxin reductase inhibition.

The thioredoxin (Trx)-thioredoxin reductase (TrxR) system plays a key role in maintaining the cellular redox balance with Trx being over-expressed in a number of cancers. Inhibition of TrxR is an important strategy for anti-cancer drug discovery. The natural product pleurotin is a well-known irreversible inhibitor of TrxR. The cytotoxicity data for benzo[1,2,4]triazin-7-ones showed very strong correlation (Pearson correlation coefficients ∼0.8) to pleurotin using National Cancer Institute COMPARE analysis. A new 3-CF3 substituted benzo[1,2,4]triazin-7-one gave submicromolar inhibition of TrxR, although the parent compound 1,3-diphenylbenzo[1,2,4]triazin-7-one was more cytotoxic against cancer cell lines. Benzo[1,2,4]triazin-7-ones exhibited different types of reversible inhibition of TrxR, and cyclic voltammetry showed characteristic quasi-reversible redox processes. Cell viability studies indicated strong dependence of cytotoxicity on substitution at the 6-position of the 1,3-diphenylbenzo[1,2,4]triazin-7-one ring.

A new era for homolytic aromatic substitution: replacing Bu3SnH with efficient light-induced chain reactions.

Herein is a pertinent review of recent photochemical homolytic aromatic substitution (HAS) literature. Issues with using the reductant Bu3SnH in an oxidative process where the net loss of a hydrogen atom occurs is discussed. Nowadays more efficient light-induced chain reactions are used resulting in HAS becoming a synthetic mechanism of choice rivaling organometallic, transition-metal and electrophilic aromatic substitution protocols. The review includes aromatic substitution as part of a tandem or cascade reaction, Pschorr reaction, as well as HAS facilitated by ipso-substitution, and Smiles rearrangement. Recently visible-light photoredox catalysis, which is carried out at room temperature has become one of the most important means of aromatic substitution. The main photoredox catalysts used are polypyridine complexes of Ru(ii) and Ir(iii), although eosin Y is an alternative allowing metal-free HAS. Other radical initiator-free aromatic substitutions have used 9-mesityl-10-methylacridinium ion and N,N-bis(2,6-diisopropylphenyl)perylene-3,4,9,10-bis(dicarboximide) as the photoredox catalyst, UV-light, photoinduced electron-transfer, zwitterionic semiquinone radical anions, and Barton ester intermediates.

Synthesis of a Spirocyclic Oxetane-Fused Benzimidazole.

A new synthesis of 2-oxa-7-azaspiro[3.5]nonane is described. Spirocyclic oxetanes, including 2-oxa-6-azaspiro[3.3]heptane were converted into o-cycloalkylaminoacetanilides for oxidative cyclizations using Oxone® in formic acid. The expanded spirocyclic oxetane successfully gave the [1,2-a] ring-fused benzimidazole. X-ray crystal structure of the resultant new tetracyclic system, 1',2'-dihydro-4'H-spiro[oxetane-3,3'-pyrido[1,2-a]benzimidazole] and the azetidine ring-opened adduct, N-(2-acetamido-4-bromophenyl)-N-{[3-(chloromethyl) oxetan-3-yl]methyl}acetamide are disclosed.

One-pot hydrogen peroxide and hydrohalic acid induced ring closure and selective aromatic halogenation to give new ring-fused benzimidazoles.

A new series of selectively dichlorinated and dibrominated five- to eight-membered-ring [1,2-a]-fused benzimidazoles and [1,4]oxazino[4,3-a]benzimidazoles are synthesized in mostly high yields of >80% using the reaction of hydrogen peroxide and hydrohalic acid with commercially available o-cyclic amine substituted anilines. Domestic bleach with HCl can also be used for a one-pot ring closure and chlorination.

Photochemical aryl radical cyclizations to give (E)-3-ylideneoxindoles.

(E)-3-Ylideneoxindoles are prepared in methanol in reasonable to good yields, as adducts of photochemical 5-exo-trig of aryl radicals, in contrast to previously reported analogous radical cyclizations initiated by tris(trimethylsilyl)silane and azo-initiators that gave reduced oxindole adducts.

Nanomechanical properties of poly(lactic-co-glycolic) acid film during degradation.

Despite the potential applications of poly(lactic-co-glycolic) acid (PLGA) coatings in medical devices, the mechanical properties of this material during degradation are poorly understood. In the present work, the nanomechanical properties and degradation of PLGA film were investigated. Hydrolysis of solvent-cast PLGA film was studied in buffer solution at 37 °C. The mass loss, water uptake, molecular weight, crystallinity and surface morphology of the film were tracked during degradation over 20 days. Characterization of the surface hardness and Young's modulus was performed using the nanoindentation technique for different indentation loads. The initially amorphous films were found to remain amorphous during degradation. The molecular weight of the film decreased quickly during the initial days of degradation. Diffusion of water into the film resulted in a reduction in surface hardness during the first few days, followed by an increase that was due to the surface roughness. There was a significant delay between the decrease in the mechanical properties of the film and the decrease in the molecular weight. A sudden decline in mechanical properties indicated that significant bulk degradation had occurred.

Tandem reactions via Barton esters with intermolecular addition and vinyl radical substitution onto indole.

A one-pot initiator-free Barton ester decomposition with tandem radical addition onto alkyl propiolates or phenylacetylene with aromatic substitution of the resultant vinyl radical allows convenient access to new 9-substituted 6,7-dihydropyrido[1,2-a]indoles. Propyl radical cyclizations compete when forming the expanded 7,8-dihydro-6H-azepino[1,2-a]indole system. 2-Thiopyridinyl S-radical is incorporated into aromatic adducts when using unsubstituted indole-1-alkanoic acid precursors. X-ray crystallography on substitution products allows selectivity of the radical addition onto less reactive internal alkynes to be determined.