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This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see [insert ACS Articles on Request author-directed link to Published Work, see https://doi.org/10.1021/acs.jmedchem.9b01006. In this work, we demonstrate that the indole-oxazole-pyrrole framework of the breitfussin family of natural products is a promising scaffold for kinase inhibition. Six new halogenated natural products, breitfussin C–H (3 – 8) were isolated and characterized from the Arctic, marine hydrozoan Thuiaria breitfussi. The structures of two of the new natural products were also confirmed by total synthesis. Two of the breitfussins (3 and 4) were found to selectively inhibit the survival of several cancer cell lines, with the lowest IC50 value of 340 nM measured against the drug-resistant triple negative breast cancer cell line MDA-MB-468, while leaving the majority of the tested cell lines not or significantly less affected. When tested against panels of protein kinases, 3 gave IC50 and Kd values as low as 200 and 390 nM against the PIM1 and DRAK1 kinases, respectively. The activity was confirmed to be mediated through ATP competitive binding in the ATP binding pocket of the kinases. Furthermore, evaluation of potential off-target and toxicological effects, as well as relevant in vitro ADME parameters for 3 revealed that the breitfussin scaffold holds promise for the development of selective kinase inhibitors.

This is an Accepted Manuscript of an article published by Taylor & Francis in Polycyclic aromatic Compounds on 09 May 2016, available online: https://www.tandfonline.com/doi/full/10.1080/10406638.2016.1179651 The dimethylated phenanthrenes 2,3-dimethylphenanthrene (4a), 2,7-dimethylphenanthrene (4b), 2,6-dimethylphenanthrene (4c) and 1,7-dimethylphenanthrene (4d) have been prepared in gram-quantities by a short sequence of directed ortho metalation (DoM) of N,N-diethylbenzamides followed by Suzuki–Miyaura cross-coupling reaction and directed remote metalation (DreM) to form 9-phenanthrols. The final phenanthrenes were obtained through protection/deprotection as triflates.

This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of Organic Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.joc.7b03210. A general method for the regioselective synthesis of a series of ortho-substituted chrysenyl N,N-diethyl-O-carbamates by the directed ortho-metalation (DoM) strategy is reported. The starting O-carbamates were prepared from the corresponding chrysenols, available by oxidative photochemical cyclization or directed remote metalation tactics. Chrysen-1-yl and chrysene-3-yl ring site selectivity of directed ortho-metalation (DoM) and anionic ortho-Fries rearrangement (AoF) protocols, with s-BuLi/TMEDA, followed by electrophilic quench using a selection of electrophiles, were observed, leading to new chrysenyl derivatives. 5-Chrysenyl N,N-diethyl-O-carbamate underwent instant AoF rearrangement even at −100 °C to furnish chrysenyl o-hydroxycarboxamide. Iterative DoM reactions were carried out to gain insight into the regioselectivity factors.

A rotational barrier study was performed on eight tertiary biaryl 2-amides using variable temperature (VT) NMR and exchange (EXSY) spectroscopy experiments. Seven out of the eight 2-amido-2′-methylbiphenyls with additional 3- and 6-substitution patterns (1-7) were found to have approximately similar rotational barriers (G‡ Tc= 56.5 – 67.5 kJ/mol). However, for both 3- and 6-substitution (8), the rotational barrier was found to be significantly higher (G‡ = 102.6-103.8 kJ/mol). Computational studies performed on all eight compounds gave results in good agreement with the experimental rotational barriers. A transition state in which atropisomerism occurs by a cooperative rotation of the Ar-CO and Ar-Ar′ bonds depending on substituent location is proposed.

International audience; The monitoring of the presence of polycyclic aromatic hydrocarbons (PAH) in the aquatic environment is a worldwide activity since some of these compounds are well-established carcinogens and mutagens. Contaminants in this class are in fact regarded as priority hazardous substances for environmental pollution (Water Framework Directive 2000/60/EC). In this study, Atlantic cod (Gadus morhua) was selected to assess in vivo effects of two PAH and their first metabolic products, namely, the corresponding trans-dihydrodiols, using biological markers. Fish were exposed for 1 wk to a single PAH (naphthalene or chrysene) and its synthetic metabolites ((1R,2R)-1,2-dihydronaphthalene-1,2-diol and (1R,2R)-1,2-dihydrochrysene-1,2-diol) by intraperitoneal injection in a continuous seawater flow system. After exposure, PAH metabolism including PAH metabolites in bile and ethoxyresorufin O-deethylase (EROD) activity, oxidative stress glutathione S-transferases (GST) and catalase (CAT) activities, and genotoxicity such as DNA adducts were evaluated, as well as general health conditions including condition index (CI), hepatosomatic index (HSI), and gonadosomatic index (GSI). PAH metabolite values were low and not significantly different when measured with the fixed-wavelength fluorescence screening method, while the gas chromatography-mass spectroscopy (GC-MS) method showed an apparent dose response in fish exposed to naphthalene. DNA adduct levels ≥0.16 × 10(-8) relative adduct level (RAL) were detected. It should be noted that 0.16 × 10(-8) RAL is considered the maximal acceptable background level for this species. The other biomarkers activities of catalase, GST, and EROD did not display a particular compound- or dose-related response. The GSI values were significantly lower in some chrysene- and in both naphthalene- and naphthalene diol-exposed groups compared to control.

Diastereoselective aza-Diels–Alder (aza-DA) reactions of ethyl (S)-N-(tert-butanesulfinyl)iminoacetate (2a) and ethyl (S)-N-(p-toluenesulfinyl)iminoacetate (2b) with different dienes including activated, non-activated, cyclic, and acyclic dienes in the presence of Lewis acids are described. Reactions with 2a were found to be more selective. Reactions of unactivated dienes (acyclic and cyclic) with stoichiometric amounts of TMSOTf as Lewis acid afforded the aza-DA adducts in modest yields and in diastereoselectivities up to 99%. A strong preference for Re-approach was observed for 2a. Cyclic dienes gave the exo adducts as major products. For the aza-DA reaction with activated Danishefsky type dienes poor diastereoselectivities were observed. In these cases, the best results were obtained using stoichiometric amounts of BF3·Et2O as Lewis acid (up to 69% de, 76% yield). The absolute configurations of six of the addition products were established by chemical correlation with known compounds. Acidic cleavage of the sulfinyl group occurred without racemization to optically active non-proteinogenic α-amino acid ethyl esters.

Accepted manuscript version. Publisher's version available at http://dx.doi.org//10.1016/j.tet.2015.09.003. The first syntheses of tubastrine and 3-dehydroxy tubastrine are described. The target compounds were prepared in four consecutive steps from commercially available starting materials. The central scaffold was formed by a microwave-assisted C–N cross-coupling reaction between 1,3-bis(tert-butoxycarbonyl)-guanidine and (E)-((4-(2-iodovinyl)-1,2-phenylene)bis(oxy))bis(tert-butyldimethylsilane) and (E)-tert-butyl(4-(2-iodovinyl)phenoxy)–dimethylsilane, respectively. The aryl vinyl iodides were obtained by a Hunsdiecker–Borodin-type reaction of aryl acrylic acids, which were easily available from trans-caffeic acid or trans-p-coumaric acid.

A general chiral building block containing the 1R,2R-trans-diol moiety was constructed utilizing the stereoselective Shi-epoxidation reaction on a tetralone scaffold assembled by a Negishi cross-coupling on N,N-diethylbenzamide. Further elaboration of this chiral building block into polycyclic aromatic compounds was demonstrated with the total synthesis of the precursor for the most carcinogenic metabolite of chrysene, (−)-(1R,2R)-1,2-dihydrochrysene-1,2-diol in 87% ee.

Anorectal function was evaluated in 11 patients with voiding dysfunction due to multiple sclerosis. In six patients with constipation, three also had symptoms of obstructed defecation and one patient was incontinent due to stercoral diarrhea. One patient was only fecal incontinent and one patient had obstructed defecation as the only symptom. Three patients had no anorectal symptoms. Anal manometry in the women compared with a control group revealed significant lower anal resting and squeeze pressures, although no significant difference of rectal sensation to distention with air was found. Pudendal nerve terminal latencies were obtained in seven patients and were all normal. In four patients latency could not be demonstrated due to poor contraction of the sphincter on stimulation of the pudendal nerve. Two of these patients were incontinent and two had both constipation and obstructed defecation. It is concluded that patients with voiding symptoms due to multiple sclerosis often reveal anorectal symptoms or motility disorders. Although anal sphincter function is reduced, fecal incontinence is not prevalent in this group. The reason for this lies probably in the fact that many of the patients are constipated, thus securing fecal continence.

The implantation of an artificial anal sphincter in five patients with anal incontinence of neuromuscular origin is described. The prosthesis, an AMS 800 artificial urinary sphincter (American Medical Systems), worked well with solid or semisolid stool, but less satisfactorily when diarrhea was present. Manometric and defecographic studies seem to indicate that the effect of the prosthesis may be ascribed partly to maintenance of an acute anorectal angle even during straining.

The implantation of an artificial anal sphincter in a man with severe anal incontinence and myasthenia gravis is described. The prosthesis used, an 'AMS 800' artificial urinary sphincter, gave the patient complete control of defecation. The technique offers the possibility of curing anal incontinence of neuromuscular origin, for which there has been no treatment until now.

To evaluate the possible effect of gastrointestinal neuropeptides on anal function, the effect of somatostatin, enkephalin, VIP, and substance P on anal canal pressure and electromyographic response of the external anal sphincter was studied in healthy subjects. Enkephalin and somatostatin elicited a significant decrease in anal canal pressure after a bolus injection of 1 microgram/kg body weight whereas VIP and substance P had no effect. Future studies must show whether these effects are of pharmacologic importance and if these peptides participate in the physiologic regulation of anorectal function.