Physiological concentrations of glucocorticoids induce pathological DNA double-strand breaks.

Steroid hormones induce the transcription of target genes by activating nuclear receptors. Early transcriptional response to various stimuli, including hormones, involves the active catalysis of topoisomerase II (TOP2) at transcription regulatory sequences. TOP2 untangles DNAs by transiently generating double-strand breaks (DSBs), where TOP2 covalently binds to DSB ends. When TOP2 fails to rejoin, called "abortive" catalysis, the resulting DSBs are repaired by tyrosyl-DNA phosphodiesterase 2 (TDP2) and non-homologous end-joining (NHEJ). A steroid, cortisol, is the most important glucocorticoid, and dexamethasone (Dex), a synthetic glucocorticoid, is widely used for suppressing inflammation in clinics. We here revealed that clinically relevant concentrations of Dex and physiological concentrations of cortisol efficiently induce DSBs in G1 phase cells deficient in TDP2 and NHEJ. The DSB induction depends on glucocorticoid receptor (GR) and TOP2. Considering the specific role of TDP2 in removing TOP2 adducts from DSB ends, induced DSBs most likely represent stalled TOP2-DSB complexes. Inhibition of RNA polymerase II suppressed the DSBs formation only modestly in the G1 phase. We propose that cortisol and Dex frequently generate DSBs through the abortive catalysis of TOP2 at transcriptional regulatory sequences, including promoters or enhancers, where active TOP2 catalysis occurs during early transcriptional response.

Enantioselective Synthesis of Secondary Amines by Combining Oxidative Rearrangement and Biocatalysis in a One-Pot Process.

This contribution describes the development of chemoenzymatic one-pot processes, which combine an oxidative rearrangement and a biotransformation catalyzed by an imine reductase (IRED), for the synthesis of highly enantiomerically enriched secondary amines, such as an aryl-substituted pyrrolidine and a benzazepine. The benefits of this chemoenzymatic one-pot approach include high overall conversions (up to >99%), high enantiomeric excesses (up to >99% ee), and a straightforward synthetic approach toward secondary amines without the need to isolate the formed intermediate. For the initial chemical reaction, namely, the oxidative rearrangement, PhI(OAc)2 in methanol is used as a non-natural reagent, whereas the enzymatic step requires only stoichiometric amounts of d-glucose along with catalytic amounts of IRED, glucose dehydrogenase (GDH), and the cofactor NADPH. This methodology, demonstrating the compatibility of a "classic" organic synthesis using a non-natural, highly reactive reagent and a subsequent biocatalytic step, can be applied for different amines as substrates, thus making this concept a versatile tool in synthetic organic chemistry in general and for enantioselective synthesis of heterocyclic secondary amines in particular.

Total Synthesis and Antibacterial Activity of Marine Tris-indole Alkaloid Tulongicin A.

Bis-indole alkaloids from marine sponges are an intriguing class of natural products with a variety of activities. However, only a preliminary biological study of tulongicin A (5), a related previously isolated marine tris-indole alkaloid, has been conducted. In this study, we accomplished the first asymmetric total synthesis of 5 via the construction of an imidazoline-linked bis-indolylmethane skeleton using a Friedel-Crafts-type reaction. Our synthesis enabled a detailed study of the antibacterial profile of 5. Compound 5 displayed bactericidal activity against Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA) strains.

Synthesis and Biological Evaluation of Simplified Ansellone Analogues with Lipophilic Side Chains as HIV Latency-Reversing Agents.

Structurally simplified analogues of ansellone A, in which the decalin skeleton is replaced with a lipophilic chain, were prepared and their HIV latency-reversing activities biologically evaluated. In particular, two analogues bearing ether and alkenyl side chains, respectively, showed comparable activities to that of ansellone A. Each of the simplified compounds was easily synthesized using Prins cyclisation chemistry.

Axially Chiral Borinic Acid Catalysts: Design, Synthesis, and Application in Alkylative Desymmetrization of 1,2-Diols.

A novel chiral borinic acid (CBA), an organocatalyst possessing a binaphthyl skeleton, was designed and synthesized. The synthesis of CBA was achieved with a 72% yield in four steps starting with optically pure 1,1'-bi-2-naphthol. The asymmetric catalytic activity was investigated in the desymmetrization of meso-1,2-diol.

Palladium-Catalyzed Intramolecular Migratory Cycloisomerization of 3-Phenoxy Acrylic Acid Ester via C-O Bond Cleavage and C-O/C-C Bonds Formation for 2,3-Disubstituted Benzofurans Synthesis.

Migratory cycloisomerization using transition metal catalyst is useful for synthesizing substituted heterocyclic compounds. We achieved palladium-catalyzed migratory cycloisomerization of 3-o-alkynylphenoxy acrylic acid ester derivatives to give 2,3-disubstituted benzofurans. Although there are several reports of benzofuran synthesis with palladium-catalyzed migratory cycloisomerization, migratory groups are limited to allyl and propargyl groups. This report is the first example of benzofuran synthesis with palladium-catalyzed cycloisomerization of C(sp2)-O bond cleavage.

Double Ring Expansion Strategy for Fused 3-Benzazepines: Alternative Synthesis of the Dolby-Weinreb Enamine.

A double ring expansion strategy for constructing fused 3-benzazepines is described. The oxidative ring expansion of spiroamine compounds with N-chlorosuccinimide and subsequent ring expansion of the resulting ketiminium ion intermediates with trimethylsilyldiazomethane afforded fused 3-benzazepines in a one-pot operation. Importantly, the Dolby-Weinreb enamine, which is a key synthetic intermediate for harringtonine alkaloids, cephalotaxines, can be accessed from commercial materials in only two steps using our developed method.

Total Synthesis of Ansellone G and Phorbadione.

The first total synthesis of marine sesterterpenoid ansellone G (2) was accomplished. This strategy utilizes the Prins cyclization reaction of a chloro-substituted homoallyl alcohol to synthesize the hydrobenzopyran skeleton. The preintroduction of the chloro groups facilitated the functional group transformation for 2 after constructing the carbon framework. Furthermore, we also successfully synthesized phorbadione (3) by dehydrating the tertiary alcohol. The HIV latency-reversing activity of the synthesized 2, 3, and deacetylated 2 was also evaluated.

Iridium-Catalyzed Intramolecular Cycloisomerization between Functionalized Alkyne with Aryl Vinyl Ether: Synthesis of 2-Vinyl-3-functionalized Methylbenzofurans.

We have developed cycloisomerization between an aryl vinyl ether and a functionalized alkyne, such as silylalkyne, to give 2,3-disubstituted benzofuran derivatives using [IrCl(cod)]2, PCy3, and NaBArF4. This catalyst system not only catalyzes the above cycloisomerization but also isomerize a terminal olefin to give an aryl vinyl ether.

Selective Reduction of α,ß-Unsaturated Weinreb Amides in the Presence of α,ß-Unsaturated Esters.

α,ß-Unsaturated esters were selectively protected in situ in the presence of α,ß-unsaturated Weinreb amides using PEt3 and trimethylsilyl trifluoromethanesulfonate (TMSOTf) in toluene under reflux. Diisobutylaluminium hydride (DIBAL-H) reduction of the mixture followed by tetra-n-butylammonium fluoride (TBAF) treatment produced α,ß-unsaturated aldehydes in good yields along with the recovered α,ß-unsaturated esters.

Discovery and structure-activity relationship of imidazolinylindole derivatives as kallikrein 7 inhibitors.

A series of imidazolinylindole derivatives were discovered as novel kallikrein 7 (KLK7, stratum corneum chymotryptic enzyme) inhibitors. Structure-activity relationship (SAR) studies led to the identification of potent human KLK7 inhibitors. By further modification of the benzenesulfonyl moiety to overcome species differences in inhibitory activity, potent inhibitors against both human and mouse KLK7 were identified. Furthermore, the complex structure of 25 with mouse KLK7 could explain the SAR and the cause of the species differences in inhibitory activity.

Design and synthesis of N1,N8-diacetylspermidine analogues having a linker with desired functional groups.

The synthesis of new N1,N8-diacetylspermidine (DiAcSpd) analogues having a linker with desired functional groups in the methylene skeleton, which have been designed by theoretical calculations, is described. We have also achieved the preparation of DiAcSpd supported on solid-phase resins, which have the potential to be used for the evolution of ligands by exponential enrichment (SELEX).

Highly Discriminative and Chemoselective Deprotection/Transformations of Acetals with the Combination of Trialkylsilyl Triflate/2,4,6-Collidine.

Acetals are the most useful protecting groups for carbonyl functional groups. In addition to the role of protection, they can also be used as synthons of carbonyl functions. Previously, we developed a chemoselective deprotection and nucleophilic substitution of acetals from aldehydes in the presence of ketals. This article describes the highly discriminative and chemoselective transformations of acetals bearing different substitution patterns, different types of acetals, as well as mixed acetals. These reactions can achieve the transformations that cannot be attained by conventional methods, and their results strongly suggest the combination of R3SiOTf/2,4,6-collidine to promote such unprecedented phenomena.

Total Synthesis of Terpenoids Employing a "Benzannulation of Carvone" Strategy: Synthesis of (-)-Crotogoudin.

Carvone is a sustainable and readily available starting material for organic synthesis. Herein, we present the syntheses of various natural product scaffolds that rely on a novel benzannulation involving the α-methyl group (C-10) of carvone to afford a versatile tetralin. The utility of our synthetic approach is highlighted by its application to a short synthesis of the ent-3,4-seco-atisane diterpenoid (-)-crotogoudin. The 13-step enantiospecific synthesis features a regioselective double oxidative dearomatization, a Diels-Alder cycloaddition with ethylene gas (to construct the bicyclo[2.2.2]octane framework), and a final acid-mediated lactonization. The versatility of this benzannulation strategy is demonstrated by its utility in the preparation of the carbon skeleton of ent-3,4-seco-abietane diterpenoids using an intramolecular oxidative dearomatization.

Comparisons of focal macular electroretinograms after indocyanine green-, brilliant blue G-, or triamcinolone acetonide-assisted macular hole surgery.

PURPOSE: To compare the effects of indocyanine green (ICG)-, brilliant blue G (BBG)-, or triamcinolone acetonide (TA)-assisted internal limiting membrane (ILM) peeling during macular hole (MH) surgery on the different components of the focal macular electroretinograms (fmERGs). METHODS: Forty-eight eyes of 48 patients with a macular hole were randomly divided into those undergoing ICG-, BBG-, or TA-assisted vitrectomy (n = 16 for each group). All patients had combined cataract and macular hole surgery with ILM peeling. The fmERGs were recorded before, and 1, 3, 6, 9, and 12 months postoperatively. The amplitudes and implicit times of the a- and b-waves, the amplitudes of the sum of the oscillatory potentials (ΣOPs), and the photopic negative responses (PhNRs) were analyzed. RESULTS: The amplitudes of all of the components of the fmERGs gradually increased with time after surgery (P < 0.005). The implicit times of the a- and b-waves were significantly prolonged at 1 month (P < 0.01) and then gradually returned to the baseline times. No significant differences were found in these changes among the groups. In pooled data from the 48 patients, the PhNR amplitude increased more than the a- and b-waves and the ΣOPs amplitudes at every time point after 3 months (P < 0.005). CONCLUSIONS: The lack of significant differences on the different components of the fmERGs indicates that none of the three agents was toxic to the macula. After closure of a MH, the function of the retinal ganglion cells may recover more than that of the other neural elements in the macular area.

Enantioselective organocatalytic oxidation of ketimine.

C3-Symmetric chiral trisimidazolines with m-chloroperbenzoic acid promoted the organocatalytic oxidation of N-sulfonyl ketimine. The present imidazoline catalysis produced oxaziridines bearing a tetrasubstituted carbon stereogenic center in high yields with up to 87% ee.

Beckmann Fragmentation and Successive Carbon-Carbon Bond Formation Using Grignard Reagents via Phosphonium Salt Intermediates.

The intermediates formed during the Beckmann fragmentation of α-alkoxy and α-alkoxy-α-alkyl oxime acetates have been successfully trapped as phosphonium salts, which were subsequently reacted with a variety of Grignard reagents to give the corresponding substituted products in good yields. Notably, this reaction proceeded smoothly even from α-alkoxy-α-alkyl oxime acetates.

Oxidative rearrangement of cyclobutanone derived N,O-ketals leading to pyrrolidone derivatives.

A halogen-induced oxidative rearrangement of N,O-ketals prepared from cyclobutanones, leading to pyrrolidone derivatives, is developed. The reaction proceeds via an iminium ether intermediate and, depending on the reaction medium, two types of pyrrolidone derivative, containing a halogen atom or hydroxyl group, can be obtained.

C3-Symmetric chiral trisimidazoline-catalyzed Friedel-Crafts (FC)-type reaction.

Imidazoline-catalyzed enantioselective Friedel-Crafts (FC)-type reactions were established using C3-symmetric chiral trisimidazolines. The imidazoline catalysts promoted the FC-type reaction of aldimines with 2-naphthols to produce the corresponding adducts in high yields with up to 99% ee.

Comparisons of cone electroretinograms after indocyanine green-, brilliant blue G-, or triamcinolone acetonide-assisted macular hole surgery.

PURPOSE: To compare the function of retinal ganglion cells (RGCs) using the photopic negative response (PhNR) in patients who had undergone indocyaine green (ICG)-assisted, brilliant blue G (BBG)-assisted, or triamcinolone acetonide (TA)-assisted internal limiting membrane (ILM) peeling during macular hole (MH) surgery. METHODS: Forty-eight eyes of 48 patients with a macular hole were randomly divided into those undergoing ICG-assisted, BBG-assisted, or TA-assisted vitrectomy (n = 16 for each group). Full-field cone ERGs were recorded before and 1, 3, 6, 9, and 12 months postoperatively. The amplitudes and implicit times of the a-waves and b-waves and the amplitudes of the oscillatory potentials (OPs) and PhNRs were measured. The mean deviations (MDs) of standard automated perimetry and the best-corrected visual acuity (BCVA) were measured. The circumferential retinal nerve fiber layer (RNFL) thickness was evaluated by SD-OCT. RESULTS: All macular holes were closed with a significant improvement of the BCVA and MD without differences among the groups. There was no significant difference between the preoperative and postoperative RNFL thickness. The implicit times of the a-waves and b-waves were significantly prolonged, and the ΣOPs amplitude was significantly decreased postoperatively in all groups. These ERG changes were not significantly different among the groups. The postoperative PhNR amplitudes were significantly lower in the ICG group than in the BBG or TA group. CONCLUSIONS: The results indicate that the PhNR may detect subclinical impairments of RGCs caused by the possible toxic effect of ICG. This finding adds to the data that BBG and TA may be safer than ICG for use during MH surgery.