Radical-Based Route to Functionalized Tetralin: Formal Total Synthesis of (±)-Hamigeran B.

A formal synthetic route to hamigeran B, an antiviral marine natural product with a unique tricyclic molecular architecture, has been developed. The key chemical transformations in the present route include a novel zinc(II)porphyrin-catalyzed photoredox radical cascade cyclization to access a functionalized tetralin, a catalyst-free benzylic radical bromination with NBS by visible-light irradiation, and a samarium(II)-induced cyclization of brominated tetralone possibly via an orthoquinodimethane-like intermediate.

Total Synthesis of (±)-Liphagal via Organic-Redox-Driven Palladium-Catalyzed Hydroxybenzofuran Formation.

A synthetic route to liphagal, a natural PI3Kα inhibitor isolated from Aka coralliphaga, was established. The present route features an organic redox process where an alkynylquinone undergoes reductive cyclization in the presence of a hydroquinone derivative such as hydroxyquinol (1,2,4-benzenetriol) and catalytic PdCl2 to provide a substituted benzofuran suitable for accessing the natural product. The benzofuran formation takes place via the redox transformation between the alkynylquinone and the electron-rich hydroquinones followed by the concomitant Pd(II)-catalyzed oxycyclization of the resultant alkynylhydroquinone.

Visceral Adipose Tissue Drives Cardiac Aging Through Modulation of Fibroblast Senescence by Osteopontin Production.

BACKGROUND: Aging induces cardiac structural and functional changes linked to the increased deposition of extracellular matrix proteins, including OPN (osteopontin), conducing to progressive interstitial fibrosis. Although OPN is involved in various pathological conditions, its role in myocardial aging remains unknown. METHODS: OPN deficient mice (OPN-/-) with their wild-type (WT) littermates were evaluated at 2 and 14 months of age in terms of cardiac structure, function, histology and key molecular markers. OPN expression was determined by reverse-transcription polymerase chain reaction, immunoblot and immunofluorescence. Luminex assays were performed to screen plasma samples for various cytokines/adipokines in addition to OPN. Similar explorations were conducted in aged WT mice after surgical removal of visceral adipose tissue (VAT) or treatment with a small-molecule OPN inhibitor agelastatin A. Primary WT fibroblasts were incubated with plasma from aged WT and OPN-/- mice, and evaluated for senescence (senescence-associated ß-galactosidase and p16), as well as fibroblast activation markers (Acta2 and Fn1). RESULTS: Plasma OPN levels increased in WT mice during aging, with VAT showing the strongest OPN induction contrasting with myocardium that did not express OPN. VAT removal in aged WT mice restored cardiac function and decreased myocardial fibrosis in addition to a substantial reduction of circulating OPN and transforming growth factor ß levels. OPN deficiency provided a comparable protection against age-related cardiac fibrosis and dysfunction. Intriguingly, a strong induction of senescence in cardiac fibroblasts was observed in both VAT removal and OPN-/- mice. The addition of plasma from aged OPN-/- mice to cultures of primary cardiac fibroblasts induced senescence and reduced their activation (compared to aged WT plasma). Finally, Agelastatin A treatment of aged WT mice fully reversed age-related myocardial fibrosis and dysfunction. CONCLUSIONS: During aging, VAT represents the main source of OPN and alters heart structure and function via its profibrotic secretome. As a proof-of-concept, interventions targeting OPN, such as VAT removal and OPN deficiency, rescued the heart and induced a selective modulation of fibroblast senescence. Our work uncovers OPN's role in the context of myocardial aging and proposes OPN as a potential new therapeutic target for a healthy cardiac aging.

Ru(II)-Catalyzed C-H Aminocarbonylation of N-(Hetero)aryl-7-azaindoles with Isocyanates.

The ruthenium(II)-catalyzed C-H aminocarbonylation of N-(hetero)aryl-7-azaindoles with isocyanates is described. The excellent site selectivity at the ortho-position within the N-(hetero)aryl ring was observed to provide ortho-amidated N-(hetero)aryl-7-azaindoles under the mild reaction conditions. The resulting 7-azaindole derivatives can be readily transformed into 7-azaindoles containing carboxylic acid and alkyl amine functional groups.

Regioselective Rearrangement of 4,4-Disubstituted 2-Hydroxycyclohexa-2,5-Dienones under Deoxyfluorination Conditions.

The dienone-phenol rearrangement is a useful tool for the synthesis of highly substituted phenols. In our previous study of the rearrangement of 4,4-disubstituted 2-hydroxycyclohexa-2,5-dienone under deoxyfluorination conditions, bond migration proceeded with very poor regioselectivity. In this paper, an acid-mediated rearrangement of O-perfluoroalkylsulfonyl difluorides with regioselective migration toward the ß'-carbon is reported. This method allowed the synthesis of a fluorinated analog of allocolchicinoids with improved total yield. Successful application to other substrates was also demonstrated.

Endeavors to access molecular complexity: strategic use of free radicals in natural product synthesis.

Free radicals, which in the past were considered unruly chemical species, have become manageable and indispensable for synthetic organic chemistry. The unique nature of free radicals has allowed practitioners in organic synthesis to design flexible approaches to produce various materials ranging from small molecules to polymers. The present Personal Account describes the author's endeavors to create molecular complexity by the strategic use of free radicals, with an emphasis on the synthesis of bioactive natural products.

Red-Light-Promoted Radical Cascade Reaction to Access Tetralins and Dialins Enabled by Zinc(II)porphyrin, A Light-Flexible Catalyst.

[5,15-Bis(pentafluorophenyl)-10,20-diphenylporphinato]zinc(II) (1), a metalloporphyrin derivative that was recently reported as an efficient photocatalyst driven by blue LEDs by our group, was found to catalyze a red-light-promoted (630 nm LEDs) radical cascade reaction of N-3-arylpropionyloxyphthalimides with radicophiles including electron-deficient alkenes and alkynes, providing access to a range of functionalized tetralin and dialin derivatives. The radical cascade reaction catalyzed by 1 took place via an oxidative quenching cycle in DMSO, where no sacrificial electron donor was required, uncovering a unique solvent effect capable of promoting the porphyrin catalysis.

Dichlorination of olefins with NCS/Ph(3)P.

A 2 : 1 mixture of NCS and Ph(3)P successfully promoted the anti-dichlorination of olefins to provide corresponding dichlorides, serving as a molecular chlorine surrogate generated in situ.

Formal synthesis of (-)-agelastatin A: an iron(II)-mediated cyclization strategy.

An iron(II)-mediated aminohalogenation of a cyclopentenyl N-tosyloxycarbamate provided new access to the key intermediate for the synthesis of (-)-agelastatin A (AA, 1), a potent antiproliferative alkaloid. The present synthetic endeavour offered an insight into the mechanism underlying the iron(II)-mediated aminohalogenation of N-tosyloxycarbamate, in which the radical properties of the N-iron intermediates in the redox states were operative.

Osteopontin promotes age-related adipose tissue remodeling through senescence-associated macrophage dysfunction.

Adipose tissue macrophages (ATMs) play an important role in obesity and inflammation, and they accumulate in adipose tissue (AT) with aging. Furthermore, increased ATM senescence has been shown in obesity-related AT remodeling and dysfunction. However, ATM senescence and its role are unclear in age-related AT dysfunction. Here, we show that ATMs (a) acquire a senescence-like phenotype during chronological aging; (b) display a global decline of basic macrophage functions such as efferocytosis, an essential process to preserve AT homeostasis by clearing dysfunctional or apoptotic cells; and (c) promote AT remodeling and dysfunction. Importantly, we uncover a major role for the age-associated accumulation of osteopontin (OPN) in these processes in visceral AT. Consistently, loss or pharmacologic inhibition of OPN and bone marrow transplantation of OPN-/- mice attenuate the ATM senescence-like phenotype, preserve efferocytosis, and finally restore healthy AT homeostasis in the context of aging. Collectively, our findings implicate pharmacologic OPN inhibition as a viable treatment modality to counter ATM senescence-mediated AT remodeling and dysfunction during aging.

Double C-H functionalization in sequential order: direct synthesis of polycyclic compounds by a palladium-catalyzed C-H alkenylation-arylation cascade.

Palladium-catalyzed cascade C-H alkenylation and arylation provides convenient access to polycyclic aromatic compounds. Treatment of 3-bromoaniline derivatives bearing a bromocinnamyl group on the nitrogen atom with a catalytic amount of [Pd(OAc)(2)] and PCy(3)·HBF(4) in the presence of Cs(2)CO(3) in dioxane affords naphthalene-fused indole derivatives in good yields. This double cyclization reaction is also applicable to heterocyclic substrates, giving fused indoles containing a heteroaromatic ring such as dibenzofuran, dibenzothiophene, carbazole, indole, or benzofuran through heterocyclic C-H arylation. When using a 2,6-unsubstituted aniline derivative, the first C-H arylation preferentially proceeds at the more hindered position of the aniline ring.

Stereoselective α-quaternization of 3-methoxycycloalk-2-enones via 1,4-diastereoinduction of alkoxy dienolates.

The alkylation of dienolates generated from 3-methoxycycloalk-2-enones having a 3'-hydroxyl alkenyl chain provides the corresponding quaternized cycloalkenones in a highly diastereoselective manner. The high degree of stereocontrol in the α-quaternization possibly implies intervention of a rigid chelating transition state that allows an efficient 1,4-asymmetric induction to take place.

Intramolecular iron(II)-catalyzed aminobromination of allyl N-tosyloxycarbamates.

Allyl N-tosyloxycarbamates are found to be catalytically transformed into ß-brominated oxazolidinones with FeBr(2)/n-Bu(4)NBr in t-BuOH.

Stereoconvergent route to chiral cyclohexenone building blocks: formal synthesis of (-)-dysidiolide.

A stereoconvergent access to chiral carbocyclic building blocks is reported. 6-(3'-Hydroxy-4'-methylpent-4'-enyl)-3-methoxy cyclohex-2-enone () that consists of four stereoisomers, i.e., racemic ca. 1 : 1 diastereomers, is converted to enantiomerically pure carbocycles through a combination of regioselective catalytic asymmetric reduction and alkylative remote stereoinduction. The present stereoconvergent strategy has allowed the formal synthesis of bioactive (-)-dysidiolide.

Design and synthesis of C35-fluorinated solamins and their growth inhibitory activities against human cancer cell lines.

The convergent synthesis of C35-fluorinated analogues of solamin, a mono-THF Annonaceous acetogenin, has been achieved by the Sonogashira coupling of the THF ring fragment and the fluorinated γ-lactone fragment. It was revealed that the number of fluorine atoms on the γ-lactone moiety affects the growth inhibitory activities against human cancer cell lines.

Asymmetric total synthesis of (+)-hexachlorosulfolipid, a cytotoxin isolated from Adriatic mussels.

The enantioselective total synthesis of (+)-hexachlorosulfolipid, a cytotoxin found in the Adriatic mussel Mytilus galloprovincialis, is described. The unique chlorinated hydrocarbon motif of the lipid is successfully furnished by a series of dichlorination reactions of chiral epoxides with chlorophosphonium reagent generated in situ from Ph(3)P/NCS. The present total synthesis has allowed the confirmation of the absolute configuration of the natural cytotoxic (+)-hexachlorosulfolipid originally proposed by Fattorusso, Ciminiello, and co-workers.

Convergent synthesis of fluorescence-labeled probes of Annonaceous acetogenins and visualization of their cell distribution.

The convergent synthesis of fluorescence-labeled solamin, an antitumor Annonaceous acetogenin, was accomplished by two asymmetric alkynylations of 2,5-diformyl tetrahydrofuran with an alkyne tagged with fluorescent groups and another alkyne with an α,ß-unsaturated γ-lactone. Assay for the growth inhibitory activity against human cancer cell lines revealed that the probe with the fluorescent groups at the end of the hydrocarbon chain may have the same mode of action as natural acetogenins. The merged fluorescence of dansyl-labeled solamin and MitoTracker Red suggests that Annonaceous acetogenins localize in the mitochondria.

A Virtual Screening Platform Identifies Chloroethylagelastatin A as a Potential Ribosomal Inhibitor.

Chloroethylagelastatin A (CEAA) is an analogue of agelastatin A (AA), a natural alkaloid derived from a marine sponge. It is under development for therapeutic use against brain tumors as it has excellent central nervous system (CNS) penetration and pre-clinical therapeutic activity against brain tumors. Recently, AA was shown to inhibit protein synthesis by binding to the ribosomal A-site. In this study, we developed a novel virtual screening platform to perform a comprehensive screening of various AA analogues showing that AA analogues with proven therapeutic activity including CEAA have significant ribosomal binding capacity whereas therapeutically inactive analogues show poor ribosomal binding and revealing structural fingerprint features essential for drug-ribosome interactions. In particular, CEAA was found to have greater ribosomal binding capacity than AA. Biological tests showed that CEAA binds the ribosome and contributes to protein synthesis inhibition. Our findings suggest that CEAA may possess ribosomal inhibitor activity and that our virtual screening platform may be a useful tool in discovery and development of novel ribosomal inhibitors.

Enantiocontrolled synthesis of polychlorinated hydrocarbon motifs: a nucleophilic multiple chlorination process revisited.

Polychlorinated hydrocarbon motifs have been synthesized in enantiomerically pure forms by means of nucleophilic multiple chlorinations of chiral epoxides, which stereospecifically incorporate halogen atoms into oxygenated molecular scaffolds. The present study demonstrates the scope of the N-chlorosuccinimide (NCS)/organophosphine reagent system that forms multiple sp(3)C-Cl bonds in a regularly repeating pattern with proper stereochemical configurations and evaluates its applicability to various epoxides having elaborate structures. It is noteworthy that tetrachlorinated motifs are produced in one step from bisepoxides by using NCS/Ph(3)P. Furthermore, Ph(2)PCl used in combination with NCS has been found to serve as a potentially useful alternative to NCS/Ph(3)P, especially for promoting dichlorination reactions of alkenyl-substituted epoxides.

Total synthesis of (-)-agelastatin A: an SH2' radical azidation strategy.

A reagent generated from TMSN3/KMnO4/BnEt3NCl was found to promote an SH2' radical azidation of a bromo silyl enol ether to furnish an azido silyl enol ether via olefin transposition. With the present azidation protocol, a new synthetic approach to agelastatin A, a potent antitumor marine alkaloid, has been established.