Titanium Alkoxide-Based Regioselective Alkyne-Alkyne Reductive Coupling Mediated by In Situ Generated Arylamidate.

Titanium alkoxide-based alkyne-alkyne reductive coupling mediated by in situ generated arylamidate is described. A high level of regioselectivity is achieved in 37 examples, where (E,E)-dienes are exclusively formed. To the best of our knowledge, this study represents the first example of an apparent amide and carbamate directing effect in metal-mediated reductive coupling.

Identification of a Kavain Analog with Efficient Anti-inflammatory Effects.

Kavain, a compound derived from Piper methysticum, has demonstrated anti-inflammatory properties. To optimize its drug properties, identification and development of new kavain-derived compounds was undertaken. A focused library of analogs was synthesized and their effects on Porphyromonas gingivalis (P. gingivalis) elicited inflammation were evaluated in vitro and in vivo. The library contained cyclohexenones (5,5-dimethyl substituted cyclohexenones) substituted with a benzoate derivative at the 3-position of the cyclohexanone. The most promising analog identifed was a methylated derivative of kavain, Kava-205Me (5,5-dimethyl-3-oxocyclohex-1-en-1-yl 4-methylbenzoate.) In an in vitro assay of anti-inflammatory effects, murine macrophages (BMM) and THP-1 cells were infected with P. gingivalis (MOI = 20:1) and a panel of cytokines were measured. Both cell types treated with Kava-205Me (10 to 200 µg/ml) showed significantly and dose-dependently reduced TNF-α secretion induced by P. gingivalis. In BMM, Kava-205Me also reduced secretion of other cytokines involved in the early phase of inflammation, including IL-12, eotaxin, RANTES, IL-10 and interferon-γ (p < 0.05). In vivo, in an acute model of P. gingivalis-induced calvarial destruction, administration of Kava-205Me significantly improved the rate of healing associated with reduced soft tissue inflammation and osteoclast activation. In an infective arthritis murine model induced by injection of collagen-antibody (ArthriomAb) + P. gingivalis, administration of Kava-205Me was able to reduce efficiently paw swelling and joint destruction. These results highlight the strong anti-inflammatory properties of Kava-205Me and strengthen the interest of testing such compounds in the management of P. gingivalis elicited inflammation, especially in the management of periodontitis.

Discovery of Macrocyclic Inhibitors of Apurinic/Apyrimidinic Endonuclease 1.

Apurinic/apyrimidinic endonuclease 1 (APE1) is an essential base excision repair enzyme that is upregulated in a number of cancers, contributes to resistance of tumors treated with DNA-alkylating or -oxidizing agents, and has recently been identified as an important therapeutic target. In this work, we identified hot spots for binding of small organic molecules experimentally in high resolution crystal structures of APE1 and computationally through the use of FTMAP analysis ( http://ftmap.bu.edu/ ). Guided by these hot spots, a library of drug-like macrocycles was docked and then screened for inhibition of APE1 endonuclease activity. In an iterative process, hot-spot-guided docking, characterization of inhibition of APE1 endonuclease, and cytotoxicity of cancer cells were used to design next generation macrocycles. To assess target selectivity in cells, selected macrocycles were analyzed for modulation of DNA damage. Taken together, our studies suggest that macrocycles represent a promising class of compounds for inhibition of APE1 in cancer cells.

[4 + 2]-Cycloaddition and 1,4-Addition of ortho-Quinone Methides by a Chiral Crotyl Silane.

Anhydrous FeCl3 in the presence of 2,6-lutidine promotes the substrate-controlled enantioselective [4 + 2]-cycloaddition and crotylation reaction between an enantioenriched ( S, E)-crotyl silane and in situ generated ortho-quinone methides ( oQMs). The reaction produces both the chiral chroman and crotylation products in a ratio reflective of the electronic nature of the parent oQM with overall combined yields up to 96%. A ring-opening and elimination sequence was subsequently developed to provide direct access to the crotylation products, containing two contiguous tertiary carbon stereocenters, in good yields and enantioselectivities.

Diastereodivergent Synthesis of Chiral Tetrahydropyrrolodiazepinediones via a One-Pot Intramolecular aza-Michael/Lactamization Sequence.

A modular and diastereodivergent synthesis of tetrahydro-1 H-pyrrolo[1,2 d]diazepine-(2,5)-diones is presented. The tetrahydropyrrolodiazepinedione scaffold is obtained via a base-mediated three-step isomerization/tandem cyclization of amino acid-coupled homoallylic amino esters. Diastereoselectivity of the process is mediated by the interplay of a kinetic cyclization event and a propensity for thermodynamic epimerization at two labile chiral centers, giving rise to two distinct major diastereomers dependent on starting material stereochemistry and reaction conditions selected. Herein, we present a synthetic and computational study for this tandem process on a variety of amino ester substrates.

Reduction of Articular and Systemic Inflammation by Kava-241 in a Porphyromonas gingivalis-Induced Arthritis Murine Model.

Rheumatoid arthritis (RA) is an inflammatory disease that has been linked to several risk factors, including periodontitis. Identification of new anti-inflammatory compounds to treat arthritis is needed. We had previously demonstrated the beneficial effect of Kava-241, a kavain-derived compound, in the management of Porphyromonas gingivalis-induced periodontitis. The present study evaluated systemic and articular effects of Kava-241 in an infective arthritis murine model triggered by P. gingivalis bacterial inoculation and primed with a collagen antibody cocktail (CIA) to induce joint inflammation and tissular destruction. Clinical inflammation score and radiological analyses of the paws were performed continuously, while histological assessment was obtained at sacrifice. Mice exposed to P. gingivalis and a CIA cocktail and treated concomitantly with Kava-241 exhibited a reduced clinical inflammatory score and a decreased number of inflammatory cells and osteoclasts within joint. Kava-241 treatment also decreased significantly tumor necrosis factor alpha (TNF-α) in serum from mice injected with a Toll-like receptor 2 or 4 (TLR-2/4) ligand, P. gingivalis-lipopolysaccharide (LPS). Finally, bone marrow-derived macrophages infected with P. gingivalis and exposed to Kava-241 displayed reduced TLR-2/4, reduced mitogen-activated protein kinase (MAPK)-related signal elements, and reduced LPS-induced TNF-α factor (LITAF), all explaining the observed reduction of TNF-α secretion. Taken together, these results emphasized the novel properties of Kava-241 in the management of inflammatory conditions, especially TNF-α-related diseases such as infective RA.

Kava analogues as agents for treatment of periodontal diseases: Synthesis and initial biological evaluation.

Six kava analogues of the structural type 3-oxocyclohex-1-en-1-yl benzoates (and corresponding benzamides) were synthesized and evaluated for their affect on periodontal deconstruction in collagen anti-body primed oral gavage model of periodontitis. The compounds were prepared through an acylation or amidation of the enolizable cyclic 1,3-diketone. We have learned that three of the analogues are responsible for the reduction of inflammatory cell counts within soft tissue. These novel kava-like molecules where the lactone is replaced by an α,ß-unsaturated ketone show promise in the prevention and treatment of inflammation and alveolar bone loss associated with periodontitis.

Kava-241 reduced periodontal destruction in a collagen antibody primed Porphyromonas gingivalis model of periodontitis.

AIM: The aim of this study was to evaluate the effect of Kava-241, an optimized Piper methysticum Kava compound, on periodontal destruction in a collagen antibody primed oral gavage model of periodontitis. METHODS: Experimental periodontitis was induced by oral gavage of Porphyromonas gingivalis (P. gingivalis) + type II collagen antibody (AB) in mice during 15 days. Mice were treated with Kava-241 concomitantly or prior to P. gingivalis gavage and compared to untreated mice. Comprehensive histomorphometric analyses were performed. RESULTS: Oral gavage with P. gingivalis induced mild epithelial down-growth and alveolar bone loss, while oral gavage with additional AB priming had greater tissular destruction in comparison with gavage alone (p < .05). Kava-241 treatment significantly (p < .05) reduced epithelial down-growth (72%) and alveolar bone loss (36%) in P. gingivalis+AB group. This Kava-241 effect was associated to a reduction in inflammatory cell counts within soft tissues and an increase in fibroblasts (p < .05). CONCLUSION: Priming with type II collagen antibody with oral gavage is a fast and reproducible model of periodontal destruction adequate for the evaluation of novel therapeutics. The effect of Kava-241 shows promise in the prevention and treatment of inflammation and alveolar bone loss associated with periodontitis. Further experiments are required to determine molecular pathways targeted by this therapeutic agent.

Multicomponent Condensation Reactions via ortho-Quinone Methides.

Iron(III) salts promote the condensation of aldehydes or acetals with electron-rich phenols to generate ortho-quinone methides that undergo Diels-Alder condensations with alkenes. The reaction sequence occurs in a single vessel to afford benzopyrans in up to 95% yield. The reaction was discovered while investigating a two-component strategy using 2-(hydroxy(phenyl)methyl)phenols to access the desired ortho-quinone methide in a Diels-Alder condensation. The two-component condensation also afforded the corresponding benzopyran products in yields up to 97%. Taken together, the two- and three-component strategies using ortho-quinone methide intermediates provide efficient access to benzopyrans in good yields and selectivities.

Total Synthesis of Nuclear Factor of Activated T-Cells-68 (NFAT-68): Sequential Use of Chiral Allenylsilane and Titanium Alkoxide-Mediated Reductive Coupling Bond Construction.

Highly enantioenriched chiral allenylsilanes 4 were prepared in high yield through a scalable synthetic sequence, employing a modified copper-catalyzed SN2' reaction. These reagents were used for the production of enantioenriched homoproparglylic ethers 5, which were subjected to titanium alkoxide-mediated reductive coupling with acetylenic esters to produce (E,E)-dienes 6 bearing α,ß,γ,δ-unsaturated esters. Both enantiomers of nuclear factor of activated T-cells-68 (NFAT-68) were synthesized in five steps with the sequential use of the two methods.

Convergent Synthesis of Novel Muramyl Dipeptide Analogues: Inhibition of Porphyromonas gingivalis-Induced Pro-inflammatory Effects by High Doses of Muramyl Dipeptide.

Porphyromonas gingivalis (P.g.)-induced TNF-α can be affected by muramyl dipeptide (MDP) in a biphasic concentration-dependent manner. We found that in P.g.-exposed macrophages, treatment with 10 µg/mL of MDP (MDP-low) up-regulated TNF-α by 29%, while 100 µg/mL or higher (MDP-high) significantly decreased it (16% to 38%). MDP-high was found to affect the ubiquitin-editing enzyme A20 and activator protein 1 (AP1). An AP1 binding site was found in the promoter region of A20. A20 promoter activity was up-regulated after transfection of AP1 cDNA in cells. Four analogues of MDP (3-6) were prepared through a convergent strategy involving the synthesis of two unique carbohydrate fragments, 7a and 7b, using the peptide coupling reagents, EDCI and HOAt. Analogue 4 improved MDP function and P.g.-induced activities. We propose a new signaling pathway for TNF-α induction activated after exposing macrophages to both P.g. and MDP-high or analogue 4.

Enantioselective Multicomponent Condensation Reactions of Phenols, Aldehydes, and Boronates Catalyzed by Chiral Biphenols.

Chiral diols and biphenols catalyze the multicomponent condensation reaction of phenols, aldehydes, and alkenyl or aryl boronates. The condensation products are formed in good yields and enantioselectivities. The reaction proceeds via an initial Friedel-Crafts alkylation of the aldehyde and phenol to yield an ortho-quinone methide that undergoes an enantioselective boronate addition. A cyclization pathway was discovered while exploring the scope of the reaction that provides access to chiral 2,4-diaryl chroman products, the core of which is a structural motif found in natural products.

Total synthesis of (+)-isatisine a: application of a silicon-directed mukaiyama-type [3 + 2]-annulation.

Complete details of an asymmetric synthesis of (+)-isatisine A (1) are described. The synthesis highlights the use of a highly diastereoselective Mukaiyama-type [3 + 2]-annulation of allylsilane 5 with the unsaturated aldehyde 9a to assemble the functionalized tetrahydrofuran core of isatisine A. A convergent route to the framework of the natural product was established that employed a substrate-controlled indole coupling that was followed by a late-stage intramolecular copper(I)-mediated amidation to complete the assembly of the tetracyclic framework of (+)-isatisine A. In addition, the scope of the [3 + 2]-annulation was evaluated and enhanced utilizing diastereomeric allylsilanes anti-5 and syn-5 to establish an efficient route to stereochemically well-defined tetrahydrofurans.

Synthesis of isochromene-type scaffolds via single-flask Diels-Alder-[4 + 2]-annulation sequence of a silyl-substituted diene with menadione.

A sequential Diels-Alder reaction/silicon-directed [4 + 2]-annulation was developed to assemble hydroisochromene-type ring systems from menadione 2. In the first step, a Diels-Alder of the 1-silyl-substituted butadiene 1 with 2 furnished an intermediate cyclic allylsilane. Subsequently, TMSOTf promoted a [4 + 2]-annulation through trapping of an oxonium, generated by condensation between an aldehyde and the TBS protected alcohol resulted in the formation of a cis-fused hydroisochromene 13.

Rhodium(II)-catalyzed alkyne amination of homopropargylic sulfamate esters: stereoselective synthesis of functionalized norcaradienes by arene cyclopropanation.

A rhodium(II) catalyzed nitrene-alkyne cycloaddition of stereochemically well-defined homopropargylic ethers is followed by arene cyclopropanation to afford unique tetracyclic norcaradiene products bearing a cyclic sulfamate. Products from the arene cyclopropanation (Buchner reaction) can be converted to fused cycloheptatrienes via a ring enlarging electrocyclization after nucleophilic ring opening of the cyclic sulfamate ester.

Divergent synthesis of functionalized carbocycles through organosilane-directed asymmetric alkyne-alkene reductive coupling and annulation sequence.

An organosilane-directed alkyne-alkene reductive coupling of readily available propargylsilanes is used to access densely functionalized chiral allylsilanes. The divergent reactivity of the allylsilanes can be controlled to afford a range of novel carbocyclic ring systems through an intramolecular allylation, [3+2] annulation, and Sakurai-like homodimerization.

Bifunctional homoallylic carbamates from chiral silane additions to in situ generated N-acyl iminium ions.

Homoallylic carbamates bearing an α,ß-unsaturated ester or an allylic carbonate were generated respectively utilizing novel chiral silanes through Lewis acid promoted asymmetric aminocrotylation. Those bifunctional building blocks could further undergo Michael addition or cyclization to selectively form functionalized lactams, azetidines, and tetrahydropyrimidinones.

Total synthesis of (-)-virginiamycin M2: application of crotylsilanes accessed by enantioselective Rh(II) or Cu(I) promoted carbenoid Si-H insertion.

A stereoselective synthesis of the antibiotic (-)-virginiamycin M(2) is detailed. A convergent strategy was utilized that proceeded in 10 steps (longest linear sequence) from enantioenriched silane (S)-15. This reagent, which was prepared via a Rh(II)- or Cu(I)-catalyzed carbenoid Si-H insertion, was used to introduce the desired olefin geometry and stereocenters of the C1-C5 propionate subunit. A modified Negishi cross-coupling or an efficient alkoxide-directed titanium-mediated alkyne-alkyne reductive coupling strategy was utilized to assemble the trisubstituted (E,E)-diene. An underutilized late-stage SmI(2)-mediated macrocyclization was employed to construct the 23-membered macrocycle scaffold of the natural product.

Total synthesis of (+)-SCH 351448.

A convergent synthesis of (+)-SCH 351448 (1), a monosodium salt of a C(2)-symmetric macrodiolide, is described. Our approach is based on a [4 + 2] annulation with a chiral allyl silane (anti-5c) to assemble the pyran subunits. Homodimerization was carried out in a stepwise fashion; initial esterification at C29' followed by macrocyclization at C29 afforded the desired macrodiolide.