Antiallergic agents from natural sources 9. Inhibition of nitric oxide production by novel chalcone derivatives from Mallotus philippinensis (Euphorbiaceae)

Three novel chalcone derivatives, mallotophilippens C (1), D (2) and E (3) were isolated from the fruits of Mallotus philippinensis MUELL. ARG. These compounds were identified, using chemical and spectral data, as 1-[6-(3,7-dimethyl-octa-2,6-dienyl)-5,7-dihydroxy-2,2-dimethyl-2H-chromen-8-yl]-3-(4-hydroxy-phenyl)-propenone, 3-(3,4-dihydroxy-phenyl)-1-[6-(3,7-dimethyl-octa-2,6-dienyl)-5,7-dihydroxy-2,2-dimethyl-2H-chromen-8-yl]-propenone and 1-[5,7-dihydroxy-2-methyl-6-(3-methyl-but-2-enyl)-2-(4-methyl-pent-3-enyl)-2H-chromen-8-yl]-3-(3,4-dihydroxy-phenyl)-propenone, respectively. They inhibited nitric oxide (NO) production and inducible NO synthase (iNOS) gene expression by a murine macrophage-like cell line (RAW 264.7), which was activated by lipopolysaccharide (LPS) and recombinant mouse interferon-gamma (IFN-gamma). Furthermore, they downregulated cyclooxygenase-2 (COX-2) gene, interleukin-6 (IL-6) gene and interleukin-1beta (IL-1beta) gene expression. These results suggest that they have anti-inflammatory and immunoregulatory effects.     

Direct catalytic asymmetric aldol reaction of hydroxyketones: asymmetric Zn catalysis with a Et(2)Zn/linked-BINOL complex

Full details of our newly developed catalyses with asymmetric zinc complexes as mimics of class II zinc-containing aldolase are described. A Et(2)Zn/(S,S)-linked-BINOL complex was developed and successfully applied to direct catalytic asymmetric aldol reactions of hydroxyketones. A Et(2)Zn/(S,S)-linked-BINOL 1 = 2/1 system was initially developed, which efficiently promoted the direct aldol reaction of 2-hydroxy-2'-methoxyacetophenone (7d). Using 1 mol % of (S,S)-linked-BINOL 1 and 2 mol % of Et(2)Zn, we obtained 1,2-dihydroxyketones syn-selectively in high yield (up to 95%), good diastereomeric ratio (up to 97/3), and excellent enantiomeric excess (up to 99%). Mechanistic investigation of Et(2)Zn/(S,S)-linked-BINOL 1, including X-ray analysis, NMR analysis, cold spray ionization mass spectrometry (CSI-MS) analysis, and kinetic studies, provided new insight into the active oligomeric Zn/(S,S)-linked-BINOL 1/ketone 7d active species. On the basis of mechanistic investigations, a modified second generation Et(2)Zn/(S,S)-linked-BINOL 1 = 4/1 with molecular sieves 3A (MS 3A) system was developed as a much more effective catalyst system for the direct aldol reaction. As little as 0.1 mol % of (S,S)-linked-BINOL 1 and 0.4 mol % of Et(2)Zn promoted the direct aldol reaction smoothly, using only 1.1 equiv of 7d as a donor (substrate/ligand = 1000). This is the most efficient, in terms of catalyst loading, asymmetric catalyst for the direct catalytic asymmetric aldol reaction. Moreover, the Et(2)Zn/(S,S)-linked-BINOL 1 = 4/1 system was effective in the direct catalytic asymmetric aldol reaction of 2-hydroxy-2'-methoxypropiophenone (12), which afforded a chiral tetrasubstituted carbon center (tert-alcohol) in good yield (up to 97%) and ee (up to 97%), albeit in modest syn-selectivity. Newly developed (S,S)-sulfur-linked-BINOL 2 was also effective in the direct aldol reaction of 12. The Et(2)Zn/(S,S)-sulfur-linked-BINOL 2 = 4/1 system gave aldol adducts anti-selectively in good ee (up to 93%). Transformations of the aldol adducts into synthetically versatile intermediates were also described.     

Facile generation method for conjugated allenyl esters based on retro-Dieckmann-type ring-opening reactions

α-Alkynyl-α-ethoxycarbonyl cyclopentanones 1a-c and cyclohexanones 2a-c were readily synthesized by the reaction of ethyl 2-oxocyclopentanonecarboxylate 6 and ethyl 2-oxocyclohexanonecarboxylate 7 with alkynyllead triacetates 5a-c obtained from lithium acetylides 4a-c and lead tetraacetate. Treatment of 1a-c and 2a-c with 1 N KOH in THF or with n-Bu₄N⁺OEt⁻ in EtOH and THF gave the corresponding conjugated allenyl esters 8a-c, 9a-c, 10a-c, and 11a-c in good to excellent yields, respectively.     

Effects of a high-affinity antibody fragment on DNA polymerase reactions near a (6-4) photoproduct site

Pyrimidine (6-4) pyrimidone photodimers are major photoproducts that have mutagenic and carcinogenic consequences. One major reason for these biological effects of (6-4) photoproducts may be base mispairing/DNA replication errors due to hydrogen bonding to bases opposite these damaged sites. We synthesized a modified 41-mer DNA containing a (6-4) photoproduct using a preformed building block, then employed it as a template for primer extension reactions catalyzed by Klenow fragment and DNA polymerases alpha, beta and delta (pol alpha, pol beta and pol delta). None of these DNA polymerases were able to bypass the (6-4) photoproduct and elongation terminated at or near the 3'-pyrimidone of the photoproduct, depending on the dNTP concentration. When a single-chain Fv (scFv) with high affinity for the (6-4) photoproduct was included in the polymerization reaction, DNA synthesis was inhibited at base positions four, six, eight or eight nucleotides prior to the 3'-pyrimidone by Klenow fragment, pol alpha, pol beta or pol delta, respectively. These results suggest that the scFv can bind to the template DNA containing a (6-4) photoproduct and inhibit extension reactions by polymerases.     

Effect of ionic surfactants on the phase behavior and structure of sucrose ester/water/oil systems

The phase behavior and structure of sucrose ester/water/oil systems in the presence of long-chain cosurfactant (monolaurin) and small amounts of ionic surfactants was investigated by phase study and small angle X-ray scattering. In a water/sucrose ester/monolaurin/decane system at 27 degrees C, instead of a three-phase microemulsion, lamellar liquid crystals are formed in the dilute region. Unlike other systems in the presence of alcohol as cosurfactant, the HLB composition does not change with dilution, since monolaurin adsorbs almost completely in the interface. The addition of small amounts of ionic surfactant, regardless of the counterion, increases the solubilization of water in W/O microemulsions. The solubilization on oil in O/W microemulsions is not much affected, but structuring is induced and a viscous isotropic phase is formed. At high ionic surfactant concentrations, the single-phase microemulsion disappears and liquid crystals are favored.     

Synthesis,Structure, and Optical Studies of Donor–Acceptor‐Type Near‐Infrared (NIR) Aza–Boron‐Dipyrromethene (BODIPY) Dyes

Six donor–acceptor‐type near‐infrared (NIR) aza–boron‐dipyrromethene (BODIPY) dyes and their corresponding aza–dipyrrins were designed and synthesized. The donor moieties at the 1,7‐positions of the aza–BODIPY core were varied from naphthyl to N‐phenylcarbazole to N‐butylcarbazole. The 3,5‐positions were also substituted with phenyl or thienyl groups in the aza–BODIPYs. Photophysical, electrochemical, and computational studies were carried out. The absorption and emission spectra of aza–BODIPYs were significantly redshifted (≈100 nm) relative to the parent tetraphenylaza–BODIPY. Fluorescence studies suggested effective energy transfer (up to 93 %) from donor groups to the aza–BODIPY core in all of the compounds under study. Time‐dependent (TD)‐DFT studies indicated effective electronic interactions between energy donor groups and aza–dipyrrin unit in all the aza–BODIPYs studied. The HOMO–LUMO gap (ΔE) calculated from cyclic voltammetry data was found to be lower for six aza–BODIPYs relative to their corresponding aza–dipyrrins.     

Catalytic asymmetric synthesis of 2,2-disubstituted terminal epoxides via dimethyloxosulfonium methylide addition to ketones

Catalytic asymmetric Corey-Chaykovsky epoxidation of ketones with dimethyloxosulfonium methylide 2 using an LLB 1a + Ar3P O complex proceeded smoothly at room temperature, and 2,2-disubstituted terminal epoxides were obtained in high enantioselectivity (91-97%) and yield (>88-99%) from a broad range of methyl ketones with 1-5 mol % catalyst loading. The use of achiral additive Ar3P O 5i was important to achieve high enantioselectivity.     

Synthesis of New Quinolone Antibiotics Utilizing Azetidine Derivatives Obtained from 1-Azabicyclo[1.1.0]butane

A series of 3-sulfenylazetidine derivatives 5a-f were synthesized via the ring-opening reactions of 1-azabicyclo[1.1.0]butane (ABB, 3) with thiols 4a-f in 50-92% yields. Treatment of ABB (3) with aromatic amines 9a-e and dibenzylamine (9f) in the presence of Mg(ClO4)2 afforded the corresponding 3-aminoazetidine derivatives 10a-f in 24-65% yields. N-Benzyl-3-bromoazetidine (13), which was obtained by the reaction of ABB (3) with benzyl bromide, gave 3-aliphatic amino-substituted azetidine derivatives 15a, b. Novel fluoroquinolones 7a-f, 11a-f, 16a, b and 25a-c were obtained by the introduction of these azetidine derivatives into the C7 position of a quinolone nucleus 6 and N1-heterocyclic quinolones 21a-c in 21-83% yields. Some of them exhibited a greater antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) in comparison with that of clinically used fluoroquinolone, levofloxacin (LVFX).     

Generalized radix representations and dynamical systems. IV

For r = (r₁,…, r_d) ∈ ?^d the mapping τ_r:?^d →?^d given byτ_r(a₁,…,a_d) = (a₂, …, a_d,−⌊r₁a₁+…+ r_da_d⌋)where ⌊·⌋ denotes the floor function, is called a shift radix system if for each a ∈ ?^d there exists an integer k > 0 with τ_r^k(a) = 0. As shown in Part I of this series of papers, shift radix systems are intimately related to certain well-known notions of number systems like β-expansibns and canonical number systems. After characterization results on shift radix systems in Part II of this series of papers and the thorough investigation of the relations between shift radix systems and canonical number systems in Part III, the present part is devoted to further structural relationships between shift radix systems and β-expansions. In particular we establish the distribution of Pisot polynomials with and without the finiteness property (F).     

Powers of rationals modulo 1 and rational base number systems

A new method for representing positive integers and real numbers in a rational base is considered. It amounts to computing the digits from right to left, least significant first. Every integer has a unique expansion. The set of expansions of the integers is not a regular language but nevertheless addition can be performed by a letter-to-letter finite right transducer. Every real number has at least one such expansion and a countable infinite number of them have more than one. We explain how these expansions can be approximated and characterize the expansions of reals that have two expansions. The results that we derive are pertinent on their own and also as they relate to other problems in combinatorics and number theory. A first example is a new interpretation and expansion of the constant K(p) from the so-called “Josephus problem.” More important, these expansions in the base allow us to make some progress in the problem of the distribution of the fractional part of the powers of rational numbers. Work partially supported by the CNRS/JSPS contract 13 569, and by the “ACI Nouvelles Interfaces des Mathématiques”, contract 04 312.