Chromic properties of dibenzo[j,l]fluoranthenes exhibiting different resonance contributions.

Chromic molecules change colour in response to external stimuli and are utilized in applications such as food additive detection, light dimmers, and biological probes. One of the common design strategies for organic chromic molecules is based on changes in the π-conjugation. We have hypothesized that non-alternant polyaromatic hydrocarbon (PAH) skeletons can be used as backbones for chromic molecules. Herein, we synthesized hydroxy-substituted dibenzo[j,l]fluoranthenes, a class of non-alternant PAHs, as novel chromic compounds and evaluated their halochromic properties by UV-vis and fluorescence spectroscopy. Under basic conditions, the 1-hydroxy derivatives show a hyperchromic shift, whereas the 9-hydroxy derivatives show a bathochromic shift and fluorescence although the skeleton of the chromophore is the same. Density functional theory calculations indicated that the different chromic properties are attributed to the differences in their resonance structures.

Multiply Twisted Chiral Macrocycles Clamped by Tethered Binaphthyls Exhibiting High Circularly Polarized Luminescence Brightness.

Invited for the cover of this issue are Masashi Hasegawa and co-workers at Kitasto University and Kyoto Prefectural University. The image depicts the reported multiply twisted chiral macrocycles as objects in a kaleidoscope. Read the full text of the article at 10.1002/chem.202202218.

Multiply Twisted Chiral Macrocycles Clamped by Tethered Binaphthyls Exhibiting High Circularly Polarized Luminescence Brightness.

Chiral macrocyclic dimers, trimers, and tetramers composed of paraphenylene and tethered binaphthyl were synthesized, and their molecular structures and chiroptical properties were investigated. X-ray analysis and theoretical calculations revealed that multiple twisted molecular structures - dimers, trimers, and tetramers - adopt figure-of-eight, Möbius triangle, and concave rectangle structures, respectively. These homologues have large ϵ values in their UV-vis absorption spectra because of the π-conjugation of the naphthalene-phenylene-naphthalene frameworks. Owing to the shape-persistent ring structure and tethering with -OCH2 CH2 O-, high fluorescence quantum yields and a relatively high dissymmetry factor gCPL in circularly polarized luminescence (CPL) spectra were achieved. This results in CPL brightness (BCPL ) of over 100, which is greater than that of the conventional organic CPL dye.

Synthesis and Properties of V-Shaped Xanthene Dyes with Tunable and Predictable Absorption and Emission Wavelengths.

V-shaped xanthene dyes capable of predicting absorption and emission wavelengths are described. These dyes were synthesized by bridging a xanthene ring and an aryl moiety of fluorescein through ether covalent bonds. These dyes showed longer absorption and emission wavelengths than those of the parent fluorescein. Furthermore, substituents introduced on the aryl moiety mainly affected the lowest unoccupied molecular orbital energy level of the molecule. Therefore, the Hammett substituent constants could be used to predict the absorption and emission wavelengths of the compound.

Synthesis of Bridged Indigos and Their Thermoisomerization and Photoisomerization Behaviors.

Bridged indigos were synthesized by bridging the two nitrogen atoms in the indigo structure with a carbon chain, and their properties were carefully examined. These bridged indigos have intrinsic planar chirality, and the enantiomers were separated using chiral high-performance liquid chromatography. When the chiral bridged indigos were subjected to thermo- and photoisomerization, the corresponding (Z)-indigo was not observed at all, and racemization was observed. This phenomenon is caused by the low activation energy of inversion due to the 1.5 bond order of the double bond of the indigo skeleton and the large energy difference between the ground states of (E)-indigo and (Z)-indigo.

Nucleophilic Addition Reaction with Dearomatization of Naphthalene Ring.

Various aromatic lactones have been synthesized and their regioselectivity (1,2-addition vs. 1,4- or 1,6-addition) investigated in reactions with organolithium species, particularly n-BuLi and sec-BuLi. The regioselectivity varied greatly depending on various factors, such as the bulkiness of both substrates and organolithium species, and types of solvent and cosolvent. In particular, 1,4-addition with dearomatization occurred preferentially using sec-BuLi as the nucleophile in tetrahydrofuran (THF) with hexamethylphosphoramide (HMPA) or N,N'-dimethylpropyleneurea (DMPU) as cosolvent. For sec-BuLi, the reaction was estimated to proceed through a single-electron transfer mechanism.

Synthetic and Biological Studies of Juglorubin and Related Naphthoquinones.

Juglorubin, juglorescein, and juglocombins A/B are naturally occurring naphthoquinone dimers isolated from Streptomyces sp. These dimers are proposed to be biogenetically derived from juglomycin C, a monomeric naphthoquinone isolated from the same Streptomyces sp. In this study, the dimerization of a juglomycin C derivative, a key step in the total syntheses of these natural products, was investigated. Juglorubin was synthesized from the minor product of the dimerization via the formation of the juglocombin A/B stereoisomers. A mechanism for the dimerization reaction as well as a plausible biosynthetic pathway to obtain juglorubin from juglomycin C are proposed. Furthermore, the antibacterial and cytotoxic activities of five synthetic compounds were evaluated. Among the compounds tested in this study, 1'-O-methyljuglocombin B dimethyl ester and juglomycin C exhibited antibacterial activity against Bacillus subtilis. 1'-O-Methyljuglocombin B dimethyl ester and juglomycin C showed cytotoxicity against human colon carcinoma HCT116 cells and human leukemia HL-60 cells. 1'-O-Methyljuglocombin B dimethyl ester exhibited cytotoxicity against human normal MRC-5 cells as strong as that against human cancer cells. In contrast, juglomycin C was less toxic against normal MRC-5 cells, indicating a significant selectivity toward cancer cells.

Synthesis, antibacterial and cytotoxic evaluation of flavipucine and its derivatives.

The antibacterial and cytotoxic activity of seven racemic lactams and both enantiomers of flavipucine were evaluated. Of the compounds tested in this study, flavipucine and phenylflavipucine displayed bactericidal activity against Bacillus subtilis. These results indicate that the pyridione epoxide moiety is a pharmacophore for antibacterial activity against B. subtilis. Flavipucine showed cytotoxic activity against several cancer cells. The cytotoxic activity of flavipucine against human leukemia HL-60 cells is as strong as that of SN-38, the active metabolite of irinotecan. In contrast, the cytotoxic activity of flavipucine against nonneoplastic HEK293 cells and human normal MRC-5 cells is weaker than that of SN-38. No significant differences in the biological activity of the racemates or enantiomers of flavipucine were observed.

Synthesis and Properties of Tribenzocarbazoles via an Acid-Promoted Retro (2+2)-Cycloaddition of Azapropellanes.

We describe herein the development of a new method to synthesize tribenzocarbazoles via an acid-promoted retro (2+2)-cycloaddition of azapropellanes, which were prepared by potassium hexamethyldisilazide (KHMDS)-promoted (2+2)-cycloaddition. The tribenzocarbazoles showed strong fluorescence both in solution and the solid state. The structural, electronic, and optical properties of the synthetic tribenzocarbazoles are also described.

Synthesis and Photochemical Properties of Axially Chiral Bis(dinaphthofuran).

Both enantiomers of axially chiral bis(dinaphthofuran) were prepared in only two steps from 1'-hydroxy-4'-methoxy-2,2'-binaphthalenyl-1,4-dione, followed by optical resolution via high-performance liquid chromatography (HPLC) using a chiral stationary phase (CSP). The absolute configurations were determined by comparison of experimental and calculated vibrational circular dichroism (VCD) spectra. Synthetic bis(dinaphthofuran) exhibited a broad and unstructured emission derived from an intramolecular excimer in both solution and solid state. The methylene bridge brings both chromophores close to each other and induces significant changes in the photophysical behavior. Chiral bis(dinaphthofuran) displayed a bathochromic shift in emission, as compared to the racemic mixture in the solid state. Furthermore, the compounds showed high circularly polarized luminescence (CPL) with a dissymmetry factor ( glum) of 10-3 at 405 nm upon excitation at 265 nm in a methanol solution. This compound serves as a model for the design and synthesis of organic materials having CPL activity.

Total Synthesis of Dendrochrysanene through a Frame Rearrangement.

The first total synthesis of dendrochrysanene (1) was achieved. The key reaction for the construction of dendrochrysanene was an oxidative frame rearrangement reaction from a phenanthrene dimer to a spiro-lactone skeleton, which we serendipitously identified. Owing to the steric hindrance of the substituent on the peri position of the phenanthrene dimer, high-temperature conditions were required for the rearrangement reaction; however, at such temperatures, the substrate decomposed. To address this issue, we added phenylethylamine or benzylamine to the reaction system. We assumed that the amine trapped generated hydrochloric acid and acted as a ligand for iron, helping to maintain an appropriate redox potential. The total synthesis of dendrochrysanene, involving this rearrangement reaction, is an important sequence interlinking phenanthrene derivatives, phenanthrene dimers, and spiro-lactone compounds, which are frequently isolated from plants of Orchidaceae.

Synthesis and Structures of Zigzag Shaped [12]Cyclo-p-phenylene Composed of Dinaphthofuran Units and Biphenyl Units.

A [12]Cyclo-p-phenylene 9 composed of dinaphthofuran units and biphenyl units was synthesized through reductive elimination of the corresponding trinuclear complex by applying Yamago's method. The X-ray crystallographic analyses of 9 revealed that it adopts a zigzag conformation in the solid state. The UV-vis and fluorescence measurements of compound 9 indicated that it also preferentially took a zigzag conformation in the solution state.

Syntheses and properties of the V-shaped dimeric xanthene dyes.

Two new types of V-shaped dimeric xanthene fluorescent dyes were synthesized and evaluated in terms of their optical properties. Based on differences in their resonance forms, these V-shaped dyes were able to adopt four different protonation states (i.e., cationic, neutral, monoanionic and dianionic states) depending on their external environment. Notably, these compounds allowed for the bright fluorescent imaging of NIH3T3 cells when they were applied to cells as the corresponding diacetylated materials.

False HDAC Inhibition by Aurone Compound.

Fluorescence assays are useful tools for estimating enzymatic activity. Their simplicity and manageability make them suitable for screening enzyme inhibitors in drug discovery studies. However, researchers need to pay attention to compounds that show auto-fluorescence and quench fluorescence, because such compounds lower the accuracy of the fluorescence assay systems by producing false-positive or negative results. In this study, we found that aurone compound 7, which has been reported as a histone deacetylase (HDAC) inhibitor, gave false-positive results. Although compound 7 was identified by an in vitro HDAC fluorescence assay, it did not show HDAC inhibitory activity in a cell-based assay, leading us to suspect its in vitro HDAC inhibitory activity. As a result of verification experiments, we found that compound 7 interferes with the HDAC fluorescence assay by quenching the HDAC fluorescence signal. Our findings underscore the faults of fluorescence assays and call attention to careless interpretation.

Total Syntheses of Juglorescein and Juglocombins†A and B.

Total syntheses of juglorescein and juglocombins A and B are reported. The highly oxygenated 6/6/5/6/6-fused pentacyclic ring system of these natural products was constructed through a bioinspired dimerization of 1,4-naphthoquinone. Notably, five new stereogenic centers were constructed in a single step by the dimerization reaction. The epoxide intermediate obtained from the dimerization was successfully converted into juglocombins A and B through photoinduced reduction of the epoxide, dehydration, and conversion of the resultant quinone into a hydroquinone derivative. The same epoxide intermediate was also converted into a dicarboxylic acid, which was transformed into juglorescein through intramolecular lactonization, hydrolysis of the resulting lactone, and removal of the protecting groups. Furthermore, the relative and absolute configurations of juglorescein and juglocombins A and B were determined.

A Bioinspired Synthesis of (±)-Rubrobramide, (±)-Flavipucine, and (±)-Isoflavipucine.

A biomimetic synthesis of naturally occurring lactams rubrobramide, flavipucine, and isoflavipucine is described. The key step is a regioselective Darzens reaction between isobutyl glyoxal and an α-bromo-ß-ketoamide. The construction of the core tricyclic ring system of rubrobramide was achieved by a cascade reaction in a single step from an α,ß-epoxy-γ-lactam. Furthermore, the absolute configuration of naturally occurring (+)-rubrobramide was determined by vibrational circular dichroism. (±)-Flavipucine and (±)-isoflavipucine were synthesized from an epoxyimide, which was prepared by reaction of isobutyl glyoxal with a protected α-bromo-ß-ketoamide. Deprotection of the epoxyimide and formation of the pyridone ring gave (±)-flavipucine, which was converted into (±)-isoflavipucine by thermal isomerization.

5-O-Acyl plumbagins inhibit DNA polymerase activity and suppress the inflammatory response.

We previously found that vitamin K3 (menadione, 2-methyl-1,4-naphthoquinone) inhibits the activity of human mitochondrial DNA polymerase (pol) γ. In this study, we focused on plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone), and chemically synthesized novel plumbagins conjugated with C2:0 to C22:6 fatty acids (5-O-acyl plumbagins). These chemically modified plumbagins displayed enhanced mammalian pol inhibition, with plumbagin conjugated to docosahexaenoic acid (C22:6-acyl plumbagin) exhibiting the strongest inhibition of pol λ among the ten 5-O-acyl plumbagins synthesized. C22:6-acyl plumbagin selectively inhibited the activities of mammalian pol species, but did not influence the activities of other pols or DNA metabolic enzymes tested. The inhibition of pol λ, a DNA repair/recombination pol, by these compounds was significantly correlated with both their suppression of lipopolysaccharide (LPS) induced tumor necrosis factor-α (TNF-α) production by mouse RAW264.7 macrophages and the reduction of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation in the mouse ear. These data indicate that 5-O-acyl plumbagins act as anti-inflammatory agents by inhibiting mammalian pol λ. These results further suggest that C22:6-acyl plumbagin is a promising anti-inflammatory candidate and that acylation could be an effective chemical modification to improve the anti-inflammatory activity of vitamin K3 derivatives, such as plumbagin.

Fluorescent dyes with directly connected xanthone and xanthene units.

Unexpected dimerization of a methoxymethyl-protected xanthone occurred upon treatment with an aryl lithium reagent generated from 2-bromo-1,3-dimethylbenzene and n-butyllithium. The hydrogen between two directing ethereal oxygen atoms was not abstracted, but that adjacent to the carbonyl group was removed to afford a dimeric compound containing two directly connected fluorescent xanthone and xanthene units. Starting from this discovery, three dimeric dyes were constructed, and their optical properties were examined. Although the two fluorescent units were orthogonal in each dye, efficient energy transfer was observed in dimeric dye 16 in three solvent systems. In contrast, solvent-dependent energy transfer was detected for another dimeric dye, 5. After close investigation, we found that the orientation factor (κ) is the main factor influencing Förster resonance energy transfer in these dyes.

Synthesis, Photochemical Properties, and Cytotoxicities of 2H-Naphtho[1,2-b]pyran and Its Photodimers.

A 2H-naphtho[1,2-b]pyran, prepared by dimerization of 2-bromo-3-methyl-1,4-naphthoquinone and O-methylation, readily undergoes solid-state [2 + 2] photodimerization to give a photodimer in excellent yield and with excellent selectivity. Retro [2 + 2] cycloaddition can be achieved by irradiation of a solution of the photodimer in chloroform. Interestingly, the 2H-naphtho[1,2-b]pyran dimerizes with a skeletal rearrangement to afford 2,5-dihydro-1-benzoxepin dimers upon irradiation in methanol or via irradiation with hexamethylditin. Furthermore, treatment of the resulting dimers with triethylamine regenerates the 2H-naphtho[1,2-b]pyran monomer. Significant differences in the color, fluorescence, and cytotoxic properties of the monomer and dimers were observed.