Design, synthesis, and biological evaluation of novel benzo[6,7]indolo[3,4-c]isoquinolines as anticancer agents with topoisomerase I inhibition.

A novel series of benzo[6,7]indolo[3,4-c]isoquinolines 3a-3f was designed by scaffold hopping of topoisomerase I inhibitor benzo[g][1]benzopyrano[4,3-b]indol-6(13H)-ones (BBPIs), which were developed by structural modification of the natural marine product lamellarin. The unconventional pentacycle was constructed by Bischler-Napieralski-type condensation of amide 11 and subsequent intramolecular Heck reaction. In vitro anticancer activity of the synthesized benzo[6,7]indolo[3,4-c]isoquinolines was evaluated on a panel of 39 human cancer cell lines (JFCR39). Among the compounds tested, N-(3-morpholinopropyl) derivative 3e showed the most potent antiproliferative activity, with a mean GI50 value of 39 nM. This compound inhibited topoisomerase I activity by stabilizing the enzyme-DNA complex.

Synthesis of Unsymmetrical Ketones Using Chelation-Controlled Sequential Substitution of N-Triazinylamide/Weinreb Amide by Organometallic Reagents.

N-(2,4-Dimethoxy-1,3,5-triazinyl)amide was found to exhibit similar behavior to N-methoxy-N-methylamide (Weinreb amide) but higher reactivity for nucleophilic substitution by organometallic reagents. Triazinylamide suppresses overaddition, leading to the formation of a tertiary alcohol by the chelating ability of the triazinyl and carbonyl groups. Ureas possessing both triazinylamino and methoxy(methyl)amino groups underwent sequential nucleophilic substitution with different organometallic reagents, which furnished unsymmetrical ketones without any detectable tertiary alcohols.

Concise synthesis and in vitro anticancer activity of benzo[g][1]benzopyrano[4,3-b]indol-6(13H)-ones (BBPIs), topoisomerase I inhibitors based on the marine alkaloid lamellarin.

Benzo[g][1]benzopyrano[4,3-b]indol-6(13H)-ones (BBPIs) are potent anticancer compounds having unique BBPIs ring system designed on the basis of the marine natural product lamellarin D. In this study, we describe an alternative synthesis of a 2-demethoxy series of BBPIs, employing van Leusen pyrrole synthesis and an intramolecular Heck reaction as the key reactions. Cytotoxicity of the derivatives against several cancer and normal cell lines is reported.

Long-Time Relaxation of Stress-Induced Birefringence of Microcrystalline Alkali Halide Crystals.

Alkali halide single crystals are most commonly used as the diluent matrix in the tablet method or disk technique for spectroscopic measurements. However, stress-induced birefringence (SIB) of alkali halides as well as intrinsic birefringence manifest during the disk formation process. Thus, the true chiroptical measurement is disturbed by optical anisotropies (OA) containing SIB and intrinsic birefringence, except in the case of optical homogeneity. SIB is generally larger than intrinsic birefringence and has a value of several thousand millidegrees in the ultraviolet-visible wavelength range, although this varies with disk type. Here, to investigate the SIB origin, alkali halide crystals were examined using polarized light, X-ray diffraction, Fourier-transform infrared, and electron backscattering diffraction spectroscopic measurements. It was found that, after stress release, the SIB exhibited nonlinear long-time relaxation, which roughly converged within several hours, with the only time-invariant intrinsic birefringence remaining being due to OA. This behavior was strongly related to an increase in the quasi-amorphous domain and the generation of an air gap between the crystallite boundaries and their pellets. Further, a straightforward correlation was found between amorphization and an increase in the disk water content caused by deliquescence. Thus, the OA of alkali halide single crystals was found to have two different origins yielding intrinsic birefringence and SIB.

Enantiopure O-ethyl phenylphosphonothioic acid: a solvating agent for the determination of enantiomeric excesses.

An improved method, which is highly reproducible, was developed for the enantioseparation of racemic O-ethyl phenylphosphonothioic acid (1a) with brucine by introducing seeding to a supersaturated solution of the diastereomeric salt mixture. The present method gave both diastereomeric salts in high yields with a diastereomeric ratio of >99.5:0.5 upon choosing the crystallization solvent (MeOH for the (R)-1a salt and MeOH/H2 O for the (S)-1a salt). The enantiopure acid showed a good chirality recognition ability for not only strong bases, such as amines and amino alcohols, but also weakly basic alcohols and was applicable as a solvating agent to the (1) H NMR determination of the enantiomeric excess of chiral amines, amino alcohols, and alcohols, including aliphatic substrates.

Algicidal sesquiterpene hydroquinones from the brown alga Dictyopteris undulata.

Bioassay-guided fractionation of a methanol extract of the brown alga, Dictyopteris undulata, led to the isolation of a novel sesquiterpene hydroquinone named zonarenone, together with seven known sesquiterpene hydroquinones, zonarol, isozonarol, yahazunol, zonaroic acid, chromazonarol, isochromazonarol, and 2-(3,7,11-trimethyl-2,6,10-dodecatrienyl)hydroquinone. The structure of zonarenone was elucidated on the basis of spectroscopic information. The isolated compounds, excepting zonaroic acid, showed moderate to high cell lysis activity against the red tide microalgal species, Heterosigma akashiwo and Heterocapsa circularisquama, at a concentration of 1 µg/mL.

Algicidal activity of glycerolipids from brown alga Ishige sinicola toward red tide microalgae.

Bioassay-guided fractionation of a methanol extract of the brown alga, Ishige sinicola, led to the isolation of five algicidal compounds. Their structures were determined to be α-monoglycerides of eicosa-5Z,8Z,11Z,14Z-tetraenoic (arachidonic) acid, octadeca-6Z,9Z,12Z,15Z-tetraenoic acid, linoleic acid and oleic acid, and 1-O-palmitoyl-3-O-(6-sulfo-α-D-quinovopyranosyl)-sn-glycerol on the basis of spectroscopic data and a comparison with the data in the literature. These glycerolipids showed moderate-to-high cell lysis activity against the red tide microalgal species, Heterosigma akashiwo, Karenia mikimotoi and Alexandrium catenella, at a concentration of 20 µg/mL.

One-step synthesis of differently bis-functionalized isoxazoles by cycloaddition of carbamoylnitrile oxide with ß-keto esters.

A new protocol for synthesizing different functionalized isoxazoles is provided. Carbamoylnitrile oxide generated from nitroisoxazolone underwent inverse electron-demand 1,3-dipolar cycloaddition with 1,3-dicarbonyl compounds in the presence of magnesium acetate that formed magnesium enolate in situ. Although electron-deficient trifluoroacetoacetate did not undergo this cycloaddition under the same conditions, conversion to sodium enolate furnish the corresponding bis-functionalized trifluoromethylisoxazole. The DFT calculations using B3LYP 6-31G+(d,p) also supported the aforementioned reactivity.

Hydroxylated surface of GaAs as a scaffold for a heterogeneous Pd catalyst.

A novel use of GaAs, namely, as a scaffold for a heterogeneous palladium catalyst, is proposed. Hydroxy groups on the GaAs surface play important roles. During the adsorption of Pd(OAc)(2) on the GaAs surface, the hydroxy groups attract Pd(ii) species by anion exchange. A subsequent redox reaction proceeds to generate Pd(0) nanoparticles, which are stabilized on the GaAs surface. This process is confirmed by surface-sensitive measurements: diffuse reflection IR spectroscopy and X-ray photoelectron spectroscopy. Moreover, a more bulk-sensitive measurement, hard X-ray photoemission spectroscopy with synchrotron radiation, also supported our considerations. The amounts of Pd(0) nanoparticles on the surface were evaluated by catalytic activity, yield, and recyclability in the Heck reaction, in addition to the deposit test.

Inverse electron-demand 1,3-dipolar cycloaddition of nitrile oxide with common nitriles leading to 3-functionalized 1,2,4-oxadiazoles.

A carbamoyl-substituted nitrile oxide was generated upon treatment of easily available 2-methyl-4-nitro-3-isoxazolin-5(2H)-one with THF (not dried); the reaction proceeded efficiently even in the absence of any special reagents and reaction conditions. The nitrile oxide caused 1,3-dipolar cycloaddition with common aliphatic nitriles or electron-rich aromatic nitriles to afford 3-functionalized 1,2,4-oxadiazoles, which are expected to serve as precursors for the preparation of a variety of functional materials by the chemical transformation of the carbamoyl group. While conventional preparative methods for 1,2,4-oxadiazoles involve the cycloaddition of an electron-rich nitrile oxide with an electron-deficient nitrile or a nitrile activated by a Lewis acid, our method employs the complementary combination of an electron-rich nitrile and an electron-deficient nitrile oxide- the inverse electron-demand 1,3-cycloaddition. The DFT calculations using B3LYP 6-31G* supported the abovementioned inverse reactivity, and also suggested the presence of an accelerating effect by the carbamoyl group as a result of hydrogen bond formation with a dipolarophilic nitrile.

Bicyclization involving pseudo-intramolecular imination with diamines.

α-Nitro-δ-keto nitriles and α-nitro-δ-keto ester were readily converted to diazabicyclo compounds having vicinal functionality upon treatment with diamines. The keto nitrile attracts the diamine nearby to an acidic hydrogen to cause the pseudo-intramolecular imination which proceeds efficiently without any catalyst at room temperature.

An anomalous hydration/dehydration sequence for the mild generation of a nitrile oxide.

A nitrile oxide containing a carbamoyl group is readily generated upon the treatment of 2-methyl-4-nitro-3-isoxazolin-5(2H)-one with water under mild reaction conditions, even in the absence of special reagents. The obtained nitrile oxide undergoes cycloaddition with dipolarophiles, alkynes and alkenes, to afford the corresponding isoxazol(in)es, which are useful intermediates in the synthesis of polyfunctionalized compounds. A plausible mechanism underlying the formation of the nitrile oxide is proposed, which involves an anomalous hydration/dehydration sequence. DFT calculations were also performed to support this mechanism.

Synthetic approach to telomerase inhibitor dictyodendrin B: synthesis of the pyrrolo[2,3-c]carbazole core.

The core structure of the telomerase inhibitor, dictyodendrin B, was synthesized by using the palladium-catalyzed cross-coupling reaction of 3-aryl-1-(2-arylethyl)-4-hydroxy-2,5-bismethoxycarbonylpyrrole triflate with 7-alkoxyindole-3-boronate as the key step.

Isolation and structure determination of algicidal compounds from Ulva fasciata.

Thirty-seven species of seaweeds including 10 Chlorophyta, 13 Phaeophyta, and 14 Rhodophyta collected from the coast of Nagasaki Prefecture, Japan, were screened for algicidal activity against the red-tide phytoplankton Heterosigma akashiwo. The green alga Ulva fasciata (Ulvaceae, Chlorophyta) showed the strongest algicidal activity among the seaweeds tested. Bioassay-guided fractionation of the methanol extract of U. fasciata led to isolation of three algicidal compounds whose structures were determined to be hexadeca-4,7,10,13-tetraenoic acid (HDTA), octadeca-6,9,12,15-tetraenoic acid (ODTA), and alpha-linolenic acid on the basis of spectroscopic information. These polyunsaturated fatty acids (PUFAs) showed potent algicidal activity against H. akashiwo (LC(50) 1.35 microg/ml, 0.83 microg/ml, and 1.13 microg/ml for HDTA, ODTA, and alpha-linolenic acid, respectively), and the result demonstrated the potential of these PUFAs for practical harmful algal bloom control.