Indole C5-Selective Bromination of Indolo[2,3-a]quinolizidine Alkaloids via In Situ-Generated Indoline Intermediate.

There are many indole alkaloids that contain diverse functional groups attached to the benzene ring on the indole core. Promising biological activities of these alkaloids have been reported. Herein, we report the indole C5-selective bromination of indolo[2,3-a]quinolizidine alkaloids by adding nearly equimolar amounts of Br3 ⋅ PyH and HCl in MeOH. The resulting reaction plausibly proceeds through an indoline intermediate by the nucleophilic addition of MeOH to the C3-brominated indolenine intermediate. Data support the intermediacy of a C3-, C5-dibrominated indolenine intermediate as a brominating agent. These conditions demonstrate excellent selectivity for indole C5 bromination of natural products and their derivatives. Thus, these simple, mild, and metal-free conditions allow for selective, late-stage bromination followed by further chemical modifications. The utility of the brominated product prepared from naturally occurring yohimbine was demonstrated through various derivatizations, including a bioinspired heterodimerization reaction.

Bioinspired Total Synthesis of (+)-Kopsiyunnanine B.

The first enantioselective total synthesis of kopsiyunnanine B, which has a unique folded and complex pentacyclic structure containing six contiguous chiral centers, has been achieved along our originally proposed biosynthetic pathway. The key reaction of this synthesis includes a bioinspired cascade that builds three ring structures and three chiral centers in one step and features the stereoselective reduction of a ß-acrylate and oxidation to an oxindole.

Constituents of Uncaria lanosa f. philippinensis and their anti-amyloidogenic activity.

The aggregation of amyloid-ß (Aß) remains the most acceptable pathological hallmark of Alzheimer's disease (AD). In search for natural products exhibiting anti-amyloidogenic effects, phytochemical analyses were conducted on Uncaria lanosa f. philippinensis leading to the purification of oxindole alkaloid uncarine E (isopteropodine) (1), the phenylethanoid tyrosol (2), the megastigmane vomifoliol (3), and the previously reported alkaloids mitraphylline and isomitraphylline. This is the first report of compounds 1-3 in the title plant, and tyrosol (2) from the genus Uncaria. Assessment of the anti-amyloidogenic potential using Thioflavin T assay showed 91% (at 50 µM) and 70% (at 25 µM) inhibitions for compound 1. Tyrosol (2) gave 76% (at 50 µM) and 63% (at 25 µM) inhibitions. These compounds may be further tested to elucidate their mechanism in the prevention of Aß aggregation. To the best of our knowledge, this is the first report on the anti-amyloid aggregation activity of compounds 1 and 2.

Sticklac-Derived Natural Compounds Inhibiting RNase H Activity of HIV-1 Reverse Transcriptase.

The emergence of drug-resistant viruses is a serious concern in current chemotherapy for human immunodeficiency virus type-1 (HIV-1) infectious diseases. Hence, antiviral drugs aiming at targets that are different from those of approved drugs are still required, and the RNase H activity of HIV-1 reverse transcriptase is a suitable target. In this study, a search of a series of natural compounds was performed to identify the RNase H inhibitors. Three compounds were found to block the RNase H enzymatic activity. A laccaic acid skeleton was observed in all three natural compounds. A hydroxy phenyl group is connected to an anthraquinone backbone in the skeleton. An acetamido-ethyl, amino-carboxy-ethyl, and amino-ethyl are bound to the phenyl in laccaic acids A, C, and E, respectively. Laccaic acid C showed a 50% inhibitory concentration at 8.1 µM. Laccaic acid C also showed inhibitory activity in a cell-based viral proliferation assay. Binding structures of these three laccaic acids were determined by X-ray crystallographic analysis using a recombinant protein composed of the HIV-1 RNase H domain. Two divalent metal ions were located at the catalytic center in which one carbonyl and two hydroxy groups on the anthraquinone backbone chelated two metal ions. Molecular dynamics simulations were performed to examine the stabilities of the binding structures. Laccaic acid C showed the strongest binding to the catalytic site. These findings will be helpful for the design of potent inhibitors with modification of laccaic acids to enhance the binding affinity.

Enantioselective Total Syntheses of (-)-Silicine and (-)-20-Episilicine.

The enantioselective total syntheses of (-)-silicine and (-)-20-episilicine, which contain a chiral piperidine with three contiguous chiral centers (D-ring) and a strained seven-membered ring (C-ring) attached to an indole, were achieved. The key steps of these syntheses included a chiral secondary amine-catalyzed formal aza-[3 + 3] cycloaddition reaction and Lewis acid-mediated irreversible ring-closing reaction. In addition, the stereochemistry at C20 was controlled at a later stage in the syntheses.

Asymmetric Total Synthesis of Senepodine F.

The first asymmetric total synthesis of the Lycopodium alkaloid senepodine F, which contains a decahydroquinoline ring (AB-ring) and a quinolizidine ring (CD-ring) connected by a methylene tether, has been achieved. The key steps of this synthesis include an organocatalytic asymmetric Diels-Alder reaction, a diastereoselective intramolecular aza-Michael reaction, and an intramolecular SN2 cyclization to construct multisubstituted nitrogen-containing heterocycles. In addition, our total synthesis led to the stereochemical reassignment on the decahydroquinoline ring of senepodine F.

Divergent Total Syntheses of Hetero-Oligomeric Iridoid Glycosides.

Divergent total syntheses of the hetero-oligomeric iridoid glycosides mainly found in Dipsacus asper were achieved. Thus, loganin (1), which is important as a monomer unit, was efficiently synthesized by stereoselective reductive cyclization using secologanin (2) as a substrate. Sequential condensation reactions of derivatives of 1 and 2 as monomer units led to the first enantioselective total syntheses of the heterooligomers cantleyoside, (E)-aldosecologanin, dipsaperine, (3R, 5S)-5-carboxyvincosidic acid 22-loganin ester, and dipsanoside A.

Total Syntheses of (+)-Villocarine A, (-)-Apogeissoschizine, and (+)-Geissoschizine.

Total syntheses of geissoschizine-type monoterpenoid indole alkaloids (MTIAs) are reported. An intramolecular Pictet-Spengler cyclization was developed for the selective construction of the 3R stereocenter. The first total synthesis of (+)-villocarine A was then achieved. Furthermore, the first total synthesis of the highly strained (-)-apogeissoschizine was also accomplished in an aza-Michael cyclization/E1cB elimination/stereoselective olefin isomerization sequence. Finally, (+)-geissoschizine, a common biosynthetic intermediate of MTIAs, was obtained from apogeissoschizine through ring-opening along with a release of ring strain.

Pandanus amaryllifolius Exhibits In Vitro Anti-Amyloidogenic Activity and Promotes Neuroprotective Effects in Amyloid-ß-Induced SH-SY5Y Cells.

Accumulation of amyloid-beta (Aß) plaques leading to oxidative stress, mitochondrial damage, and cell death is one of the most accepted pathological hallmarks of Alzheimer's disease (AD). Pandanus amaryllifolius, commonly recognized as fragrant screw pine due to its characteristic smell, is widely distributed in Southeast Asia and is consumed as a food flavor. In search for potential anti-AD agents from terrestrial sources, P. amaryllifolius was explored for its in vitro anti-amyloidogenic and neuroprotective effects. Thioflavin T (ThT) assay and the high-throughput screening multimer detection system (MDS-HTS) assay were used to evaluate the extracts' potential to inhibit Aß aggregations and oligomerizations, respectively. The crude alcoholic extract (CAE, 50 µg/mL) and crude base extract (CBE, 50 µg/mL) obstructed the Aß aggregation. Interestingly, results revealed that only CBE inhibited the Aß nucleation at 100 µg/mL. Both CAE and CBE also restored the cell viability, reduced the level of reactive oxygen species, and reversed the mitochondrial dysfunctions at 10 and 20 µg/mL extract concentrations in Aß-insulted SY-SY5Y cells. In addition, the unprecedented isolation of nicotinamide from P. amaryllifolius CBE is a remarkable discovery as one of its potential bioactive constituents against AD. Hence, our results provided new insights into the promising potential of P. amaryllifolius extracts against AD and further exploration of other prospective bioactive constituents.

Asymmetric Total Syntheses of Mitragynine, Speciogynine, and 7-Hydroxymitragynine.

A number of alkaloids found in Mitragyna species belonging to the Rubiaceae family have been shown to have potent biological activity such as analgesic properties. Here, we report the asymmetric total syntheses of mitragynine, speciogynine, and 7-hydroxymitragynine, which are classified as corynantheine-type monoterpenoid indole alkaloids, isolated from Mitragyna speciosa. These syntheses were accomplished within 12 steps and in >11% total yield from commercial 3-(trimethylsilyl)propanal using an organocatalytic anti-selective Michael reaction and bioinspired transformations.

Secorubenine, a Monoterpenoid Indole Alkaloid Glycoside from Adina rubescens: Isolation, Structure Elucidation, and Enantioselective Total Synthesis.

A new pentacyclic monoterpenoid indole alkaloid glycoside named secorubenine (1) was isolated from the heartwood of Adina rubescens, collected in Indonesia. The structure was elucidated by spectroscopic analysis and chemical modification of isolated secorubenine (1). The bioinspired enantioselective total synthesis of 1 was accomplished in 12 steps, whereafter its structure was determined and the absolute stereochemistry was confirmed.

Borocyclic Radicals Prepared from Orthoquinone-Containing Polycyclic Aromatics by Photoirradiation.

Borocyclic radicals with highly conjugated aromatics were generated from orthoquinone-containing polycyclic aromatic compounds by trapping the photoinduced triplet state with simple boron halide under irradiation with light of appropriate wavelength. The picene-based borocyclic radical was remarkably stable when stored at 23 °C in a desiccator for over 1 year. The crystal structure of this stable radical had a stacking structure of a planar π-conjugated system, and the electrical conductivity was higher than those of ordinary organic radical systems.

Asymmetric Total Synthesis and Structure Elucidation of Huperzine H.

A first asymmetric total synthesis of huperzine H has been achieved in a 12% overall yield from commercially available (+)-pulegone. The key steps of this synthesis include a highly diastereoselective Mukaiyama-Michael addition reaction of a pyrrole bearing a silyl enol ether and an intramolecular SN2 cyclization reaction with iodinated pyrrole acting as an effective nucleophile for the formation of the nine-membered ring. As a result, the relative and absolute stereochemistry of huperzine H is established.

Bioinspired Transformations Using Strictosidine Aglycones: Divergent Total Syntheses of Monoterpenoid Indole Alkaloids in the Early Stage of Biosynthesis.

A series of bioinspired transformations that are applied to convert strictosidine aglycones into monoterpenoid indole alkaloids is reported. The highly reactive key intermediates, strictosidine aglycones, were prepared in situ by simple removal of a silyl protecting group from the silyl ether derivatives, and converted selectively via bioinspired transformations under substrate control into heteroyohimbine- and corynantheine-type, and akagerine and naucleaoral related alkaloids. Thus, concise, divergent total syntheses of 13 monoterpenoid indole alkaloids, (-)-cathenamine, (-)-tetrahydroalstonine, (+)-dihydrocorynantheine, (-)-corynantheidine, (-)-akagerine, (-)-dihydrocycloakagerine, (-)-naucleaoral B, (+)-naucleidinal, (-)-naucleofficines D and III, (-)-nauclefiline, and (-)-naucleamides A and E, were accomplished in fewer than 13 steps.

Rhamnogalacturonan-I as a nematode chemoattractant from Lotus corniculatus L. super-growing root culture.

Introduction: The soil houses a tremendous amount of micro-organisms, many of which are plant parasites and pathogens by feeding off plant roots for sustenance. Such root pathogens and parasites often rely on plant-secreted signaling molecules in the rhizosphere as host guidance cues. Here we describe the isolation and characterization of a chemoattractant of plant-parasitic root-knot nematodes (Meloidogyne incognita, RKN). Methods: The Super-growing Root (SR) culture, consisting of excised roots from the legume species Lotus corniculatus L., was found to strongly attract infective RKN juveniles and actively secrete chemoattractants into the liquid culture media. The chemo-attractant in the culture media supernatant was purified using hydrophobicity and anion exchange chromatography, and found to be enriched in carbohydrates. Results: Monosaccharide analyses suggest the chemo-attractant contains a wide array of sugars, but is enriched in arabinose, galactose and galacturonic acid. This purified chemoattractant was shown to contain pectin, specifically anti-rhamnogalacturonan-I and anti-arabinogalactan protein epitopes but not anti-homogalacturonan epitopes. More importantly, the arabinose and galactose sidechain groups were found to be essential for RKN-attracting activities. This chemo-attractant appears to be specific to M. incognita, as it wasn't effective in attracting other Meloidogyne species nor Caenorhabditis elegans. Discussion: This is the first report to identify the nematode attractant purified from root exudate of L corniculatus L. Our findings re-enforce pectic carbohydrates as important chemicals mediating micro-organism chemotaxis in the soil, and also highlight the unexpected utilities of the SR culture system in root pathogen research.

Amakusamine from a Psammocinia sp. Sponge: Isolation, Synthesis, and SAR Study on the Inhibition of RANKL-Induced Formation of Multinuclear Osteoclasts.

A simple methylenedioxy dibromoindole alkaloid, amakusamine (1), was isolated from a marine sponge of the genus Psammocinia, and its structure was determined from spectroscopic data, time-dependent density-functional theory calculations, and synthesis. Compound 1 inhibited the receptor activator of nuclear factor-κB ligand (RANKL)-induced formation of multinuclear osteoclasts with an IC50 value of 10.5 µM in RAW264 cells. The structure-activity relationship of 1 was also investigated with synthetic derivatives.

Root-knot nematode chemotaxis is positively regulated by l-galactose sidechains of mucilage carbohydrate rhamnogalacturonan-I.

Root-knot nematodes (RKNs) are plant parasites and major agricultural pests. RKNs are thought to locate hosts through chemotaxis by sensing host-secreted chemoattractants; however, the structures and properties of these attractants are not well understood. Here, we describe a previously unknown RKN attractant from flaxseed mucilage that enhances infection of Arabidopsis and tomato, which resembles the pectic polysaccharide rhamnogalacturonan-I (RG-I). Fucose and galactose sidechains of the purified attractant were found to be required for attractant activity. Furthermore, the disaccharide α-l-galactosyl-1,3-l-rhamnose, which forms the linkage between the RG-I backbone and galactose sidechains of the purified attractant, was sufficient to attract RKN. These results show that the α-l-galactosyl-1,3-l-rhamnose linkage in the purified attractant from flaxseed mucilage is essential for RKN attraction. The present work also suggests that nematodes can detect environmental chemicals with high specificity, such as the presence of chiral centers and hydroxyl groups.

Calcium sulfate and calcium carbonate as root-knot-nematode attractants and possible trap materials to protect crop plants.

Root-knot nematodes (RKNs, genus Meloidogyne) are a class of plant parasites that seek out and infect the roots of many plant species. The identification of RKN attractants can be used in agriculture in conjunction with nematode-trapping technology to redirect RKN movements and eventually reduce their prevalence in the field. Here, we discovered that some commercial silica gels can attract nematodes. Silica gels that attract nematodes contain calcium sulfate. Calcium sulfate and calcium carbonate showed strong nematode attraction properties. When plant seeds were surrounded by calcium sulfate or calcium carbonate, nematodes were not attracted to the plant seeds. We propose that calcium sulfate and calcium carbonate can be used in agriculture as a novel material to trap RKN.

Discovery, characterization and functional improvement of kumamonamide as a novel plant growth inhibitor that disturbs plant microtubules.

The discovery and useful application of natural products can help improve human life. Chemicals that inhibit plant growth are broadly utilized as herbicides to control weeds. As various types of herbicides are required, the identification of compounds with novel modes of action is desirable. In the present study, we discovered a novel N-alkoxypyrrole compound, kumamonamide from Streptomyces werraensis MK493-CF1 and established a total synthesis procedure. Resulted in the bioactivity assays, we found that kumamonamic acid, a synthetic intermediate of kumamonamide, is a potential plant growth inhibitor. Further, we developed various derivatives of kumamonamic acid, including a kumamonamic acid nonyloxy derivative (KAND), which displayed high herbicidal activity without adverse effects on HeLa cell growth. We also detected that kumamonamic acid derivatives disturb plant microtubules; and additionally, that KAND affected actin filaments and induced cell death. These multifaceted effects differ from those of known microtubule inhibitors, suggesting a novel mode of action of kumamonamic acid, which represents an important lead for the development of new herbicides.

Epoxyquinophomopsins A and B from endophytic fungus Phomopsis sp. and their activity against tyrosine kinase.

Two new quinone derivatives, epoxyquinophomopsins A (1) and B (2), were purified from the EtOAc extract of endophytic fungus Phomopsis sp isolated from Morus cathayana. The structures of both compounds were determined based on 1D and 2D NMR and mass spectral data, as well as by x-ray diffraction analysis for 1. Compounds 1 and 2 were screened against eight receptor- (RTKs) and eight non-receptor tyrosine kinases (nRTKs). Both compounds showed strong inhibitory properties against Bruton's Tyrosine Kinase (nRTK) with their kinase activity were 19% and 20%, respectively. Only compound 1 that showed strong inhibitory properties against RTKs EGFR and HER-4 with its kinase activity were 16 and 15%, respectively. Thus, both compounds have potential as tyrosine kinase inhibitors.