A population stereotaxic positron emission tomography brain template for the macaque and its application to ischemic model.

PURPOSE: Positron emission tomography (PET) is a non-invasive imaging tool for the evaluation of brain function and neuronal activity in normal and diseased conditions with high sensitivity. The macaque monkey serves as a valuable model system in the field of translational medicine, for its phylogenetic proximity to man. To translation of non-human primate neuro-PET studies, an effective and objective data analysis platform for neuro-PET studies is needed. MATERIALS AND METHODS: A set of stereotaxic templates of macaque brain, namely the Institute of High Energy Physics & Jinan University Macaque Template (HJT), was constructed by iteratively registration and averaging, based on 30 healthy rhesus monkeys. A brain atlas image was created in HJT space by combining sub-anatomical regions and defining new 88 bilateral functional regions, in which a unique integer was assigned for each sub-anatomical region. RESULTS: The HJT comprised a structural MRI T1 weighted image (T1WI) template image, a functional FDG-PET template image, intracranial tissue segmentations accompanied with a digital macaque brain atlas image. It is compatible with various commercially available software tools, such as SPM and PMOD. Data analysis was performed on a stroke model compared with a group of healthy controls to demonstrate the usage of HJT. CONCLUSION: We have constructed a stereotaxic template set of macaque brain named HJT, which standardizes macaque neuroimaging data analysis, supports novel radiotracer development and facilitates translational neuro-disorders research.

Asymmetric Total Synthesis of (-)-Pavidolide B via a Thiyl-Radical-Mediated [3 + 2] Annulation Reaction.

The development of an efficient strategy for the asymmetric total synthesis of the bioactive marine natural product (-)-pavidolide B is described in detail. The development process and detours leading to the key thiyl-radical-mediated [3 + 2] annulation reaction, which constructed the central C ring with four contiguous stereogenic centers in one step, are depicted. Subsequently, the seven-membered D ring is constructed via a ring-closing metathesis reaction followed by a Rh(III)-catalyzed isomerization. This strategy enables the total synthesis of (-)-pavidolide B in the longest linear sequence of 10 steps.

Formal Total Synthesis of Hybocarpone Enabled by Visible-Light-Promoted Benzannulation.

The formal total synthesis of hybocarpone was achieved in eight steps from commercially available 1,2,4-trimethoxybenzene. Key transformations include a visible-light-promoted benzannulation to construct the key α-naphthol intermediate and a modified CAN-mediated dimerization/hydration cascade sequence to generate the vicinal all-carbon quaternary centers in a stereocontrolled manner. The total synthesis of boryquinone was also achieved in seven steps.

Total Syntheses of Crinipellins Enabled by Cobalt-Mediated and Palladium-Catalyzed Intramolecular Pauson-Khand Reactions.

Efficient total syntheses of the naturally occurring, potent antibiotic compounds (-)-crinipellin A and (-)-crinipellin B are described. The key advanced intermediate, a fully functionalized tetraquinane core, was constructed by a novel thiourea/palladium-catalyzed Pauson-Khand reaction. This intermediate can serve as a common intermediate for the collective total synthesis of other members of the crinipellin family.

Enantioselective Total Synthesis of (-)-Pavidolide B.

The enantioselective synthesis of (-)-pavidolide B (1) was achieved in a linear sequence of 10 steps. The key steps are (a) an enantioselective organocatalytic cyclopropanation; (b) a radical-based cascade annulation for the regio- and diastereo-selective synthesis of the highly functionalized lactone 3 bearing the characteristic tricyclic core and seven contiguous stereocenters;

A Concise Synthesis of Presilphiperfolane Core through a Tandem TMTU-Co-Catalyzed Pauson-Khand Reaction and a 6π Electrocyclization Reaction (TMTU=Tetramethyl Thiourea).

The synthesis of strained polycyclic systems from readily available precursors with a minimum number of steps and with regio- and stereochemical control constitutes an important synthetic challenge. Herein, we report a tandem reaction comprising Co-TMTU (tetramethyl thiourea)-catalyzed Pauson-Khand (PK) and 6π-electrocyclization reactions for the formation of the highly strained core of presilphiperfolanols. The developed chemistry has been applied to the total syntheses of 4-epi-presilphiperfolan-8-ol and 7-epi-presilphiperfolan-1-ol.

Bioinspired Total Synthesis of Homodimericin†A.

Homodimericin A is a remarkable fungal metabolite. This highly oxygenated racemic unsaturated polyketide poses a significant synthetic challenge owing to its sterically demanding central cagelike core containing eight contiguous stereogenic centers (including three quaternary stereocenters) and several carbonyl functionalities. On the basis of its proposed biogenetic synthesis, we designed a total synthesis of homodimericin A that proceeds in seven steps and features a double Michael reaction, an intramolecular Diels-Alder reaction, and an ene reaction.

Bioinspired Asymmetric Synthesis of Hispidanin†A.

The first enantiospecific synthesis of hispidanin A (4), a dimeric diterpenoid from the rhizomes of Isodon hispida, was achieved with a longest linear sequence of 12 steps in 6.5 % overall yield. A key component is the use of the abundant and naturally occurring diterpenoids (+)-sclareolide and (+)-sclareol as starting materials, which enables the gram-scale preparation of the key intermediates totarane (1) and s-trans-12E,14-labdadien-20,8ß-olide (2). Subsequently a thermal or an erbium-catalyzed intermolecular Diels-Alder reaction of totarane (1) with labdadienolide (2) provide convergent and rapid access to the natural product hispidanin A (4). The synthetic studies have offered significant impetus for the efficient construction of these architecturally complex natural products.

Synthesis of 2,3-Disubstituted Indoles and Benzofurans by the Tandem Reaction of Rhodium(II)-Catalyzed Intramolecular C-H Insertion and Oxygen-Mediated Oxidation.

A highly effective and straightforward method to construct a wide range of functionalized 2,3-disubstituted indoles has been developed. The method involves the tandem reaction of rhodium(II)-catalyzed denitrogenative annulation of triazole-based benzyl anilines and oxygen-mediated oxidative aromatization. The developed method can also be used to synthesize 2,3-disubstituted benzofurans by replacing the benzyl anilines with benzyl phenols.

Gold-Catalyzed Enantio- and Diastereoselective Syntheses of Left Fragments of Azadirachtin/Meliacarpin-Type Limonoids.

Meliacarpin-type limonoids are an important class of organic insecticides. Their syntheses are challenging due to their chemical complexity. Here, we report the highly enantio- and diastereoselective synthesis of the left fragments of azadirachtin I and 1-cinnamoylmelianolone, being two important family members of meliacarpin-type limonoids, via pairwise palladium- and gold-catalyzed cascade reactions. Gold-catalyzed reactions of 1,7-diynes were performed as model studies, and the efficient construction of tetracyclic late-stage intermediates was achieved on the basis of this key transformation. Our unique route gave both of the left fragments in 23 steps from the commercially available chiral starting material (-)-carvone. This study significantly advances research on the synthesis of the meliacarpin-type limonoids.

Effective Chirality Transfer in [3+2] Reaction between Allenyl-Rhodium and Enal: Mechanistic Study Based on DFT Calculations.

Theoretical calculation was performed to study the chirality transfer in a newly reported intramolecular [3+2] cycloaddition of enal and alleno rhodium species, generated in situ from an enynol precursor. [3.3.0] bicyclic system which contains two bridgehead quaternary carbons that can be achieved, the chirality of which are controlled by those of the starting material, and the product stereoselectivity is only determined by the α-position of the acetylene moiety. Density functional theory calculations predicted that only the cis [3.3.0] bicyclic product could be generated, regardless of either erythro or threo substrate, which was also confirmed by experimental observations.

Isolation and Asymmetric Total Synthesis of Perforanoid A.

A novel limonoid, perforanoid A, was isolated, and an asymmetric total synthesis was achieved in 10 steps. The key steps are chiral tertiary aminonaphthol mediated enantioselective alkenylation of an aldehyde to an allylic alcohol, Pd-catalyzed coupling of the allylic alcohol with vinyl ether to form the γ-lactone ring, and cyclopentenone ring formation through a Rh-catalyzed Pauson-Khand reaction. Preliminary studies show that perforanoid A is cytotoxic towards HEL, K562, and CB3 tumor cell lines.

One-pot synthesis of tetracyclic fused imidazo[1,2-a]pyridines via a three-component reaction.

A novel three-component reaction has been developed to assemble biologically and pharmaceutically important tetracyclic fused imidazo[1,2-a]pyridines in a one-pot fashion utilizing readily available 2-aminopyridines, isatins and isocyanides. The three-component coupling proceeds through the Groebke-Blackburn-Bienaymé reaction followed by a retro-aza-ene reaction and subsequent nucleophilic reaction of the in-situ generated imidazo[1,2-a]pyridines bearing an isocyanate functional group.

Direct construction of vicinal all-carbon quaternary stereocenters in natural product synthesis.

Molecules containing vicinal all-carbon quaternary stereocenters are found in many secondary metabolites, and they exhibit a variety of biological and pharmacological activities. However, the construction of such a structural motif remains a significant challenge in natural product synthesis. Only in recent years have considerable efforts been made to construct vicinal quaternary stereocenters in a single-step operation. In this review, we focus on the different types of methods that have been successfully used in the total synthesis of natural products. Based on the classified reactions for the simultaneous generation of vicinal all-carbon quaternary stereocenters, the total syntheses of the natural products are discussed, placing emphasis on the diastereoselective preparation of vicinal quaternary carbon centers and the subsequent total syntheses.

Diastereoselective synthesis of cyclopentanoids: applications to the construction of the ABCD tetracyclic core of retigeranic acid†A.

A concise and efficient approach for the construction of the tetracyclic carbon skeleton of retigeranic acid A is described. The key transformations include a novel Rh-catalyzed [3+2] cycloaddition of enyol to afford cyclopentanoid E, bearing two contiguous quaternary stereocenters at the bridgehead positions, and an intramolecular Pauson-Khand reaction to construct the advanced tetracyclic core structure of retigeranic acid A.

Concise stereoselective synthesis of oxaspirocycles with 1-tosyl-1,2,3-triazoles: application to the total syntheses of (±)-Tuberostemospiroline and (±)-stemona-lactam†R.

A 4-substituted-1-tosyl-1,2,3-triazole-based stereoselective synthesis of structurally diverse oxaspirocycles is reported. The synthesis involves Rh-catalyzed loss of nitrogen from 4-substituted-1-tosyl-1,2,3-triazoles, Grignard reaction, and a ring-closing metathesis reaction as key steps. By employing readily available and stable 4-substituted-1-tosyl-1,2,3-triazoles as surrogates of diazo compounds and nitrogen sources, two types of oxaspirocycles were obtained. The latter compounds, which contain adjacent nitrogen stereocenters, could serve as the core structures of many natural products. This chemistry has been successfully applied to the total syntheses of (±)-tuberostemospiroline and (±)-stemona-lactam R.

Efficient total synthesis of bioactive natural products: a personal record.

In this account, we have highlighted our most recent works towards the total synthesis of bioactive natural products, which have resulted in the development of several novel synthetic methods. Inspired and guided by strategies based on diversity-oriented synthesis, we have successfully applied the novel synthetic methodologies developed in our lab to the total synthesis of a diverse collection of structurally challenging targets. We have also documented the evolution of these synthetic strategies. The total syntheses described in this account have been organized from the perspective of different molecules whilst still alluding to the parallel synthetic strategies involved.

Therapeutic targeting of hepatocellular carcinoma cells with antrocinol, a novel, dual-specificity, small-molecule inhibitor of the KRAS and ERK oncogenic signaling pathways.

Until recently, sorafenib has been the only treatment approved by the U.S. Food and Drug Administration for patients with advanced hepatocellular carcinoma (HCC). Some patients, however, exhibit resistance to this treatment and subsequently experience cancer progression, recurrence, or death. Therefore, identifying a new alternative treatment for patients with little or no response to sorafenib treatment is vital. In this study, we explored the therapeutic potential and underlying molecular mechanism of antrocinol ((3aS,4R,6aS,10aR)-4-(hydroxymethyl)-7,7-dimethyldecahydro-1H-naphtho[1,8a-c]furan-1-one) in patients with HCC. The results indicated that antrocinol was more therapeutically effective than antrocin, Stivarga, and sorafenib against HCC cell lines. Antrocinol also substantially suppressed the expression of KRAS-GTP, p-MEK1/2, p-ERK1/2, and p-AKT in the Huh7 cell line. Additionally, antrocinol-induced apoptosis in the Huh7 cell line, inhibited the formation of tumorspheres, and suppressed the expression of cancer stem cell markers CD133, KLF4, CD44, OCT4, SOX2, and c-Myc. Animal studies revealed that antrocinol alone considerably suppressed tumor growth in nonobese diabetic/severe combined immunodeficient mice inoculated with Huh7 tumorspheres. It also synergistically enhanced the anticancer effect of sorafenib, resulting in enhanced suppression of tumor growth (p < 0.001) and tumorsphere formation (p < 0.001). In tumor samples resected from mice treated with antrocinol alone or in combination with sorafenib, immunohistochemical analysis revealed an increase in BAX expression and a decrease in ERK and AKT protein expression. To the best of our knowledge, this is the first report of the anti-HCC activity of antrocinol. With its higher therapeutic efficacy than that of sorafenib, antrocinol is a candidate drug for patients with HCC who demonstrate little or no response to sorafenib treatment.

Dissecting the phenotypes of Plk1 inhibition in cancer cells using novel kinase inhibitory chemical CBB2001.

Polo-like kinase 1 (Plk1) is a mitotic serine/threonine kinase and its kinase activity is closely interrelated to cell cycle progression, various types of cancer development and often correlates with poor prognosis. Thus, it is of prime importance to characterize the phenotypes of Plk1 inhibition in cells for drug development and clinical application. Here, we report a novel kinase inhibitory chemical, CBB2001, which specifically inhibited Plk1 kinase activity in vitro with an IC(50) of 0.39 µM. In cervical carcinoma HeLa cells, we found that treatment of CBB2001 caused mitotic cell cycle arrest (EC(50)=0.72 µM) and induction of 'polo' cells (EC(50)=0.32 µM). Interestingly, the cell cycle arrest induced by CBB2001 was associated with accumulation of Plk1 (EC(50)=0.61 µM) and Geminin (EC(50)=0.43 µM) proteins, but distinct from the phenotypes induced by Aurora kinase inhibitors. The inhibitory effects of CBB2001 were phenocopied by RNA interferences of Plk1. We also confirmed the cell cycle inhibitory effects of CBB2001 in other cancer cells. Moreover, CBB2001 inhibited the growth of HeLa cells with an IC(50) of 0.85 µM in MTT assays, which is better than that of reported Plk1 inhibitory chemicals ON01910 (IC(50)=6.46 µM) and LFM-A13 (IC(50)=37.36 µM). CBB2001 also inhibited mouse xenograft tumor growth. Furthermore, CBB2001 inhibited mitotic exit and delayed degradation of APC/C substrates, Geminin, Cyclin B1 and Aurora A. These specific phenotypes may serve as specific features for Plk1 inhibition and for Plk1-based clinic trials.

Synthesis of Desacyl Furanmonogones A and B.

A strategy for the stereoselective synthesis of desacyl furanmonogones A and B has been achieved. The key steps in this synthesis are (1) an Fe(ClO4)3-mediated oxidative radical cyclization for construction of a cis-fused [5-6]-bicyclic core with a bridged lactone substitute, (2) a phosphorane-mediated rearrangement to convert the cis-fused [5-6]-bicyclic core to the corresponding trans-fused [5-6]-bicyclic core, and (3) a Au-catalyzed cascade reaction for formation of the 4,5-seco-3(2H)-furanone motif.