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.

A Synthetic Route to The Core Structure of (-)-Retigeranic Acid A.

Retigeranic acid A is a uniquely structured pentacyclic sesterterpene bearing eight stereogenic centers. We report a concise route to the core structure of (-)-retigeranic acid A. The stereochemistry of its six chiral centers and three quaternary carbon centers was well-controlled. This route features two intramolecular Pauson-Khand reactions (IMPKRs): the first forged the D and E rings to deliver the triquinane subunit, and the second constructed the A and B rings and diastereoselectively installed the quaternary C6a center.

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.

Asymmetric Total Synthesis of (-)-Guignardones A and B.

The asymmetric total synthesis of (-)-guignardones A (2) and B (1) has been accomplished. The highly oxidized 6-oxabicyclo[3.2.1]octane core was constructed from d-quinic acid via substitution/desulfurization reaction with thiophenol to forge the bridged ring scaffold, and a Pummerer rearrangement and 1,4-addition/elimination sequence was employed to install the ß-carbonyl group at the congested C-1 position. A late-stage Knoevenagel condensation-6π-electrocyclization and directed hydrogenation formed (-)-guignardone B (1), which was subjected to dehydration to furnish (-)-guignardone A (2).

Concise gram-scale synthesis of Euphorikanin A skeleton through a domino ring-closing metathesis strategy.

Euphorikanin A is a diterpenoid possessing a highly congested and unprecedented 5/6/7/3-fused tetracyclic ring skeleton. To access the challenging chemical structure of Euphorikanins, an efficient total synthetic approach is described. The stereoselective synthesis of the core structure of Euphorikanin A has been achieved from a simple dienyne building block, and a domino ring-closing metathesis (RCM) strategy was used for the gram-scale synthesis of the highly strained Euphorikanin A core. This paves the way for the synthesis of structurally diverse Euphorikanins.

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.

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.

Stereoselective Pd-Catalyzed Decarboxylative Allylation: Assembly of Highly Functionalized Allylic Amines Bearing a Quaternary Center.

Here, we report a practical and reliable methodology to direct construction of tri- and tetrasubstituted olefins bearing an allylic amine, with the concomitant construction of the sterically congested quaternary stereocenter through stereoselective palladium-catalyzed cascade decarboxylation of vinyloxazolidinones.

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.

Retro-metal-ene versus retro-Aldol: mechanistic insight into Rh-catalysed formal [3+2] cycloaddition.

Theoretical calculations have been performed to investigate the mechanism and stereoselectivity of rhodium-catalysed intramolecular [3+2] cycloaddition for construction of a substituted hexahydropentalene complex. A new C-C bond cleavage mechanism, retro-Aldol-type, is proposed and verified for this Rh-catalysed [3+2] cycloaddition reaction.

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.

Stereoselective Total Synthesis of (±)-5- epi-Cyanthiwigin I via an Intramolecular Pauson-Khand Reaction as the Key Step.

A convenient approach to the construction of the 5-6-7 tricarbocyclic fused core structure of cyanthiwigins via a Co-mediated Pauson-Khand reaction as a key step has been developed. The cyathane core intermediate obtained by this strategy was used in the concise synthesis of (±)-5- epi-cyanthiwigin I. The developed chemistry paves the way for the total synthesis of structurally diverse cyanthiwigins.

Total Synthesis of Sinensilactam A.

The total synthesis of naturally occurring (±)-sinensilactam A was achieved in 18 steps. The key steps of this work are a rhodium-catalyzed [3 + 2] cycloaddition for construction of the two all-carbon vicinal quaternary centers and a convergent and tandem condensation of the in situ generated N-acyliminium intermediate with aldehyde 20. This enabled implementation of a unified strategy for stereoselective formation of the tetracyclic hemiaminal core of sinensilactam A in a later stage. The total syntheses of applanatumol F and C8- epi-applanatumol D are also achieved using this strategy.

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 rhodium-catalyzed tandem reaction of N-sulfonyl triazoles with indoles: access to indole-substituted indanones.

An efficient strategy for the synthesis of structurally diverse indole-substituted indanones via a rhodium(ii)-catalyzed tandem reaction of N-sulfonyltriazoles with indoles was developed. The reaction involves rhodium(ii)-catalyzed denitrogenation of the N-sulfonyltriazoles to form an oxonium ylide, followed by nucleophilic addition of the indoles and subsequent skeletal rearrangement. This strategy provides straightforward access to indanone frameworks bearing quaternary carbon centers.

Diastereoselective Synthesis of Diquinanes and Triquinanes Bearing Vicinal Quaternary Carbon Stereocenters from Acyclic Allene-based Precursors via a Cascade Reaction.

A cascade benzenethiol-mediated intramolecular [3 + 2] cycloaddition reaction between an allene and an α,ß-unsaturated aldehyde or ester is developed for the diastereoselective synthesis of [3.3.0] bicyclic system bearing two quaternary atoms at their bridgehead positions. Notably, these structurally complex systems can be found in a wide range of natural products.

Formal Total Synthesis of (±)-Lycojaponicumin C.

The formal total synthesis of (±)-lycojaponicumin C has been accomplished. Key transformations include a Rh-catalyzed formal [3 + 2] cycloaddition reaction to construct the bicyclic [3.3.0] scaffold bearing two vicinal quaternary carbon centers, a stereoselective γ-hydroxyl directed Michael addition to introduce the vinyl group at a bulky position, and a late-stage ring-closing metathesis reaction to form the cyclohexanone ring.

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.

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.