Cyclic Sesquiterpene-Flavanone [4+2] Hybrids, Syzygioblanes A-C, Found in an Indonesian Traditional Medicine, "Jampu Salo" (Syzygium oblanceolatum).

A plant used in an Indonesian traditional herbal medicine as a diabetes treatment and known locally as "Jampu Salo" was collected on Sulawesi Island, Indonesia. It was identified as Syzygium oblanceolatum (C. B. Rob.) Merr. (Myrtaceae) and found for the first time in Sulawesi; it was previously reported only in the eastern Philippines and Borneo. A phytochemical study of S. oblanceolatum led to the isolation of three unprecedented meroterpenoids, syzygioblanes A-C (1-3, respectively). These compounds might be biosynthesized through [4+2] cycloaddition of various germacrane-based cyclic sesquiterpenoids with the flavone desmethoxymatteucinol to form a spiro skeleton. The unique and complex structures were elucidated by microcrystal electron diffraction analysis in addition to general analytical techniques such as high-resolution mass spectrometry, various nuclear magnetic resonance methods, and infrared spectroscopy. Synchrotron X-ray diffraction and calculations of electronic circular dichroism spectra helped to determine the absolute configurations. The newly isolated compounds exhibited collateral sensitivity to more strongly inhibit the growth of a multidrug resistant tumor cell line compared to a chemosensitive tumor cell line.

Total Synthesis of a TNBC-Selective Cytotoxic Bromo Nor-eremophilane, PC-A, and Its Preliminary Structure-Activity Relationships.

PC-A (1), a bromo nor-eremophilane, showed selective antiproliferative activity against a triple-negative breast cancer (TNBC) cell line. This unique activity prompted us to establish a total synthesis to facilitate a structure-activity relationship (SAR) study and selectivity optimization. An enantioselective first total synthesis of 1 was achieved starting from (R)-carvone through a side chain extension with a Mukaiyama aldol reaction and decalin construction. The synthesized decalin derivatives and debromo PC-A (2) were evaluated for antiproliferative activity against five human tumor cell lines, including TNBC, to assess preliminary SAR correlations.

Unusual Vilasinin-Class Limonoids from Trichilia rubescens.

Eight vilasinin-class limonoids, including the unusually chlorinated rubescins K-M (1-3), the 2,3-epoxylated rubescin N (4), and rubescins O-R (5-8), were newly isolated from Trichilia rubescens. The structures of the isolated compounds were determined through spectroscopic and spectrometric analyses, as well as ECD calculations. The natural occurrence of chlorinated limonoids 1-3 was confirmed by chemical methods and HPLC analysis of a roughly fractionated portion of the plant extract. Eight selected limonoids, including previously known and new compounds, were evaluated for antiproliferative activity against five human tumor cell lines. All tested limonoids, except 8, exhibited significant potency, with IC50 values of <10 µM; in particular, limonoid 14 strongly inhibited tumor cell growth, with IC50 values of 0.54-2.06 µM against all tumor cell lines, including multi-drug-resistant cells.

Caged Xanthones and Biphenyls Isolated from the Tropical Plant Garcinia lateriflora.

Four cytotoxic heptacyclic caged-xanthones [gambogefic acids B-E (1-4)], a cytotoxic hexacyclic caged-xanthone [garcilatelic acid (5)], and four biphenyl derivatives [garcilatelibiphenyls A-D (6-9)] were newly isolated in a phytochemical study of a 50% MeOH/CH2Cl2 extract of Garcinia lateriflora (Clusiaceae). The isolated compounds were evaluated for antiproliferative activity against five human tumor cell lines including a vincristine-resistant line. The new caged-xanthones displayed potent activity with IC50 values from 0.5 to 6.7 µM against all tested tumor cell lines.

Cytotoxicity Activity, Metabolite Profiling, and Isolation Compound from Crude Hexane Extract of Cleome rutidospermae.

OBJECTIVE: This study isolated the chemical compounds and evaluated the cytotoxic activity of the crude hexane extract of Cleome rutidospermae herb (CRH). METHODS: The isolate was purified using silica gel, column chromatography, and preparative thin layer chromatography (PTLC). Furthermore, the structure of the compounds was identified by spectroscopic methods using 1D, 2D NMR, and mass spectrometry. The cytotoxic activity of CRH at a concentration of 20 ug/mL was also tested against MCF-7, A549, KB, KB-VIN, and MDA-MB-231 cancer cells using the sulforhodamine B (SRB) method. RESULTS: The CRH contained compounds of unsaturated fatty acid, saturated fatty acid, lipid, glycerol, ω-3 fatty acid, and cholesterol. Two compounds were obtained from the plant, and their structures were identified as (1) Stigmasta-5,22-dien-3-ol (STML) and (2) 1,2-Benzene dicarboxylic acid, 1,2-bis (2-Ethylhexyl) esters (DEHP). These compounds were reported in this plant for the first time. In comparison, CRH had % growth inhibition in the proliferation of MCF-7 cells up to 28.1%, with cancer cells A549, KB, KB-VIN, and MDA-MB-231 by >50% Compared to the negative DMSO of 0.20%, while the positive control could inhibit the growth of all cancer cells (100%). CONCLUSION: Our findings suggested that crude herb from the plant CRH was the potential for breast cancer treatment.

Total Synthesis of Waltherione A, a Quinolone Alkaloid Fused with Oxabicyclo[3.2.1]octane.

Waltherione A (1), a unique quinolone alkaloid fused with oxabicyclo[3.2.1]octane, was isolated originally from Waltheria douradinha and recently by us from a methanol extract of Melochia umbellata along with the related 3,4-dimethoxyquinoline paliasanines A-E. Compound 1 showed selective cytotoxicity against A549 and MCF-7 cell lines. Its interesting structural and biological features prompted several attempts at total synthesis and clarification of the absolute configuration, although none were successful to date. Now, we have accomplished the first total synthesis of 1 starting from commercially available benzosuberone in 21 steps as well as elucidated its absolute configuration.

Novel α-Trifluoromethyl Chalcone Exerts Antitumor Effects Against Prostate Cancer Cells.

BACKGROUND/AIM: Despite treating advanced prostate cancer (PCa) with androgen deprivation therapy, it eventually progresses to castration-resistant PCa. Subsequently, taxanes are administered, but when PCa becomes resistant to taxanes, another treatment is needed, which has not yet been established. We previously synthesized a novel α-trifluoromethyl chalcone, YS71, and reported its antitumor effects against PCa cells. In this study, we confirmed its efficacy against androgen-sensitive, androgen-independent, and taxane-resistant PCa cells. MATERIALS AND METHODS: The PCa cell lines used were LNCaP, PC-3, DU145, PC-3-TxR (paclitaxel-resistant), PC-3-TxR/CxR (paclitaxel- and cabazitaxel-resistant), DU145-TxR, and DU145-TxR/CxR. The antiproliferative effects of YS71 were evaluated using proliferation assay. The reverse transcriptase transcription-polymerase chain reaction and western blot were performed to determine the expression level of androgen receptor (AR), whereas luciferase assay was performed to determine the AR activity. Furthermore, TUNEL assay and western blot were performed to investigate the mechanism of the antiproliferative effect. RESULTS: YS71 exerted a dose-dependent antitumor effect, inhibited AR activity, and induced apoptosis in all PCa cells in a dose-dependent manner. Western blot showed that YS71 increased the levels of apoptosis-related proteins, cleaved caspase-3, and cleaved PARP, and decreased the levels of the antiapoptotic proteins, Bcl-xL and Bcl-2. In addition, microarray analysis revealed that YS71 decreased several cancer-related genes. CONCLUSION: YS71 exhibits antitumor activity by inducing apoptosis in PCa cells, including taxane-resistant cells. It could be a potential future therapeutic option for hormone- and chemotherapy-resistant PCa.

A New Bis-indole Alkaloid, Spermaocymine A, and an Anthraquinone from Spermacoce ocymoides.

A phytochemical study on Spermacoce ocymoides has led to the isolation of a novel bis-indole alkaloid, spermaocymine A (2), together with the known alkaloid 4-methyl-borreverine (1), as well as an anthraquinone, 8-hydroxy-2-(hydroxymethyl)-1-methoxyanthracene-9,10-dione (3). The structures of the isolated compounds were elucidated by analyzing spectroscopic and spectrometric data, including one-dimensional (1D)- and 2D-NMR and high resolution (HR)-MS. Newly isolated alkaloid 2 was a C-3,14-stereoisomer of 1, the first natural stereoisomer of related bis-indoles containing an indeno[1,2-b]indole skeleton with an epiminoethano bridge. When 1-3 were assayed against five tumor cell lines including multi-drug resistant cells, compound 1 exhibited potent antiproliferative activity with IC50 values of 6.2-11.5 µM.

Suppression of androgen receptor signaling induces prostate cancer migration via activation of the CCL20-CCR6 axis.

The suppression of androgen receptor (AR) expression exacerbates the migration potential of prostate cancer. This study identified a previously unrecognized regulation of the AR-controlled pathway that promotes migration potential in prostate cancer cells. Prostate cancer cells that pass through a transwell membrane (mig cells) have a higher migration potential with a decreased AR expression than parental cells. In this study, we aimed to elucidate the mechanism of migration enhancement associated with the suppression of AR signaling. Expression of C-C motif ligand 20 (CCL20) is upregulated in mig cells, unlike in the parental cells. Knockdown of AR with small interfering RNA (siAR) in LNCaP and C4-2B cells increased CCL20 secretion and enhanced the migration of cancer cells. Mig cells, CCL20-treated cells, and siAR cells promoted cell migration with an enhancement of AKT phosphorylation and Snail expression, while the addition of a C-C chemokine receptor 6 (CCR6, the specific receptor of CCL20) inhibitor, anti-CCL20 antibody, and AKT inhibitor suppressed the activation of AKT and Snail. With 59 samples of prostate cancer tissue, CCL20 secretion was profuse in metastatic cases despite low AR expression levels. Snail expression was associated with the expression of CCL20 and CCR6. A xenograft study showed that the anti-CCL20 antibody significantly inhibited Snail expression, thereby suggesting a new therapeutic approach for castration-resistant prostate cancer with the inhibition of the axis between CCL20 and CCR6.

Synthesis of a Model Compound of the Unique Meroterpenoids Cryptolaevilactones.

Cryptolaevilactones (CLs) A-L, found in the leaves and twigs of Cryptocarya laevigata, are unique natural meroterpenoids with a spiro[3.5]nonane skeleton. We report the total synthesis of a simplified model compound of CLs A-C. The synthetic route included introduction of a styryl group and coupling of a lactone moiety to a spiro ring system, which was constructed by a pinacol-like rearrangement.

Tapered self-written waveguide for a silicon photonic chip I/O.

An optical coupling method with high alignment tolerance by self-written waveguide (SWW) formation is a promising candidate for co-packaged optics (CPO) by silicon photonics (SiPh). However, conventional SWWs cannot be used with Si waveguides because visible light for SWW formation cannot radiate from the waveguide facet. Here, we devised a new, to the best of our knowledge, optical circuit with SiOxNy waveguides for SWW formation from an SiPh chip. With our circuit, we achieved optical coupling between an SiPh chip and a standard single-mode fiber (SSMF) with a tapered SWW (TSWW). The lowest excess coupling loss compared to butt coupling with a high-numerical aperture (NA) fiber is approximately 0.6 dB over the C-band with the TSWW. In addition, our coupling method has higher alignment tolerances than butt coupling with a high-NA fiber (HNF).

Vitamin E Enhances Cancer Immunotherapy by Reinvigorating Dendritic Cells via Targeting Checkpoint SHP1.

Despite the popular use of dietary supplements during conventional cancer treatments, their impacts on the efficacies of prevalent immunotherapies, including immune-checkpoint therapy (ICT), are unknown. Surprisingly, our analyses of electronic health records revealed that ICT-treated patients with cancer who took vitamin E (VitE) had significantly improved survival. In mouse models, VitE increased ICT antitumor efficacy, which depended on dendritic cells (DC). VitE entered DCs via the SCARB1 receptor and restored tumor-associated DC functionality by directly binding to and inhibiting protein tyrosine phosphatase SHP1, a DC-intrinsic checkpoint. SHP1 inhibition, genetically or by VitE treatment, enhanced tumor antigen cross-presentation by DCs and DC-derived extracellular vesicles (DC-EV), triggering systemic antigen-specific T-cell antitumor immunity. Combining VitE with DC-recruiting cancer vaccines or immunogenic chemotherapies greatly boosted ICT efficacy in animals. Therefore, combining VitE supplement or SHP1-inhibited DCs/DC-EVs with DC-enrichment therapies could substantially augment T-cell antitumor immunity and enhance the efficacy of cancer immunotherapies. SIGNIFICANCE: The impacts of nutritional supplements on responses to immunotherapies remain unexplored. Our study revealed that dietary vitamin E binds to and inhibits DC checkpoint SHP1 to increase antigen presentation, prime antitumor T-cell immunity, and enhance immunotherapy efficacy. VitE-treated or SHP1-silenced DCs/DC-EVs could be developed as potent immunotherapies. This article is highlighted in the In This Issue feature, p. 1599.

Chemical Space Expansion of Flavonoids: Induction of Mitotic Inhibition by Replacing Ring B with a 10π-Electron System, Benzo[b]thiophene.

Natural products, which are enzymatically biosynthesized, have a broad range of biological activities. In particular, many flavonoids are known to contribute to human health with low toxicity. We previously reported that novel benzo[b]thiophenyl (BT) flavones with a 10π-electron BT ring B replacing the usual 6π-electron phenyl ring showed potent antiproliferative activity against human tumor cell lines. Interestingly, the activity profiles against cell cycle progression of the BT-flavones totally changed depending on the combination of substituents at the C-3 and C-5 positions. This finding encouraged an extension of these studies on the impact of BT to related flavonoids, such as chalcones, isoflavones, and aurones. Accordingly, 10 isoflavones, 29 chalcones, and four aurones were synthesized and evaluated for antiproliferative activity against five human tumor cell lines including a multi-drug-resistant cell line. Among these compounds, BT-isoflavone 7, BT-chalcones 48, 52, 57, 66, and 77, and BT-aurone 80 displayed significant antiproliferative effects against all tested tumor cell lines. The structure-antiproliferative activity relationships clearly demonstrated the importance of BT instead of phenyl as ring B for the isoflavone and chalcones, but not the aurones. Flow cytometry and immunocytochemical studies demonstrated that the active BT-flavonoids led to cell cycle arrest at the prometaphase by induction of multipolar spindle formation. The present studies should contribute greatly to the synthesis and functional analysis of biologically active flavonoid derivatives for chemical space expansion.

Radiosynthesis and in Vivo and ex Vivo Evaluation of Isomeric [11C]methoxy Analogs of Nimesulide as Brain Cyclooxygenase-2-Targeted Imaging Agents.

Our previous studies identified that nimesulide analogs which bear a methoxy substituent at the para-position of the phenyl ring could be potential radiotracer candidates for detecting disorders related to cyclooxygenase-2 (COX-2) expression and activity in vivo using positron emission tomography (PET) in the brain. The present study was conducted to evaluate the in vivo characteristics of 11C-labeled para-methoxy nimesulide ([11C]1d) as a brain COX-2-targeted imaging agent compared to other isomeric methoxy analogs of nimesulide ([11C]1b and [11C]1c). [11C]1b-d were synthesized with reasonable yield and purity by the methylation of the O-desmethyl precursor with [11C]methyl triflate in the presence of NaOH at room temperature. We performed in vivo biodistribution analysis, brain PET imaging, ex vivo autoradiography, and metabolite analysis in mice. The uptake of [11C]1b-d was lower in the brain than in other tissues, including in the blood, and both [11C]1c and [11C]1d were rapidly metabolized. However, [11C]1d showed a small, but significant, specific signal and heterogeneous distribution in the brain. In vivo evaluation suggested that [11C]1d might correlate with COX-2 expression in the brain. Given its instability in vivo, [11C]1d seems unsuitable as a brain-COX-2 radioimaging agent. Further structural refinement of these radiotracers is necessary to enhance their uptake in the brain and to achieve sufficient metabolic stability.

The allergy mediator histamine confers resistance to immunotherapy in cancer patients via activation of the macrophage histamine receptor H1.

Reinvigoration of antitumor immunity remains an unmet challenge. Our retrospective analyses revealed that cancer patients who took antihistamines during immunotherapy treatment had significantly improved survival. We uncovered that histamine and histamine receptor H1 (HRH1) are frequently increased in the tumor microenvironment and induce T cell dysfunction. Mechanistically, HRH1-activated macrophages polarize toward an M2-like immunosuppressive phenotype with increased expression of the immune checkpoint VISTA, rendering T cells dysfunctional. HRH1 knockout or antihistamine treatment reverted macrophage immunosuppression, revitalized T cell cytotoxic function, and restored immunotherapy response. Allergy, via the histamine-HRH1 axis, facilitated tumor growth and induced immunotherapy resistance in mice and humans. Importantly, cancer patients with low plasma histamine levels had a more than tripled objective response rate to anti-PD-1 treatment compared with patients with high plasma histamine. Altogether, pre-existing allergy or high histamine levels in cancer patients can dampen immunotherapy responses and warrant prospectively exploring antihistamines as adjuvant agents for combinatorial immunotherapy.

α-Trifluoromethyl Chalcones as Potent Anticancer Agents for Androgen Receptor-Independent Prostate Cancer.

α-Trifluoromethyl chalcones were prepared and evaluated for their antiproliferative activities against androgen-independent prostate cancer cell lines as well as five additional types of human tumor cell lines. The most potent chalcone 5 showed superior antitumor activity in vivo with both oral and intraperitoneal administration at 3 mg/kg. Cell-based mechanism of action studies demonstrated that 5 induced cell accumulation at sub-G1 and G2/M phases without interfering with microtubule polymerization. Furthermore, several cancer cell growth-related proteins were identified by using chalcone 5 as a bait for the affinity purification of binding proteins.

Effects of substituent pattern on the intracellular target of antiproliferative benzo[b]thiophenyl chromone derivatives.

A new biological scaffold was produced by replacing the 6π-electron phenyl ring-B of a natural flavone skeleton with a 10π-electron benzothiophene (BT). Since aromatic rings are important for ligand protein interactions, this expansion of the π-electron system of ring-B might change the bioactivity profile. One of the resulting novel natural product-inspired compounds, 2-(benzo[b]thiophen-3-yl)-5-hydroxy-7-isopropoxy-6-methoxyflavone (6), effectively arrested the cell cycle at the G2/M phase and displayed significant antiproliferative effects with IC50 values of 0.05-0.08 µM against multiple human tumor cell lines, including a multidrug resistant line. A structure-activity relationship study revealed that a 10π-electron system with high aromaticity, juxtaposed 4-oxo and 5-hydroxy groups, and 7-alkoxy groups were important for potent antimitotic activity. Interestingly, two BT-flavonols (3-hydroxyflavone), 16 and 20, with 3-hydroxy and 5-alkoxy groups, induced distinct biological profiles affecting the cell cycle at the G1/S phase by inhibition of DNA replication through an interaction with topoisomerase I.

Synthesis of Thio-lignan Analogues, Bioequivalent Salvinal without Unfavored Aldehyde.

The oxygen in the benzofuran (BF) of three antiproliferative natural neolignans, salvinal (1), obovaten (2), and 2-[7-methoxy-2-(4-methoxyphenyl)-3-methylbenzofuran-5-yl]ethanol (3), was replaced with sulfur to form the new biological scaffold benzothiophene (BT) thio-lignans 4-6. Compounds 1-6 and 18 synthesized derivatives were evaluated for antiproliferative activity against five human cancer cell lines, including a multidrug-resistant cell line. Thio-salvinal (4) displayed significant antiproliferative effects with half-maximal inhibitory concentration (IC50) values of 0.57-0.95 µM against all tested cell lines, except for the HER2 negative breast cancer cell line MCF-7. This thio-lignan was 6.5-9.4 times more potent than parent 1. However, the related thio-lignans, 5 and 6, showed much weaker antiproliferative effects than 4 and were less potent than the parent natural benzofuran lignans 2 and 3. Newly synthesized thio-lignan 33 affected cell cycle progression at 24 and 48 h in the G2/M transition and S phase, respectively, as well as promoted sub-G1 induction by stimulating microtubule depolymerization and nuclear fragmentation. Since a highly reactive aldehyde in salvinal is generally not appropriate for drug development, we have successfully found nonaldehyde derivative 33 showing biological activity similar to salvinal by replacing BF with BT and an aldehyde with 1,3-dioxolane.

Bicyclic Chalcones as Mitotic Inhibitors for Overcoming Androgen Receptor-Independent and Multidrug-Resistant Prostate Cancer.

To improve the biological effects of the lead compound 5'-chloro-2,2'-dihydroxychalcone (Cl-DHC), bicyclic aromatic chalcones were designed, synthesized, and evaluated against androgen-independent prostate cancer (PCa) DU145 and PC-3 cell proliferation. Newly synthesized bi-naphthyl derivatives 2 and 3 suppressed the proliferation of these two cell lines and also taxane-resistant prostate cancer cell lines at a submicromolar level. The two compounds were 4-18 times more potent than the parent molecule Cl-DHC. A structure-activity relationship analysis revealed that the orientation of the 10π-electron ring-A naphthalene had a significant effect on the activity. Mode-of-action studies in KB-VIN cells demonstrated that 2 and 3 arrested cells in mitosis at prometaphase and metaphase followed by induction of sub-G1 accumulation. Thus, 2 and 3 have good potential as leads for continued development of treatments for cancers especially for not only androgen-independent PCa but also multidrug-resistant tumors.

Rise and fall of Landau's quasiparticles while approaching the Mott transition.

Landau suggested that the low-temperature properties of metals can be understood in terms of long-lived quasiparticles with all complex interactions included in Fermi-liquid parameters, such as the effective mass m⋆. Despite its wide applicability, electronic transport in bad or strange metals and unconventional superconductors is controversially discussed towards a possible collapse of the quasiparticle concept. Here we explore the electrodynamic response of correlated metals at half filling for varying correlation strength upon approaching a Mott insulator. We reveal persistent Fermi-liquid behavior with pronounced quadratic dependences of the optical scattering rate on temperature and frequency, along with a puzzling elastic contribution to relaxation. The strong increase of the resistivity beyond the Ioffe-Regel-Mott limit is accompanied by a 'displaced Drude peak' in the optical conductivity. Our results, supported by a theoretical model for the optical response, demonstrate the emergence of a bad metal from resilient quasiparticles that are subject to dynamical localization and dissolve near the Mott transition.