Furanosesquiterpenes and Related Natural Products from Myoporum Species: Isolation and Semisynthesis.

Myoporum species are recognized as toxic plants. Essential oils from the leaves of these species contain furanosesquiterpenes, which comprise the active toxins. In this report, natural products isolation studies of three Myoporum species (M. insulare, M. parvifolium, and M. montanum) afforded two previously unreported furanosesquiterpenes (24 and 25) and three unprecedented γ-lactone-containing analogues (26-28), along with nine previously reported furanosesquiterpenes and five other natural products. Among the 14 furanosesquiterpenes and related compounds isolated in this study, we observed three distinct types of furanosesquiterpene structures isolated from each of these Myoporum species. Semisyntheses of four sesquiterpene natural products were completed from (-)-ngaione over two steps in each case. This included the synthesis of the lactam-containing sesquiterpene myoporumine A.

Distinctive Arbutin-Containing Markers: Chemotaxonomic Significance and Insights into the Evolution of Proteaceae Phytochemistry.

Natural products isolation studies of eight endemic Tasmanian Proteaceae species - Agastachys odorata, Persoonia juniperina, Hakea megadenia, Hakea epiglottis, Orites diversifolius, Orites acicularis, Orites revolutus, and Telopea truncata - and three endemic Australian Proteaceae species Banksia serrata, Banksia praemorsa, and Banksia marginata were undertaken. Two previously unreported glycoside-derived natural products were identified, in addition to four other tremendously rare arbutin esters. The results of this study provide further evidence consistent with the proposal that these distinctive arbutin esters represent markers that can provide valuable insights into the chemical evolution of plant species within the family Proteaceae.

Strategies for the synthesis of Stemona alkaloids: an update.

Covering: 2009 to 2022The Stemona alkaloids, which are found in plant species from the family Stemonaceae, represent a tremendously large and structurally-diverse family of natural products. This review presents and discusses a selection of case studies, grouped by alkaloid class, that showcase the key strategies and overall progress that has been made in the synthesis of Stemona alkaloids and related compounds since 2009. Structural reassignments that have been reported over this period are also identified where necessary.

Synthesis of Pyrrolidine- and γ-Lactam-Containing Natural Products and Related Compounds from Pyrrole Scaffolds.

Polycyclic alkaloid natural products featuring pyrrolidine and pyrrolidinone motifs remain enduring targets of total synthesis endeavors. Pyrrole and its derivatives have been exploited to access many such frameworks, including alkaloids belonging to the Aspidosperma, Stemona, and batzelladine families. In this article, a selection of exemplars that highlight the utility of pyrrole-based approaches to facilitate total syntheses of pyrrolidine- and pyrrolidinone-containing alkaloids and related molecules are showcased.

Discovery of Periodinane Oxy-Assisted (POA) Oxidation Mechanism in the IBX-Controlled Oxidative Dearomatization of Pyrroles Mediated by Acetic Acid.

The 2-iodoxybenzoic acid (IBX)-controlled oxidative dearomatization of pyrroles occurs very slowly (or not all) in many organic solvents, including DMSO in which IBX is soluble. Interestingly, although IBX is only partially soluble in acetic acid, this solvent mediates the pyrrole oxidative dearomatization. With the aid of density functional theory (DFT) calculations, we have discovered a new mode of reactivity, termed the periodinane oxy-assisted (POA) oxidation mechanism, which explains this observation.

Revised Structures of Dehydrostenines A and B: Total Syntheses of (±)-Dehydrostenine A and Structure Assigned to Dehydrostenine B.

The first total syntheses of the Stemona alkaloid dehydrostenine A and the structure assigned to dehydrostenine B have been completed from a simple pyrrole substrate in 10 and 11 steps, respectively. Two independent Brønsted-acid-mediated intramolecular Michael additions were exploited to construct the tetracyclic dehydrostenine core. As a result of synthetic studies and associated analysis of the relevant literature, revisions of the structures originally assigned to dehydrostenines A and B are proposed.

Computational Investigation into the Mechanistic Features of Bromide-Catalyzed Alcohol Oxidation by PhIO in Water.

Iodosobenzene (PhIO) is known to be a potent oxidant for alcohols in the presence of catalytic bromide in water. In order to understand this important and practical oxidation process, we have conducted density functional theory studies to shed light on the reaction mechanism. The key finding of this study is that PhIO is not the reactive oxidant itself. Instead, the active oxidant is hypobromite (BrO-), which is generated by the reaction of PhIO with bromide through an SN2-type reaction. Critically, water acts as a cocatalyst in the generation of BrO- through lowering the activation energy of this process. This investigation also demonstrates why BrO- is a more powerful oxidant than PhIO in the oxidation of alcohols. Other halide additives have been reported experimentally to be less effective catalysts than bromide-our calculations provide a clear rationale for these observations. We also examined the effect of replacing water with methanol on the ease of the SN2 reaction, finding that the replacement resulted in a higher activation barrier for the generation of BrO-. Overall, this work demonstrates that the hypervalent iodine(III) reagent PhIO can act as a convenient and controlled precursor of the oxidant hypobromite if the right conditions are present.

Clinical Comparison of Two Confrontation Naming Measures in Spanish-Speaking People with Epilepsy.

OBJECTIVE: Research on the lateralizing value of neuropsychological tests is limited among Latino people with epilepsy (PWE). This study aims to evaluate the utility of two confrontation naming measures in laterality determination. METHOD: Data were collected from 71 Latino PWE who completed the Vocabulario Sobre Dibujos (VSD) and the Pontón-Satz Modified Boston Naming Test (MBNT). Raw and standardized scores were examined to determine diagnostic accuracy for predicting left hemisphere (LH) epilepsy for the full sample and using a sample-specific median split of educational attainment. RESULTS: The MBNT demonstrated adequate classification accuracy (65.7%, 77.1%) as did the VSD (54.3%, 74.3%) for predicting LH seizure laterality using raw and standardized scores, respectively. For participants with ≥ 9 years of education (HEdu), receiver operator characteristic curve analyses showed a raw/percentile cutoff of ≤ 26/≤ 5th on the VSD, yielding 53%-58% sensitivity/87%-83% specificity. A raw score cutoff of ≤ 17 on MBNT produced 47% sensitivity/78% specificity for HEdu participants. CONCLUSIONS: The VSD was found to have greater flexibility in determining cutoff scores using either raw or standardized scores for predicting seizure laterality. This study provides interpretation guidance, emphasizing education as a pertinent variable, to optimize lateralization accuracy for Latino PWE.

Novel Short-Chain Quinones to Treat Vision Loss in a Rat Model of Diabetic Retinopathy.

Diabetic retinopathy (DR), one of the leading causes of blindness, is mainly diagnosed based on the vascular pathology of the disease. Current treatment options largely focus on this aspect with mostly insufficient therapeutic long-term efficacy. Mounting evidence implicates mitochondrial dysfunction and oxidative stress in the central etiology of DR. Consequently, drug candidates that aim at normalizing mitochondrial function could be an attractive therapeutic approach. This study compared the mitoprotective compounds, idebenone and elamipretide, side-by-side against two novel short-chain quinones (SCQs) in a rat model of DR. The model effectively mimicked type 2 diabetes over 21 weeks. During this period, visual acuity was monitored by measuring optokinetic response (OKR). Vision loss occurred 5-8 weeks after the onset of hyperglycemia. After 10 weeks of hyperglycemia, visual function was reduced by 65%. From this point, the right eyes of the animals were topically treated once daily with the test compounds. The left, untreated eye served as an internal control. Only three weeks of topical treatment significantly restored vision from 35% to 58-80%, while visual acuity of the non-treated eyes continued to deteriorate. Interestingly, the two novel SCQs restored visual acuity better than idebenone or elamipretide. This was also reflected by protection of retinal pathology against oxidative damage, retinal ganglion cell loss, reactive gliosis, vascular leakage, and retinal thinning. Overall, mitoprotective and, in particular, SCQ-based compounds have the potential to be developed into effective and fast-acting drug candidates against DR.

Polygodial and Ophiobolin A Analogues for Covalent Crosslinking of Anticancer Targets.

In a search of small molecules active against apoptosis-resistant cancer cells, including glioma, melanoma, and non-small cell lung cancer, we previously prepared α,ß- and γ,δ-unsaturated ester analogues of polygodial and ophiobolin A, compounds capable of pyrrolylation of primary amines and demonstrating double-digit micromolar antiproliferative potencies in cancer cells. In the current work, we synthesized dimeric and trimeric variants of such compounds in an effort to discover compounds that could crosslink biological primary amine containing targets. We showed that such compounds retain the pyrrolylation ability and possess enhanced single-digit micromolar potencies toward apoptosis-resistant cancer cells. Target identification studies of these interesting compounds are underway.

Bioactivity Profiles of Cytoprotective Short-Chain Quinones.

Short-chain quinones (SCQs) have been investigated as potential therapeutic candidates against mitochondrial dysfunction, which was largely thought to be associated with the reversible redox characteristics of their active quinone core. We recently reported a library of SCQs, some of which showed potent cytoprotective activity against the mitochondrial complex I inhibitor rotenone in the human hepatocarcinoma cell line HepG2. To better characterize the cytoprotection of SCQs at a molecular level, a bioactivity profile for 103 SCQs with different compound chemistries was generated that included metabolism related markers, redox activity, expression of cytoprotective proteins and oxidative damage. Of all the tested endpoints, a positive correlation with cytoprotection by SCQs in the presence of rotenone was only observed for the NAD(P)H:quinone oxidoreductase 1 (NQO1)-dependent reduction of SCQs, which also correlated with an acute rescue of ATP levels. The results of this study suggest an unexpected mode of action for SCQs that appears to involve a modification of NQO1-dependent signaling rather than a protective effect by the reduced quinone itself. This finding presents a new selection strategy to identify and develop the most promising compounds towards their clinical use.

Genomic and transcriptomic insights into Raffaelea lauricola pathogenesis.

BACKGROUND: Laurel wilt caused by Raffaelea lauricola is a lethal vascular disease of North American members of the Lauraceae plant family. This fungus and its primary ambrosia beetle vector Xyleborus glabratus originated from Asia; however, there is no report of laurel wilt causing widespread mortality on native Lauraceae trees in Asia. To gain insight into why R. lauricola is a tree-killing plant pathogen in North America, we generated and compared high quality draft genome assemblies of R. lauricola and its closely related non-pathogenic species R. aguacate. RESULTS: Relative to R. aguacate, the R. lauricola genome uniquely encodes several small-secreted proteins that are associated with virulence in other pathogens and is enriched in secondary metabolite biosynthetic clusters, particularly polyketide synthase (PKS), non-ribosomal peptide synthetase (NRPS) and PKS-NRPS anchored gene clusters. The two species also exhibit significant differences in secreted proteins including CAZymes that are associated with polysaccharide binding including the chitin binding CBM50 (LysM) domain. Transcriptomic comparisons of inoculated redbay trees and in vitro-grown fungal cultures further revealed a number of secreted protein genes, secondary metabolite clusters and alternative sulfur uptake and assimilation pathways that are coordinately up-regulated during infection. CONCLUSIONS: Through these comparative analyses we have identified potential adaptations of R. lauricola that may enable it to colonize and cause disease on susceptible hosts. How these adaptations have interacted with co-evolved hosts in Asia, where little to no disease occurs, and non-co-evolved hosts in North America, where lethal wilt occurs, requires additional functional analysis of genes and pathways.

DFT-Based Comparison between Mechanistic Aspects of Amine and Alcohol Oxidation Mediated by IBX.

Density functional theory was utilized to investigate plausible mechanisms for amine and alcohol oxidation by an iodine(V) hypervalent reagent (IBX). In this contribution, we found that amine and alcohol oxidation both proceed by similar mechanisms. The reactions initiate from ligand exchange to give four coordinate intermediates followed by a redox process giving an iodine(III) species and oxidized substrates. Interestingly, for both the ligand-exchange and the redox steps a hypervalent twist is required for the reaction to proceed via an energetically more accessible route. The ligand-exchange process was found to be mediated by a proton-shuttling agent such as water, a second IBX, or a second substrate. While the ligand-exchange step for both amine and alcohol occurs with almost identical activation energy (particularly when water is considered as the shuttling agent), the redox step for the amine takes place with much lower activation energy than that for the alcohol. Finally, we ascertained that five coordinate amide iodine(V) complexes are unreactive toward redox reactions due to the fact that in such cases two electrons from the coordinated amide are required to occupy a 3c-4e σ* orbital which is too high in energy to be reachable.

Improving neuropsychological seizure lateralization in Spanish-speaking people with epilepsy in the US: The need to account for education and demographic differences.

OBJECTIVE: The objective of the study was to investigate the predictive seizure lateralization ability of the Neuropsychological Screening Battery for Hispanics (NeSBHIS) in an optimally, demographically matched cohort of primarily immigrant Spanish-speaking people with epilepsy (PWE) living in the US. Linguistically and culturally appropriate neuropsychological measures for Spanish-speaking people are increasingly needed in the US, especially as this diverse, international population grows. The NeSBHIS was developed to meet this need. Previous studies were inconclusive regarding its utility in epilepsy lateralization with PWE. Sample size and demographic variables, particularly educational levels, which anchor neuropsychological normative data and guide clinical use, limited the conclusions of earlier studies. METHODS: A retrospective study, the NeSBHIS battery's ability to predict seizure lateralization in a large cohort of Spanish-speaking PWE (n = 108) was conducted using normative data based on refined, smaller education ranges suggested by the author of the NeSBHIS, Pontón. RESULTS: Regression analysis revealed that four NeSBHIS subtests representing different cognitive domains produced the best model for predicting lateralization: 1) language, 2) attention/mental control, 3) visual memory recall, and 4) verbal memory recall. Prediction accuracy overall was 62% (67.3% for left hemisphere (LH) and 55.8% for right hemisphere (RH)). CONCLUSION: This study demonstrated the clinical utility of the NeSBHIS in seizure lateralization in a large cohort of Spanish-speaking PWE by analyzing standardized scores based on refined, education-based normative samples. These results also highlight that demographic variables, in particular, education, which varies greatly across Spanish-speaking nations in terms of compulsory educational opportunity and quality, must be accounted for more carefully in clinical and research practice.

Pressurized Hot Water Extraction and Capillary Electrophoresis for Green and Fast Analysis of Useful Metabolites in Plants.

The search for useful compounds from plants is an important research area. Traditional screening that involves isolation and identification/quantitation is tedious, time consuming, and generates a significant amount of chemical waste. Here, we present a simple, fast, and green strategy to assess ≥0.1% wt/wt quantities of useful compounds in plants/spices using pressurized hot water extraction using a household espresso machine followed by chemical analysis using capillary electrophoresis. Three demonstrations with polygodial, cinnamaldehyde, coumarin, and shikimic acid as target metabolites are shown. Direct analysis of extracts was by the developed micellar electrokinetic chromatography and capillary zone electrophoresis methods. The approach, which can be implemented in less developed countries, can process many samples within a day, much faster than traditional techniques that would normally take at least a day. Finally, 0.8-1.1% wt/wt levels of shikimic acid were found in Tasmanian-pepperberry and Tasmanian-fuschia leaves via the approach.

Climate Change, Public Health, and Policy: A California Case Study.

Anthropogenic activity will bring immediate changes and disruptions to the global climate with accompanying health implications. Although policymakers and public health advocates are beginning to acknowledge the health implications of climate change, current policy approaches are lagging behind. We proposed that 4 key policy principles are critical to successful policymaking in this arena: mainstreaming, linking mitigation and adaptation policy, applying population perspectives, and coordination. We explored California's progress in addressing the public health challenges of climate change in the San Joaquin Valley as an example. We discussed issues of mental health and climate change, and used the San Joaquin Valley of California as an example to explore policy approaches to health issues and climate change. The California experience is instructive for other jurisdictions.

Methods for the synthesis of annulated pyrroles via cyclisation strategies.

Pyrrole, pyrrolidine, and indolizidine alkaloids represent important classes of natural products. Historically, these heterocycles and their derivatives have been the focus of significant interest in organic synthesis. In this report, we review the methods that have been employed to synthesise annulated pyrroles via transformations that include: Friedel-Crafts acylations and alkylations, Michael additions, Heck couplings, hydroarylations, carbenoid insertions, and radical cyclisations.

Epilepsy surgery in the underserved Hispanic population improves depression, anxiety, and quality of life.

OBJECTIVE: The objective of this study was to investigate the effect of epilepsy surgery on depression, anxiety, and quality of life (QOL) in a Hispanic, primarily immigrant, Spanish-speaking population with intractable epilepsy (IE). METHODS: Patients with IE from a comprehensive epilepsy treatment center in an urban, public healthcare setting who underwent resective brain surgery between 2008 and 2014 (N=47) and completed presurgical and postsurgical neuropsychological evaluation were retrospectively identified. Presurgical and 1-year postsurgical Beck Depression Inventory-II (BDI-II), Beck Anxiety Inventory (BAI), and QOLIE-31 ratings were analyzed as postsurgical outcome measures. One-tailed paired sample t-tests were used to evaluate whether scores improved postoperatively. Established severity level classifications of depression and anxiety (i.e., minimal, mild, moderate, or severe) were used to analyze changes in occurrence of depression and anxiety. RESULTS: Medium to large improvements on the BDI-II and most QOLIE-31 subscales, with a smaller effect on the BAI and remaining QOLIE-31 subscales, were noted 1-year postsurgery. Levels of depression and anxiety were significantly reduced 1-year postsurgery. Depression, anxiety, and QOL improvements were robust and unaffected by gender, levels of education, or hemisphere of surgery. CONCLUSIONS: This study supports the positive benefits of epilepsy surgery on depression, anxiety, and QOL in Hispanic, primarily undocumented immigrant, Spanish-speaking people with epilepsy (PWE) in the US. These results are useful for educating this particular population about the possible benefits of surgery for IE and can enhance presurgical counseling.

Arbutin Derivatives Isolated from Ancient Proteaceae: Potential Phytochemical Markers Present in Bellendena, Cenarrhenes, and Persoonia Genera.

Extensive phytochemical studies of the paleoendemic Tasmanian Proteaceae species Bellendena montana, Cenarrhenes nitida, and Persoonia gunnii were conducted employing pressurized hot water extraction. As part of these studies, six novel glycosides were isolated, including rare examples of glycoside-containing natural products featuring tiglic acid esters. These polar molecules may represent potential phytochemical markers in ancient Proteaceae.