Biomimetic and Concise Total Syntheses of Prenylated and Bicyclo[2.2.2]diazaoctane-Containing Indole Alkaloids Including Taichunamide A, Notoamide N and Versicolamide B.

Total syntheses of the title prenylated indole alkaloids together with seven others are reported. Biogenetic considerations have been employed in devising the reaction sequences leading to these targets with, in the opening stages, electrochemically-derived indole-3-carboxaldehyde 15 being subject to an aldol-type condensation reaction involving diketopiperazine derivative 19. This led, after prototopic shifts, intramolecular Diels-Alder cycloaddition and hydrolysis/deprotection steps, to the racemic forms of the bicyclo[2.2.2]diazaoctane-containing natural product stephacidin A (2) and its C6 epimer 3. Epoxidation of the last compound afforded, following rearrangement of the primary oxidation products, a mixture of (±)-taichunamide A [(±)-4] and (±)-versicolamide B [(±)-7]. Related protocols allowed for the conversion of (±)-stephacidin A [(±)-2] into (±)-notoamide B [(±)-5]. Analogous aldol condensation, nucleophilic reduction, and epoxidation steps led to the formation of (-)-notoamide E and its conversion into notoamide C as well as the indole fragmentation product amoenamide E. A late-stage chlorination reaction applied to (±)-stephacidin A provided access to the spirocyclic oxindole (±)-notoamide N [(±)-6].

Total Syntheses of the Structures Assigned to Denigrins A, B, C, F, and G, 3,4-Diaryl-Pyrrole and -Pyrrolidinone Alkaloids, and the Conversion of Congener B into the Co-metabolite Spirodactylone.

The title marine natural products have been prepared by total synthesis and in the case of congeners 3, 6, and 7 for the first time. Each of these was obtained by manipulation of readily prepared denigrin B (2). The structure, 3, assigned to denigrin C is shown to be incorrect. Reaction of compound 2 with DDQ has led, in high yield, to the related natural product spirodactylone (16), while treating the corresponding permethyl ether 15 with PIFA/BF3·Et2O provides compound 20, embodying an isomeric framework.

The first linkage map for Australo-Papuan Treefrogs (family: Pelodryadidae) reveals the sex-determination system of the Green-eyed Treefrog (Litoria serrata).

Amphibians represent a useful taxon to study the evolution of sex determination because of their highly variable sex-determination systems. However, the sex-determination system for many amphibian families remains unknown, in part because of a lack of genomic resources. Here, using an F1 family of Green-eyed Treefrogs (Litoria serrata), we produce the first genetic linkage map for any Australo-Papuan Treefrogs (family: Pelodryadidae). The resulting linkage map contains 8662 SNPs across 13 linkage groups. Using an independent set of sexed adults, we identify a small region in linkage group 6 matching an XY sex-determination system. These results suggest Litoria serrata possesses a male heterogametic system, with a candidate sex-determination locus on linkage group 6. Furthermore, this linkage map represents the first genomic resource for Australo-Papuan Treefrogs, an ecologically diverse family of over 220 species.

The useful biological properties of sucrose esters: Opportunities for the development of new functional foods.

Sucrose esters have been deployed as surfactants in many food products since the 1950s. In addition to their useful physical characteristics, sucrose esters also have interesting biological properties that enhance their utility. This review critically examines the broad suite of biological activities that has been attributed to both synthetically-derived and naturally-occurring sucrose esters. These include insecticidal, molluscicidal, plant growth-regulating, anti-microbial, anti-tumor, anti-oxidant, anti-depressive, neuro-protective, anti-inflammatory and anti-plasmodial effects. In addition to providing a summary of the structure-activity profiles of sucrose esters, the various known mechanisms-of action of these compounds are also discussed. Furthermore, since sucrose esters are well-known surfactants, the potential to advantageously apply their industrially desirable physical characteristics in combination with their biological properties is considered. Recent advances in synthetic chemistry that have facilitated the deployment of biologically active sucrose esters as food additives are also described.

Formal Total Syntheses of (+)- and (-)-Aspidophytine from a Common, Homochiral Precursor.

A formal total synthesis of (-)-aspidophytine (2), a key substructure associated with the heterodimeric indole alkaloid haplophytine (1) and itself a natural product, has been established by employing the homochiral and enzymatically derived cis-1,2-dihydrocatechol 8 as a starting material. Specifically, compound 8 has been converted into the pentacyclic product 26, an advanced intermediate associated with a previously reported synthesis of aspidophytine (2). Simple modifications to the reaction sequence have also allowed for the identification of a synthetic pathway leading from dihydrocatechol 8 to (+)-aspidophytine (ent-2).

Total Syntheses of the Structures Assigned to the Marine Natural Products Orthoscuticellines A-E.

The readily prepared and vinylated ß-carboline 11 has been converted over one or two steps into compounds 1-5, the structures assigned to the recently reported marine natural products orthoscuticellines A-E. The spectral data recorded on the synthetically derived compounds are fully consistent with the assigned structures and, on making allowances for variations in the pH of the medium in which the spectra of the natural products were recorded, it is concluded that the structures assigned to orthoscuticellines A-E are most likely correct. Certainly, the calculated 13C NMR spectra of the α-, γ-, and δ-carboline isomers of compounds 1-5 suggest that orthoscuticellines A-E do incorporate the assigned ß-carboline core.

Expeditious Access to Morphinans by Chemical Synthesis.

Morphinans are essential medicines derived entirely from poppy supply chains rendered increasingly volatile by climate change. Here, we report a seven-step, asymmetric chemical synthesis of (-)-codeine from simple materials that requires a total combined reaction time of fewer than 24 hours. The efficiency of our approach arises from a double-Heck cyclization reaction that generates two rings and two contiguous stereogenic carbon centres in the one pot. A subsequent photo-redox hydroamination protocol provides a novel, atom-economical means for assembling the piperidine D-ring of codeine. Simple modifications to the closing stages of our sequence offer effective access to pharmacologically valuable derivatives of N-demethyl codeine. Our work highlights the capacity for contemporary, stand-alone chemical synthesis regimes to diversify access to essential opiate medicines.

The Chemical Synthesis of the Crinine and Haemanthamine Alkaloids: Biologically Active and Enantiomerically-Related Systems that Serve as Vehicles for Showcasing New Methodologies for Molecular Assembly.

The title alkaloids, often referred to collectively as crinines, are a prominent group of structurally distinct natural products with additional members being reported on a regular basis. As such, and because of their often notable biological properties, they have attracted attention as synthetic targets since the mid-1950s. Such efforts continue unabated and more recent studies on these alkaloids have focused on using them as vehicles for showcasing the utility of new synthetic methods. This review provides a comprehensive survey of the nearly seventy-year history of these synthetic endeavors.

EGFR mutation and HPV infection in sinonasal inverted papilloma and squamous cell carcinoma.

BACKGROUND: To evaluate the involvement of EGFR signalling and HPV infection in a cohort of inverted sinonasal papilloma (ISP) and sinonasal squamous cell carcinoma (SNSCC) and their value for prognosis and clinical treatment. METHODS: We analysed 55 ISP, 14 SNSCC associated with ISP (SNSCC-isp) and and 60 SNSCC not associated with ISP (SNSCC-novo) for EGFR gene mutation and copy number gain, protein expression of EGFR and phosporylated EGFR (pEGFR), and HPV-infection and KRAS mutation. Findings were correlated to clinico-pathological and follow-up data. RESULTS: We found EGFR exon 20 mutations in 38% (7/18) ISP, in 50% (6/12) SNSCC-isp and in 5% (1/19) SNSCC-novo. EGFR was expressed in 92% of ISP, while pEGFR was observed in 54% (21/39). SNSCC-isp and SNSCC-novo demonstrated comparable expression of EGFR (57% and 33%) and of pEGFR (44% and 38%). We observed an inverse relation between EGFR exon 20 mutation and pEGFR expression. Four of 39 (10%) ISP carried HPV-16. Oncogenic HPV was detected in 3/12 (25%) SNSSC-isp and in 1/8 (13%) SNSCC-novo. KRAS mutations were not detected in any of the samples. HPV infection was inversely correlated with pEGFR expression but not with EGFR mutation. ISP with EGFR activation by mutation or by phosphorylation had longer ISP-free survival, however, neither EGFR exon 20 mutation, pEGFR expression nor HPV infection demonstrated prognostic value in SNSCC. CONCLUSIONS: EGFR exon 20 mutation is frequent in ISP and SNSCC-isp, while activation of EGFR through phosphorylation also plays an important role. Our data indicate that a large proportion of SNSCC patients could benefit from therapy with modern EGFR inhibitors.

Valorization of poly(lactic acid) wastes via mechanical recycling: Improvement of the properties of the recycled polymer.

Poly(lactic acid) (PLA) is a biobased polymer that represents one of the most interesting alternatives to fossil-fuel based polymers in food packaging applications. Most of the PLA used in food packaging is used only once and then discarded, even though the PLA types used in packaging have good properties and stability. Therefore, it seems reasonable to consider the possibility of recycling the used polymer through a mechanical recycling process. The main aims of this work are to study the effect of the mechanical recycling on the properties of PLA and the usefulness of different upgrading methods to obtain recycled PLA with improved properties. A commercial type of PLA was subjected to accelerated thermal, photochemical and hydrolytic aging and then reprocessed. During reprocessing, aged PLA was blended with virgin PLA and a commercial chain extender was added. Results point out that recycling causes the degradation of PLA, and negatively affects the thermal stability and mechanical properties. However, addition of virgin PLA, and the chain extender, led to an increase of up to 9% in the intrinsic viscosity and 8% in the Vickers hardness of the recycled material. These results suggest that mechanically recycled PLA with improved performance can be obtained, a fact which might improve the recyclability of PLA and thus the environmental impact of this material.

Effect of simulated mechanical recycling processes on the structure and properties of poly(lactic acid).

The aim of this work is to study the effects of different simulated mechanical recycling processes on the structure and properties of PLA. A commercial grade of PLA was melt compounded and compression molded, then subjected to two different recycling processes. The first recycling process consisted of an accelerated ageing and a second melt processing step, while the other recycling process included an accelerated ageing, a demanding washing process and a second melt processing step. The intrinsic viscosity measurements indicate that both recycling processes produce a degradation in PLA, which is more pronounced in the sample subjected to the washing process. DSC results suggest an increase in the mobility of the polymer chains in the recycled materials; however the degree of crystallinity of PLA seems unchanged. The optical, mechanical and gas barrier properties of PLA do not seem to be largely affected by the degradation suffered during the different recycling processes. These results suggest that, despite the degradation of PLA, the impact of the different simulated mechanical recycling processes on the final properties is limited. Thus, the potential use of recycled PLA in packaging applications is not jeopardized.

Conversion of the Enzymatically Derived (1S,2S)-3-Bromocyclohexa-3,5-diene-1,2-diol into Enantiomerically Pure Compounds Embodying the Pentacyclic Framework of Vindoline.

The enzymatically derived and enantiomerically pure (1S,2S)-3-bromocyclohexa-3,5-diene-1,2-diol (7) has been elaborated over 17 steps into compounds 8 and 32, each of which embodies the pentacyclic framework and much of the functionality associated with the alkaloid vindoline (3). This work sets the stage for effecting the conversion of the related metabolite (1S,6R)-5-ethyl-1,6-dihydroxycyclohexa-2,4-diene-1-carboxylic acid (4) into compound 3, the latter being a biogenetic precursor to the clinically significant anticancer agents vinblastine and vincristine.

Heat capacity anomaly in a self-aggregating system: Triblock copolymer 17R4 in water.

The reverse Pluronic, triblock copolymer 17R4 is formed from poly(propylene oxide) (PPO) and poly(ethylene oxide) (PEO): PPO14 - PEO24 - PPO14, where the number of monomers in each block is denoted by the subscripts. In water, 17R4 has a micellization line marking the transition from a unimer network to self-aggregated spherical micelles which is quite near a cloud point curve above which the system separates into copolymer-rich and copolymer-poor liquid phases. The phase separation has an Ising-like, lower consolute critical point with a well-determined critical temperature and composition. We have measured the heat capacity as a function of temperature using an adiabatic calorimeter for three compositions: (1) the critical composition where the anomaly at the critical point is analyzed, (2) a composition much less than the critical composition with a much smaller spike when the cloud point curve is crossed, and (3) a composition near where the micellization line intersects the cloud point curve that only shows micellization. For the critical composition, the heat capacity anomaly very near the critical point is observed for the first time in a Pluronic/water system and is described well as a second-order phase transition resulting from the copolymer-water interaction. For all compositions, the onset of micellization is clear, but the formation of micelles occurs over a broad range of temperatures and never becomes complete because micelles form differently in each phase above the cloud point curve. The integrated heat capacity gives an enthalpy that is smaller than the standard state enthalpy of micellization given by a van't Hoff plot, a typical result for Pluronic systems.

RANEY® cobalt--an underutilised reagent for the selective cleavage of C-X and N-O bonds.

RANEY® cobalt, which was first prepared in the 1930s, is known to function effectively as a catalyst for certain chemoselective reductions. However, its utility in chemical synthesis does not seem to have been fully appreciated. This first comprehensive survey of the literature on chemical transformations involving RANEY® cobalt attempts to redress matters by, among other things, highlighting the differences between the performance of this system and its much more well-known but usually less selective congener RANEY® nickel. A reliable method for preparing consistently effective RANEY® cobalt is presented together with a protocol that avoids the need to use it with high pressures of dihydrogen. As such, it is hoped more attention will now be accorded to the title reagent that offers considerable promise as a powerful tool for chemical synthesis, particularly in the assembly of polycyclic frameworks through tandem reductive cyclisation processes.

Synthesis of 4-Alkyl-2-chloro Imidazoles Using Intermolecular Radical Additions.

Here, we report an intermolecular radical addition-based reaction sequence that permits preparation of functionalized imidazoles via a 5-step/3-pot procedure. In contrast to traditional, transition-metal mediated protocols, which generally provide access to 2-substituted imidazoles, the strategy described here allows incorporation of a structurally diverse range of complex alkyl side chains at the 4-position. This work demonstrates that intermolecular free-radical addition reactions are a powerful alternative to traditional methods used to synthesize medicinally important heterocyclic frameworks.

Short Formal Syntheses of Lycorine and Congeners Using a 5-Endo-Trig/6-Endo-Trig Radical Cyclization Sequence.

Here, we report a practical route to medicinally interesting lycorine congeners alongside formal syntheses of various lycorine-type natural products, including lycorine itself. The efficiency of our strategy derives from a back-to-back 5-endo-trig/6-endo-trig radical cyclization sequence, which we systematically studied both experimentally and computationally. The results of our work will facilitate future development of urgently needed antiviral therapeutics based on lycorine.

The Amphibian Genomics Consortium: advancing genomic and genetic resources for amphibian research and conservation.

Amphibians represent a diverse group of tetrapods, marked by deep divergence times between their three systematic orders and families. Studying amphibian biology through the genomics lens increases our understanding of the features of this animal class and that of other terrestrial vertebrates. The need for amphibian genomics resources is more urgent than ever due to the increasing threats to this group. Amphibians are one of the most imperiled taxonomic groups, with approximately 41% of species threatened with extinction due to habitat loss, changes in land use patterns, disease, climate change, and their synergistic effects. Amphibian genomics resources have provided a better understanding of ontogenetic diversity, tissue regeneration, diverse life history and reproductive modes, antipredator strategies, and resilience and adaptive responses. They also serve as critical models for understanding widespread genomic characteristics, including evolutionary genome expansions and contractions given they have the largest range in genome sizes of any animal taxon and multiple mechanisms of genetic sex determination. Despite these features, genome sequencing of amphibians has significantly lagged behind that of other vertebrates, primarily due to the challenges of assembling their large, repeat-rich genomes and the relative lack of societal support. The advent of long-read sequencing technologies, along with computational techniques that enhance scaffolding capabilities and streamline computational workload is now enabling the ability to overcome some of these challenges. To promote and accelerate the production and use of amphibian genomics research through international coordination and collaboration, we launched the Amphibian Genomics Consortium (AGC) in early 2023. This burgeoning community already has more than 282 members from 41 countries (6 in Africa, 131 in the Americas, 27 in Asia, 29 in Australasia, and 89 in Europe). The AGC aims to leverage the diverse capabilities of its members to advance genomic resources for amphibians and bridge the implementation gap between biologists, bioinformaticians, and conservation practitioners. Here we evaluate the state of the field of amphibian genomics, highlight previous studies, present challenges to overcome, and outline how the AGC can enable amphibian genomics research to "leap" to the next level.

Revisiting Diagnosis and Treatment of Hypertrophic Cardiomyopathy: Current Practice and Novel Perspectives.

Sarcomeric hypertrophic cardiomyopathy (HCM) is a prevalent genetic disorder characterised by left ventricular hypertrophy, myocardial disarray, and an increased risk of heart failure and sudden cardiac death. Despite advances in understanding its pathophysiology, treatment options for HCM remain limited. This narrative review aims to provide a comprehensive overview of current clinical practice and explore emerging therapeutic strategies for sarcomeric HCM, with a focus on cardiac myosin inhibitors. We first discuss the conventional management of HCM, including lifestyle modifications, pharmacological therapies, and invasive interventions, emphasizing their limitations and challenges. Next, we highlight recent advances in molecular genetics and their potential applications in refining HCM diagnosis, risk stratification, and treatment. We delve into emerging therapies, such as gene editing, RNA-based therapies, targeted small molecules, and cardiac myosin modulators like mavacamten and aficamten, which hold promise in modulating the underlying molecular mechanisms of HCM. Mavacamten and aficamten, selective modulators of cardiac myosin, have demonstrated encouraging results in clinical trials by reducing left ventricular outflow tract obstruction and improving symptoms in patients with obstructive HCM. We discuss their mechanisms of action, clinical trial outcomes, and potential implications for the future of HCM management. Furthermore, we examine the role of precision medicine in HCM management, exploring how individualised treatment strategies, including exercise prescription as part of the management plan, may optimise patient outcomes. Finally, we underscore the importance of multidisciplinary care and patient-centred approaches to address the complex needs of HCM patients. This review also aims to encourage further research and collaboration in the field of HCM, promoting the development of novel and more effective therapeutic strategies, such as cardiac myosin modulators, to hopefully improve the quality of life and outcome of patients with sarcomeric HCM.

Synthetic studies on amaryllidaceae and other terrestrially derived alkaloids.

The total syntheses of a wide range of terrestrially derived alkaloids, especially ones isolated from members of the Amaryllidaceae family, are described. Two recurring themes associated with these syntheses are the use of two types of building blocks, namely ring-fused cyclopropanes, especially geminally-dihalogenated ones, and enzymatically derived cis-1,2-dihydrocatechols. These have often served as precursors to 2- or 3-halogenated 2-cyclohexen-1-ols that are themselves engaged in cross-coupling reactions, radical addition-elimination processes and/or Claisen- or Overman-type rearrangements so as to construct the highly functionalized six-membered rings associated with the target alkaloids.

Solasodine suppress MCF7 breast cancer stem-like cells via targeting Hedgehog/Gli1.

BACKGROUND: Recently, a novel therapy to treat cancer has been to target cancer stem-like cells (CSCs). The aim of this study was to investigate the effect of solasodine, a steroidal alkaloid isolated from Solanum incanum L., on MCF7 CSCs and to understand the compound's underlying mechanism of action. METHOD: A tumorsphere formation assay was used to evaluate the effects of solasodine on the proliferation and self-renewal ability of MCF7 CSCs. The level of expression of proteins associated with cancer stemness markers and Hh signaling mediators was determined. The interaction between solasodine and Gli1 was calculated by molecular docking and further demonstrated by cellular thermal shift assay. RESULTS: Solasodine significantly decreased the proliferation of MCF7 tumorspheres and showed a stronger cytotoxicity on breast cancer cells with higher levels of Gli1 expression. The results showed that the levels of CD44 and ALDH1 expression were suppressed. Furthermore, expression of CD24 was enhanced by solasodine, via a mechanism that involved dampening Gli1 expression and blocking the nuclear translocation of this protein in MCF7 tumorspheres. Computational studies predicted that solasodine showed a high affinity with the Gli1 zinc finger domain that resulted from hydrogen-bonds to the THR243 and ASP216 amino acids residues. In addition, solasodine specifically bound with Gli1 and enhanced Gli1 protein stability in MCF7 cells. CONCLUSION: Here, our findings indicated that solasodine can directly suppresses Hh/Gli1 signaling, and is a novel anticancer candidate that targets CSCs.