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Diels–Alder cycloaddition reaction is one of the most powerful strategies for the construction of six-membered carbocyclic and heterocyclic systems, in most cases with high regio- and stereoselectivity. In this review, an insight into the most relevant advances on sustainable Diels–Alder reactions since 2010 is provided. Various environmentally benign solvent systems are discussed, namely bio-based derived solvents (such as glycerol and gluconic acid), polyethylene glycol, deep eutectic solvents, supercritical carbon dioxide, water and water-based aqueous systems. Issues such as method’s scope, efficiency, selectivity and reaction mechanism, as well as sustainability, advantages and limitations of these reaction media, are addressed.

Heterocycles A must-read handbook on heterocycle chemistry with a focus on sustainability Heterocycles feature prominently in our daily life—they are essential for pharmaceuticals, agrochemicals, and fine chemicals. More, numerous natural, bioactive products contain heterocyclic compounds. As a result, heterocyclic chemistry continues to be one of the most important areas of study in organic chemistry. Heterocycles provides an important reference on a wide range of topics relating to heterocyclic chemistry, with a heavy emphasis on sustainable methods and greener syntheses. The book describes state-of-the-art synthetic methods, such as photochemical reactions, dearomatization reactions, organocatalysis, transition metal catalysis, and biocatalysis. It also covers: * Sustainable methods, like flow chemistry, mechanochemistry, and multicomponent synthesis * Strategies for the synthesis of heterocyclic macrocycles and medium-sized rings * Characterization of heterocyclic compounds Heterocycles is a useful reference for organic chemists, natural products chemists, catalytic chemists, and medicinal chemists in academia and industry.

Corroles and hexaphyrins are porphyrinoids with great potential for diverse applications. Like porphyrins, many of their applications are based on their unique capability to interact with light, i.e., based on their photophysical properties. Corroles have intense absorptions in the low-energy region of the uv-vis, while hexaphyrins have the capability to absorb light in the near-infrared (NIR) region, presenting photophysical features which are complementary to those of porphyrins. Despite the increasing interest in corroles and hexaphyrins in recent years, the full potential of both classes of compounds, regarding biological applications, has been hampered by their challenging synthesis. Herein, recent developments in the synthesis of corroles and hexaphyrins are reviewed, highlighting their potential application in photodynamic therapy.

Integrase inhibitors (INIs) are an important class of drugs for treating HIV-2 infection, given the limited number of drugs active against this virus. While the clinical efficacy of raltegravir and dolutegravir is well established, the clinical efficacy of bictegravir for treating HIV-2 infected patients has not been determined. Little information is available regarding the activity of bictegravir against HIV-2 isolates from patients failing raltegravir-based therapy. In this study, we examined the phenotypic and matched genotypic susceptibility of HIV-2 primary isolates from raltegravir-naïve and raltegravir-failing patients to raltegravir, dolutegravir, and bictegravir, and to the new spiro-β-lactam BSS-730A. The instantaneous inhibitory potential (IIP) was calculated to help predict the clinical activity of bictegravir and BSS-730A. Isolates from raltegravir-naïve patients were highly sensitive to all INIs and BSS-730A. Combined integrase mutations E92A and Q148K conferred high-level resistance to raltegravir, and E92Q and T97A conferred resistance to raltegravir and dolutegravir. The antiviral activity of bictegravir and BSS-730A was not affected by these mutations. BSS-730A displayed strong antiviral synergism with raltegravir. Mean IIP values at Cmax were similar for all INIs and were not significantly affected by resistance mutations. IIP values were significantly higher for BSS-730A than for INIs. The high IIP values of bictegravir and BSS-730A for raltegravir-naïve and raltegravir-resistant HIV-2 isolates highlight their potential value for treating HIV-2 infection. Overall, the results are consistent with the high clinical efficacy of raltegravir and dolutegravir for HIV-2 infection and suggest a promising clinical profile for bictegravir and BSS-730A.

Herein, the synthesis and anticancer activity evaluation of a series of novel β-carbolines is reported. The reactivity of nitrosoalkenes towards indole was explored for the synthesis of novel tryptophan analogs where the carboxylic acid was replaced by a triazole moiety. This tryptamine was used in the synthesis of 3-(1,2,3-triazol-4-yl)-β-carbolines via Pictet–Spengler condensation followed by an oxidative step. A library of compounds, including the novel 3-(1,2,3-triazol-4-yl)-β-carbolines as well as methyl β-carboline-3-carboxylate and 3-tetrazolyl-β-carboline derivatives, was evaluated for their antiproliferative activity against colorectal cancer cell lines. The 3-(1H-tetrazol-5-yl)-β-carbolines stood out as the most active compounds, with values of half-maximal inhibitory concentration (IC50) ranging from 3.3 µM to 9.6 µM against colorectal adenocarcinoma HCT116 and HT29 cell lines. The results also revealed a mechanism of action independent of the p53 pathway. Further studies with the 3-tetrazolyl-β-carboline derivative, which showed high selectivity for cancer cells, revealed IC50 values below 8 μM against pancreatic adenocarcinoma PANC-1, melanoma A375, hepatocarcinoma HEPG2, and breast adenocarcinoma MCF-7 cell lines. Collectively, this work discloses the 3-tetrazolyl-β-carboline derivative as a promising anticancer agent worthy of being further explored in future works.

Direct pulp capping consists of a procedure in which a material is directly placed over the exposed pulp to maintain dental vitality. Although still widely used in clinical practice, previous in vitro studies found that the biomaterial Life® presented high cytotoxicity, leading to cell death. This study aimed to identify the Life® constituents responsible for its cytotoxic effects on odontoblast-like cells (MDPC-23). Aqueous medium conditioned with Life® was subjected to liquid–liquid extraction with ethyl acetate. After solvent removal, cells were treated with residues isolated from the organic and aqueous fractions. MTT and Trypan blue assays were carried out to evaluate the metabolic activity and cell death. The organic phase residue promoted a significant decrease in metabolic activity and increased cell death. On the contrary, no cytotoxic effects were observed with the mixture from the aqueous fraction. Spectroscopic and spectrometric methods allowed the identification of the toxic compounds. A mixture of the regioisomers ortho, para, and meta of N-ethyl-toluenesulfonamide was identified as the agent responsible for the toxicity of biomaterial Life® in MDPC-23 cells. These findings contribute to improving biomaterial research and development.

The synthesis and reactivity of tetrazol-5-yl-phosphorus ylides towards N-halosuccinimide/TMSN3 reagent systems was explored, opening the way to new haloazidoalkenes bearing a tetrazol-5-yl substituent. These compounds were obtained as single isomers, except in one case. X-ray crystal structures were determined for three derivatives, establishing that the non-classical Wittig reaction leads to the selective synthesis of haloazidoalkenes with (Z)-configuration. The thermolysis of the haloazidoalkenes afforded new 2-halo-2-(tetrazol-5-yl)-2H-azirines in high yields. Thus, the reported synthetic methodologies gave access to important building blocks in organic synthesis, vinyl tetrazoles and 2-halo-2-(tetrazol-5-yl)-2H-azirine derivatives.

Photodynamic therapy (PDT) is a medical procedure useful for several benign conditions (such as wound healing and infections) and cancer. PDT is minimally invasive, presents few side effects, good scaring, and is able to minimal tissue destruction maintaining organ anatomy and function. Endoscopic access to the uterus puts PDT in the spotlight for endometrial disease treatment. This work systematically reviews the current evidence of PDT’s potential and usefulness in endometrial diseases. Thus, this narrative review focused on PDT applications for endometrial disease, including reports regarding in vitro, ex vivo, animal, and clinical studies. Cell lines and primary samples were used as in vitro models of cancer, adenomyosis and endometrioses, while most animal studies focused the PDT outcomes on endometrial ablation. A few clinical attempts are known using PDT for endometrial ablation and cancer lesions. This review emphasises PDT as a promising field of research. This therapeutic approach has the potential to become an effective conservative treatment method for endometrial benign and malignant lesions. Further investigations with improved photosensitisers are highly expected.

Aza- and diazafulvenium methide systems are versatile building blocks for the synthesis of pyrroles and pyrazoles. These extended dipoles participate in sigmatropic [1,8]H shifts and 1,7-electrocyclizations giving vinyl pyrroles and pyrazoles. Under flash vacuum pyrolysis conditions these heterocycles undergo interesting rearrangements. Aza- and diazafulvenium methides can be intercepted by dipolarophiles. Derivatives with carboxylate groups at C-4 and/or C-5 act exclusively as 1,7-dipoles affording products resulting from the addition across the 1,7-positions. These 1,7-cycloadducts include chlorin and bacteriochlorin type macrocycles as well as steroidal analogues, compounds with relevance in medicinal chemistry. In contrast with this chemical behavior, 5-trifluoromethylazafulvenium methides can participate in both 1,7- and 1,3-dipolar cycloadditions. The generation and reactivity of benzodiazafulvenium methides is also discussed.

Allelopathy, the release of chemicals by plants that inhibit the germination and growth of competing species, can be an important trait for invasive success. However, little is known about potential biogeographical differences in allelopathy due to divergent regional eco-evolutionary histories. To test this, we examined the allelochemical potential of the highly invasive species Centaurea solstitialis from six world regions including native (Spain, Turkey) and non-native ranges (Argentina, Chile, California and Australia). Seeds from several populations in each region were collected and grown under common garden conditions. Allelopathic potential and chemical composition of three leaf extract concentrations of C. solstitialis from each region: 0.25%, 0.5% 0.75% (w/v−1) were assessed on the phytometer Lactuca sativa. The main allelochemicals present in the leaf-surface extract were sesquiterpene lactones that varied in major constitutive compounds across regions. These leaf extracts had strong inhibitory effects on L. sativa seed germination and net growth. Summed across regions, the 0.25% concentration suppressed germination by 72% and radicle elongation by 66%, relative to the controls. At the 0.5% concentration, no seeds germinated when exposed to extracts from the non-native ranges of Argentina and Chile, whereas germination and radicle growth were reduced by 98% and 89%, respectively, in the remaining regions, relative to controls. Germination and seedling growth were completely inhibited at the 0.75% concentration extract for all regions. Some non-native regions were characterized by relatively lower concentrations of allelochemicals, suggesting that there is biogeographical variation in allelopathic expression. These findings imply that rapid selection on the biochemical signatures of an exotic invasive plant species can be highly region-specific across the world.