Organotrifluoroborates are an important functional group that is used in synthesis, diagnostics, and, more recently, in theranostics. Here, we present a practical, one‐step synthesis of ammonium and sulfonium trifluoroborate zwitterionic derivatives by N‐ or S‐ alkylation of bromomethyltrifluoroborate. The reaction proceeds smoothly to produce the desired compounds with good to excellent yields. In particular, the preparation of some sulfonium trifluoroborate derivatives, which avoids the use of expensive or troublesome reagents, their complete spectroscopic characterization, and an example of their application in a click‐chemistry reaction are reported.

Despite nearly two centuries of investigation, the photochemistry of alpha-santonin continues to reveal unexpected reactivity. In this study, we systematically explored the behavior of alpha-santonin under UVC (254 nm) and UVA (390 and 456 nm) irradiation in protic and aprotic solvents, uncovering a marked dependence of product distribution on both irradiation wavelength and solvent environment. While irradiation at 254 nm in aprotic solvents selectively afforded lumi-santonin (1), irradiation at 390 nm promoted further rearrangement to mazdasantonin (4). In protic media, solvent polarity and steric hindrance strongly influenced the reaction outcome, leading to photosantonic acid esters and lactone derivatives. Notably, irradiation in secondary and tertiary alcohols at 390 nm provided two previously undescribed lumi-derivatives. Mechanistic investigations suggest the involvement of competing diradical and zwitterionic pathways. These results demonstrate that modern wavelength-controlled photochemistry can still uncover unexplored transformations even within classical photochemical systems such as alpha-santonin.

Despite being discovered over a century ago, lathyrane diterpenoids have only recently attracted significant attention from the organic chemistry community due to their distinctive carbon framework, characterized by a 5/11/3 tricyclic system. The conformational rigidity of these scaffolds promotes close spatial proximity between functional groups, making transannular reactions a powerful tool for the construction of new complex polycyclic architectures. In parallel, compounds from the genus Euphorbia have emerged as versatile molecular frameworks in medicinal chemistry, exhibiting a wide range of biological activities, including cytotoxic, antiviral, and neuroprotective effects. This review summarizes recent advances in the field, with particular emphasis on synthetic strategies, structural diversity, and medicinal chemistry aspects of this intriguing class of secondary metabolites.

Gossypol, a major metabolite of cotton plants, has been used for the first time as a source material for the preparation of derivatives employed in asymmetric catalysis. Specifically, the (R)-enantiomer of the 6,6',7,7'-O-tetramethyl derivative of apogossypol has been synthesized in five steps and 47% total yield from enantiopure (-)-(R)-gossypol. This axially chiral diol was used as a ligand in the enantioselective boron-catalyzed Diels-Alder reactions of 2'-hydroxychalcones and dienes, achieving high yields and moderate enantioselectivities. Considering the potentially high amounts of gossypol isolable from agricultural wastes of cotton crops, these results open the way for the introduction of a promising new class of biomass-derived asymmetric catalysts.

Boron neutron capture therapy (BNCT) is an oncological treatment based on the neutron capture reaction on 10B. The only two compounds approved for phase I/II clinical trials are sodium borocaptate (BSH) and 4-boronophenylalanine (BPA). While BPA has been widely exploited in clinical trials, the use of BSH is limited due to its insufficient uptake by tumor cells. Herein, we report a novel formulation based on silk fibroin nanoparticles (SFNs), capable of loading a large amount of borocaptate ions. The nanoparticles have been characterized and tested on U87 glioma cells, and boron uptake was measured using neutron autoradiography, which involved irradiating the samples in a thermal neutron field. Measurements demonstrated the crucial role of the nanocarrier in enhancing boron internalization. Notably, SFNs-BSH achieved 29.5 ppm total boron uptake in U87 cells - comparable to clinical BPA - at 4x lower dose.

The possibility of duplicating the efficiency and selectivity of natural processes under laboratory conditions remains a significant challenge for organic chemists. In this letter, we demonstrated that it is possible to introduce pinpoint modifications and to reshape the terpene skeleton of easily available oleananes in a biomimetic fashion. Furthermore, aromatization of the A ring of the triterpene system is reported here for the first time, mimicking what occurs exclusively in nature in sediments.

The photoreactivity of steroids represented a hot topic in the middle of the last century and in this project, we "rediscover" it through the exploration of the photochemical behavior of Δ1-3-keto-steroids. In terms of number of products obtained, the photochemistry of Δ1-3-keto-steroids is less complicated than that of Δ4-3-keto- and Δ1,4-3-keto-steroids, furnishing an efficient and tunable method to remodel the classic steroid 6/6/6/5 ring system. In this scenario, this approach can represent a simple strategy to interconvert a class of easily available steroids to another difficult-to-access from natural sources. As a proof of concept, the synthesis 5,6-dihydro-ophiopogonol A (11), a very close analog of natural ophiopogonol A (7), was accomplished in just four steps starting from easily available diosgenin (8).

Background: Boron Neutron Capture Therapy (BNCT) is a promising cancer treatment that combines tumor-selective boron delivery agents with thermal neutrons to kill cancer cells while sparing normal tissue. BNCT requires boron-containing compounds that exhibit high tumor selectivity and achieve therapeutic boron concentrations within tumor cells. This work focuses on the early development of a novel boron cluster carbohydrate derivative based on the glucosamine structure. Our results indicate that this derivative may have advantages over the typical boron delivery agent used in clinical applications and may significantly improve boron delivery capacity at the cellular level. Methods: The performance of the compound in terms of boron uptake was tested in the U87-MG glioblastoma cell line employing neutron autoradiography imaging and quantification. Results: The compound was non-toxic for cells, and it showed a remarkable capacity to enrich cells with boron. The ratio between boron concentration provided in the culture medium and boron concentration achieved in cells was compared to that obtained with boronophenylalanine (BPA), the gold standard in BNCT. The result demonstrated a significantly better performance compared with BPA, showing that the novel agent can concentrate boron in cells more than in culture medium. Conclusions: The encouraging preliminary results provide a starting point for its potential application in in vivo tests.

The synthesis of glycosides generally requires the use of building blocks that need to be readily prepared, avoiding tricky reaction steps and boring purifications. Thioglycosides represent key donor intermediates for their activation in glycosylation reactions and for their great stability. Moreover, the presence of a benzylidene moiety confers to the molecule a double advantage: it can influence the stereochemistry of the glycosylation reaction and can be selectively opened to generate different species having a free secondary hydroxyl group. Here, the preparation of p-Tolyl 1-thio-4,6-O-benzylidene-2,3-di-O-benzyl-beta-d-pyranoses of glucose, galactose, and mannose are described. The global procedure involved the exploitation of simple reactions and crystallization techniques, having a chromatographic purification for the last step only.

Since the introduction of the Shi catalyst, the organocatalytic epoxidation of olefins has become an area of continued research interest. To explore the possibility of enhancing the efficiency and stability of the catalyst, the synthesis of a galactose‐derived trifluoromethyl ketone, and its use for stereoselective epoxidation reaction that exploits a transitory dioxirane as active species are herein reported. The trifluoromethyl ketone was built on the C6 of a protected d ‐galactopyranose. The organocatalyst was obtained smoothly in a few steps, and when utilized for stereoselective epoxidation exhibited excellent stability as no chemical alterations were observed during the reaction. The stereoselectivity, although sometimes moderate, appears surprisingly high considering the conformational freedom of the trifluoromethyl ketone moiety. DFT calculations were performed to investigate the interactions involved in regulating the observed selectivities. Moreover, a new mnemonic model has been developed to serve as a fast‐predicting tool for epoxidation of new substrates.

Boronated carbohydrate derivatives have good potential for targeting malignant cells in Boron Neutron Capture Therapy (BNCT) due to their preferential glucose uptake. In particular, with the introduction of the ammonium trifluoroborate moiety, boronated sugars can function as both BNCT agents and Positron Emission Tomography (PET) tracers. Their 18F radiolabeling allows real-time tracking of biodistribution. This study evaluates the chemical, metabolic, and plasma stability of ammonium trifluoroborates for pharmaceutical purposes using LC-HRMS, presenting stability data under various conditions -acidic, basic, pseudophysiological, and oxidative- and highlighting degradation products and mechanisms. The data are supported by 1H NMR and 19F NMR. Metabolic and plasma stabilities, along with preliminary toxicological data (MTT assays), are also provided to better predict the clinical applicability of these compounds.

EDITORIAL article Front. Nat. Prod., 05 January 2024Sec. Biological Activities of Natural Products Volume 2 - 2023 | https://doi.org/10.3389/fntpr.2023.1338469

Asymmetric epoxidation represents a hot topic in organic synthesis. In recent years, organocatalysts based on sugar skeletons have been exploited in asymmetric epoxidation to achieve enantiomeric pure epoxides. In this work, two different endocyclic ketones derived from glucose and galactose protected with a 4,6-O-benzylidene group have been prepared and exploited for Shi-type epoxidation. The two carbohydrates show an opposite preferential stereoselective epoxidation on various olefins, affording the epoxides in high conversions and modest enantioselectivities. DFT calculations disclosed the reasons behind the inversion of selectivity achieved by the two catalysts, showing that a delicate balance between the catalyst conformation, its protecting groups, and the secondary interactions with the substrate govern the final observed results.

The discovery of new bioactivities is closely related to the generation of novel scaffolds, and in the past few years different strategies have been proposed to obtain unknown architectures from the manipulation of known compounds. In the present study, we exploited a vintage photochemical approach for the discovery of an unexpected pathway of reactivity related to Δ1-3-oxo-pentacyclic triterpenic acids gaining access to a new class of natural-unnatural 5(10→1)abeo-pentacyclic triterpenic acids.

Cannabinoid subtype 1 receptors (CB 1 Rs) are an important class of G protein-coupled receptors (GPCRs) belonging to the endocannabinoid system. CB 1 Rs play a crucial modulatory role in the functioning of other neurotransmitter systems and are involved in a wide range of physiological functions and dysfunctions; thus, they are considered one of the most important targets for drug development, as well as diagnostic purposes. Despite this, only a few molecules targeting this receptor are available on the pharmaceutical market, thus emphasizing the need to gain a deeper understanding of the complex activation pathways of CB 1 Rs and how they regulate diseases. As part of this review, we provide an overview of pharmacological and imaging tools useful for detecting CB 1 Rs. Herein, we summarize the derivations of cannabinoids and terpenoids with fluorescent compounds, radiotracers, or photochromic motifs. CB 1 Rs’ molecular probes may be used in vitro and, in some cases, in vivo for investigating and exploring the roles of CB 1 Rs together with the starting point for the development of CB 1 R-targeted drugs.

The discovery of new glycosylation reactions is still a major challenge in carbohydrate chemistry. Traditional glycosylation reactions require the preparation of sugar donors with anomeric active or latent leaving groups. Dehydrative glycosylation is a fascinating alternative that enables the direct formation of the glycosidic bond from the hemiacetal, eliminating the need for (sometimes unstable) leaving groups, and allowing to reduce reaction, work-up, and purification times. Although some interesting methods of dehydrative glycosylation have been reported, in order to compete with conventional chemical glycosylation, a greater number of efficient and stereoselective methods need to be developed. Herein, a dehydrative procedure that uses a combination of iodine, triphenylphosphine, and a base (DMAP or imidazole) is described. This methodology allows for the preparation of sugar derivatives from commercially available 1-hydroxy glycosyl donors. The reaction takes place under mild conditions through the in situ-formation of an anomeric iodide intermediate, which, upon reaction with an alcohol, gives the corresponding glycosides up to quantitative yields and with high α-stereoselectivity.

Glycosylation is the key reaction by which our body can produce and modify carbohydrates and their conjugates which are molecules essential for life. The study of the diversity of their functions is a current and ever-expanding topic that requires the ability to provide pure saccharides quickly, efficiently and in a controlled way which can be achieved by chemical synthesis. Although the influence of the donor and the promoter on the outcome of a glycosylation reaction is well documented, the search for new methodologies and new promoters/activators is constantly expanding. In this review, after an introduction dealing with well-known glycosylation strategies, we describe the most recent advances in terms of the use of innovative approaches, focalizing the study on new promoters and leaving groups exploited in the last ten years.

Polypharmacological targeting of lipid mediator networks offers potential for efficient and safe anti-inflammatory therapy. Because of the diversity of its biological targets, curcumin (1a) has been viewed as a privileged structure for bioactivity or, alternatively, as a pan-assay interference (PAIN) compound. Curcumin has actually few high-affinity targets, the most remarkable ones being 5-lipoxygenase (5-LOX) and microsomal prostaglandin E2 synthase (mPGES)-1. These enzymes are critical for the production of pro-inflammatory leukotrienes and prostaglandin (PG)E2, and previous structure-activity-relationship studies in this area have focused on the enolized 1,3-diketone motif, the alkyl-linker and the aryl-moieties, neglecting the rotational state of curcumin, which can adopt twisted conformations in solution and at target sites. To explore how the conformation of curcuminoids impacts 5-LOX and mPGES-1 inhibition, we have synthesized rotationally constrained analogues of the natural product and its pyrazole analogue by alkylation of the linker and/or of the ortho aromatic position(s). These modifications strongly impacted 5-LOX and mPGES-1 inhibition and their systematic analysis led to the identification of potent and selective 5-LOX (3b, IC50 = 0.038 µM, 44.7-fold selectivity over mPGES-1) and mPGES-1 inhibitors (2f, IC50 = 0.11 µM, 4.6-fold selectivity over 5-LOX). Molecular docking experiments suggest that the C2-methylated pyrazolocurcuminoid 3b targets an allosteric binding site at the interface between catalytic and regulatory 5-LOX domain, while the o, o'-dimethylated desmethoxycurcumin 2f likely binds between two monomers of the trimeric mPGES-1 structure. Both compounds trigger a lipid mediator class switch from pro-inflammatory leukotrienes to PG and specialized pro-resolving lipid mediators in activated human macrophages.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy considered curable by modern clinical management. Nevertheless, the prognosis for T-ALL high-risk cases or patients with relapsed and refractory disease is still dismal. Therefore, there is a keen interest in developing more efficient and less toxic therapeutic approaches. T-ALL pathogenesis is associated with Notch signaling alterations, making this pathway a highly promising target in the fight against T-ALL. Here, by exploring the anti-leukemic capacity of the natural polyphenol curcumin and its derivatives, we found that curcumin exposure impacts T-ALL cell line viability and decreases Notch signaling in a dose- and time-dependent fashion. However, our findings indicated that curcumin-mediated cell outcomes did not depend exclusively on Notch signaling inhibition, but might be mainly related to compound-induced DNA-damage-associated cell death. Furthermore, we identified a novel curcumin-based compound named CD2066, endowed with potentiated anti-proliferative activity in T-ALL compared to the parent molecule curcumin. At nanomolar concentrations, CD2066 antagonized Notch signaling, favored DNA damage, and acted synergistically with the CDK1 inhibitor Ro3306 in T-ALL cells, thus representing a promising novel candidate for developing therapeutic agents against Notch-dependent T-ALL.

The synthesis of D-glucoheptose derivative containing a boronic moiety is described herein. Starting from benzyl 6,7-dideoxy-2,3,4-tri-O-benzyl-beta-D-gluco-ept-6-enopyranoside, the introduction of the boronic acid was performed through a metathesis reaction by using MIDA vinyl boronic acid and the 2nd generation Grubbs catalyst. Hydrogenation led to the final product in only two reaction steps. This new sugar-containing boronic acid in the skeleton could mimic carbohydrate behavior and follow the glucose uptake in living cells. The in vitro toxicity tests performed in fibroblasts and glioma tumor cell lines showed minimal toxicity. Boron uptake measured using ICP-MS was minimal in fibroblasts, while in glioma cells showed a value of 6 ng of total boron accumulation per mg of cells, implying that compound 1a is able to accumulate selectively in the tumor tissues compared to normal.