Search Results (113)

Spirocyclic compounds are experiencing a research surge due to their unique 3D structure, offering enhanced pharmacological, industrial, and material applications. They are increasingly used in medicinal chemistry to improve drug-like properties, such as solubility and target binding, and are also being utilized for advanced material applications, including electronics and photonics. In this communication, 3-(4-hydroxyphenyl)-1′,3′,6-trimethyl-2′H,3H,4H-spiro[furo[3,2-c]pyran-2,5′-pyrimidine]-2′,4,4′,6′(1′H,3′H)-tetraone was prepared via a two-stage transformation including a tandem Knoevenagel–Michael reaction and NBS-induced cyclization. At the first stage, a previously unknown ionic scaffold, morpholin-4-ium 5-((4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)(4-hydroxyphenyl)methyl)-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-olate was also isolated. Structures of the newly synthesized compounds were established by ¹H and ¹³C NMR, IR spectroscopy, high-resolution mass spectrometry, and elemental analysis. Full article

Hydantoins, exemplified by the imidazolidine-2,4-dione core, are privileged scaffolds in medicinal chemistry due to their compact structure, versatile hydrogen-bonding capacity, ability to fine-tune physicochemical properties for drug-like molecules, and potential to engage a diverse array of biological targets. This review highlights major advances in hydantoin-based drug discovery since 2019, emphasizing their evolving applications in oncology; neurology; infectious diseases; and cardiovascular, metabolic, and immune disorders. Recent studies demonstrate their success as kinase inhibitors, androgen receptor antagonists, and metalloprotease inhibitors, and emerging roles in modulating sterol isomerase, glycogen synthase kinase-3β, and ADAMTS family enzymes. Novel hybrid scaffolds—such as catechol–hydantoins, β-carboline–hydantoins, and spirocyclic thiohydantoins—have yielded potent and selective anticancer and antiviral leads. The discovery of BAY-9835 and GLPG1972 underscores the clinical potential of hydantoin-based metalloproteinase inhibitors in cardiovascular and osteoarthritic conditions. Furthermore, new antimicrobial, antimalarial, and antileishmanial derivatives illustrate the scaffold’s capacity to address multidrug resistance and neglected tropical diseases. Advances in computational design, stereochemical optimization, and hybridization strategies have expanded the structural and functional diversity of hydantoins, enhancing their target selectivity and pharmacokinetic profiles. Overall, hydantoins and their analogs remain at the forefront of small-molecule drug discovery, offering rich prospects for therapeutic innovation in diverse disease areas. Full article

The clinical efficacy of chemotherapy against rapidly proliferating cells stimulates both the development of new agents and the reassessment of established drugs. Spectroscopic methods (UV, FT-IR, and ¹H NMR) were applied to characterize prospidium chloride and related substances. The FT-IR spectrum of prospidium chloride, arising from vibrational transitions within the alkyl fragments of the dispirotripiperazinium cation, is reported with band assignments. Electronic transitions between molecular orbitals are analyzed using quantum–mechanical selection rules (Laporte and spin selection rules). The n→σ* transition (ΔS = 0) corresponds to the absorption maximum at λmax = 282 ± 0.40 nm (ε = 3.89 ± 0.08 L·mol⁻¹·cm⁻¹). A ¹H NMR spectrum (700 MHz) was used to assign chemical shifts δ (ppm), J-coupling constants (Hz), and gauche conformational features of prospidium chloride and its dihydroxy and epoxy impurities. Quantitative ¹H NMR (qNMR) was applied to determine the content of the active pharmaceutical ingredient and related substances. The methods provide complementary structural information for the characterization of prospidium chloride. Full article

1,3-Dipolar cycloaddition reactions of nitrile imines are a powerful tool for the construction of spirocyclic frameworks, yet controlling chemoselectivity remains challenging when dipolarophiles contain multiple reactive sites. In this study, we investigated the cycloaddition of nitrile imines with 5-arylmethylene-2-methylthiohydantoins, which possess both exocyclic C=C and endocyclic C=N bonds. Nitrile imines were generated from hydrazonoyl chlorides under basic conditions and reacted with the thiohydantoin substrates under optimized reaction conditions. The cycloaddition proceeded smoothly, affording spiro-fused thiohydantoin–pyrazoline derivatives. In all cases, the reaction occurred selectively at the exocyclic C=C bond, while the C=N bond remained unreactive even in the presence of excess dipole. This chemoselectivity is attributed to the greater steric accessibility of the exocyclic double bond. These results clarify key factors governing nitrile imine chemoselectivity and provide a reliable approach to structurally complex spirocyclic thiohydantoin derivatives. Full article

Nucleophilic ring-opening of bis(oxiranes), containing several reactive centers, can be used to elaborate straightforward atom-economy and stereoselective approaches to polyfunctionalized compounds. In the present work, ring-opening of cis- and trans-diastereomers of a spirocyclic bis(oxirane), containing a cyclooctane core (namely, 1,8-dioxadispiro[2.3.2.3]dodecane), upon treatment with various amines, was studied. Trans-isomer afforded aminoalcohols with 9-oxabicyclo[3.3.1]nonane moiety, formed via domino-process, including opening of an oxirane ring followed by intramolecular cyclization. Ring-opening of cis-isomer gave aminosubstituted cis-cyclooctane-1,5-diols, derived from independent reaction of two oxirane moieties. Activation of oxirane rings by the addition of LiClO₄, acting as a Lewis acid, allowed the involvement of a number of primary and secondary aliphatic amines as well as aniline derivatives in the reaction. Scope and limitations of the reaction were studied and a series of aminoalcohols with a 9-oxabicyclo[3.3.1]nonane core and symmetric diaminodiols with a cyclooctane core were obtained. Full article

Intensive analysis of the culture broth of the marine-derived Penicillium sp. strain SCH3-Sd2 led to the isolation of one spirocyclic diketopiperazine alkaloid, spirotryprostatin H (1), as well as two indolyl diketopiperazines, fumitremorgins O and P (2 and 3). The planar structures of 1–3 were elucidated by comprehensive spectroscopic analyses, while their absolute configurations were determined by combined NOESY and ECD analyses, and the configuration of the proline moiety was further confirmed using the advanced Marfey’s method. The evaluation of the antibacterial activity of compounds 1–3 against six bacterial strains revealed weak and selective activity only against Kocuria rhizophila KCTC 1915, with minimum inhibitory concentration (MIC) values of 64, 128, and 64 μg/mL, respectively. Full article

A strategy for constructing trifluoromethylated spiroisoxazolones has been developed. This approach relies on the 1,3-dipolar cycloaddition of CF₃-substituted nitrile imines, generated in situ from trifluoroacetyl hydrazonoyl bromides and K₂CO₃, with the exocyclic double bond of 4-benzylidene-3-methylisoxazol-5(4H)-ones. The reaction provides a series of trifluoromethylated spiro(isoxazolone-pyrazoline) derivatives in moderate to high yields (up to 93%). The protocol exhibits broad substrate compatibility with respect to aromatic substituents on both reaction partners. To the best of our knowledge, the introduction of a trifluoromethyl group at the 3-position of the pyrazoline ring via nitrile imine cycloaddition chemistry has not been previously reported. The resulting products incorporate a valuable CF₃-substituted pyrazoline pharmacophore spiro-fused to an isoxazolone core and may be of interest for medicinal chemistry programs. Full article

A new rhodamine-based fluorescent probe (RDC, rhodamine-based derivative) was rationally designed and synthesized for the highly selective, sensitive, and quantitative detection of Cu²⁺. The probe demonstrated outstanding specificity toward Cu²⁺, even in the presence of competing metal ions (e.g., Al³⁺, Fe³⁺, Cr³⁺, Na⁺, and K⁺), exhibiting negligible interference and confirming its robust anti-interference capability. A spectroscopic analysis revealed that Cu²⁺ induced spirocyclic ring cleavage, resulting in a colorless-to-pink colorimetric transition and enhancement of the yellow–green fluorescence at 590 nm. Upon addition of Cu²⁺, the fluorescence spectrum showed a linear response in the concentration range of 0.4–20 μM, with a correlation coefficient (R²) of 0.9907 and the limit of detection (LOD) calculated to be 0.12 μM. Meanwhile, Job’s plot analysis verified that the binding stoichiometry between RDC and Cu²⁺ was 1:1. The probe exhibits rapid response kinetics (<5 min) and non-destructiveness properties, enabling in vivo imaging. Under stress conditions, Cu²⁺ accumulated predominantly in root tips (its primary target tissue), with the following distribution hierarchy: root tips > maturation zone epidermis > xylem vessels > cortical cell walls. In conclusion, RDC is a well-characterized, high-performance tool with high accuracy, excellent selectivity, and superior sensitivity for plant Cu²⁺ studies, and this work opens new technical avenues for rhodamine-based probes in plant physiology, environmental toxicity monitoring, and rational design of phytoremediation strategies. Full article

Spirocyclic architectures, which feature two rings sharing a single atom, are common in natural products and exhibit beneficial biological and material properties. Due to the significance of these architectures, biocatalytic dearomative spirocyclization has recently emerged as a powerful approach for constructing three-dimensional spirocyclic frameworks under mild, sustainable conditions and with exquisite stereocontrol. This review surveys the latest advances in biocatalyzed spirocyclization of all-carbon arenes (phenols and benzenes), aza-aromatics (indoles and pyrroles), and oxa-aromatics (furans). We highlight cytochrome P450s, flavin-dependent monooxygenases, multicopper oxidases, and novel metalloenzyme platforms that effect regio- and stereoselective oxidative coupling, epoxidation/semi-pinacol rearrangement, and radical-mediated cyclization to produce diverse spirocycles. Mechanistic insights gleaned from structural, computational, and isotope-labeling studies are discussed where necessary to help the readers further understand the reported reactions. Collectively, these examples demonstrate the transformative potential of biocatalysis to streamline access to spirocyclic scaffolds that are challenging to prepare through traditional methods, underscoring biocatalysis as a transformative tool for synthesizing pharmaceutically relevant spiroscaffolds while adhering to green chemistry paradigms to ultimately contribute to a cleaner and more sustainable future. Full article

A phytochemical study of Ganoderma applanatum identified four predominant triterpenoids, with ganoapplanilactone C (GATC) exhibiting the most significant lipid-reducing effects in high-fat diet-fed zebrafish, surpassing atorvastatin at 5 μM. Histopathological analysis confirmed GATC’s protective effects on the liver against high-fat diet-induced damage. The Enzyme-Linked Immunosorbent Assay (ELISA) results showed a positive correlation between GATC treatment and liver health markers, as well as antioxidant enzymes, while they revealed a negative correlation with triglycerides and inflammatory cytokines. Metabolomic profiling demonstrates GATC’s impact on metabolites such as amino acids, fatty acids, and the mechanistic Target of Rapamycin (mTOR) signaling pathway, suggesting its role in regulating multiple metabolic processes. The increase in Adenosine Monophosphate-activated protein kinase (AMPK) phosphorylation in the GATC-treated groups indicates the activation of the AMPK/mTOR pathway, a key mechanism in lipid metabolism and liver protection. Molecular docking studies highlighted the importance of GATC’s spirocyclic ketone system and hydroxyl group in binding to target proteins. These findings underscore GATC’s potential as a therapeutic agent for metabolic dysfunction-associated steatotic liver disease (MASLD), emphasizing its superior efficacy compared to other triterpenoids due to its unique C-23 spiro 5/7 system. This study provides valuable insights into the prevention and treatment of MASLD using G. applanatum-derived compounds. Full article

An efficient stereoselective strategy for the synthesis of chiral bisspiro barbituric acid–oxindole derivatives was developed. The asymmetric Michael addition/cyclization tandem reaction between benzylidene barbituric acids and oxindolylmalonitriles was catalyzed by squaramide catalyst, and the corresponding spirocyclic products were obtained in good-to-high yields (up to 97%) with excellent stereoselectivities (up to >99% ee, >20:1 dr). At the same time, the practicality of the reaction was verified by the gram-scale preparation reaction. Full article

Spirocalcaridines A and B are among the most challenging members of the marine invertebrate-derived Leucetta alkaloids. Approaches to the construction and elaboration of the highly compact spirocyclic core are described. The synthesis of tricyclic guanidine via tandem oxidative amination dearomatizing spirocyclization (TOADS) using hypervalent iodine set the stage for total synthesis via the migration of the C4/C8 double bond to the C4/C5 position, followed by oxidation. The undesired but not surprising propensity of the spirocyclic cyclohexadienone to undergo rearrangement to the phenol hindered the desired olefin migration. Furthermore, initial efforts to install the oxidation sequentially, first at C5 and then at C4 in the complete carbon skeleton, were fraught with unforeseen challenges and unusual outcomes. In addition, the scope and limitations of hypervalent iodine-mediated tandem oxidative dearomatizing spirocyclization on various substrates were explored. Urethanes and thiourethanes underwent spirocyclization with an excellent yield, whereas the reaction with allylic substrates and species lacking the p-methoxy substituent did not proceed. Attempts to prepare other guanidine precursors are briefly discussed. Full article

3-Oxetanone-derived spirooxazolidines represent a class of building blocks for accessing diverse saturated heterocycles, but their synthetic methods remain unexplored. Herein, we demonstrate a highly atom-economic approach for the synthesis of diverse 3-oxetanone-derived N-propargyl spirooxazolidines via a CuBr₂/TFA co-catalyzed four-component A³-based cascade reaction of a 1,2-amino alcohol, a 3-oxetanone, a formaldehyde, and an alkyne. This strategy is characterized by a wide substrate range and excellent chemoselectivity. In addition, the synthesized spirocycles could also be easily converted into other valuable compounds, facilitating potentially useful synthetic applications. Full article

This research employs 2-methylene-tetrahydronaphtalene-1-ones and N-cyclopropylanilines as starting materials, integrating photocatalysis and organic phosphoric acid catalysis to synthesize 2-amino-spiro[4.5]decane-6-ones via a [3 + 2] cycloaddition approach. This method boasts the advantage of mild reaction conditions that are photocatalyst-free and metal catalyst-free. It achieves 100% atom conversion of the substrates, aligning with the principles of green chemistry. Additionally, it attains a high diastereoselectivity result of up to 99:1, demonstrating good stereoselectivity. In the derivatives of 2-methylene-tetrahydronaphtalene-1-ones, substrates with alkane rings of different sizes or thiophene replacing the phenyl ring are also amenable to this method, enabling the synthesis of different [4.4], [4.5], and [4.6] spirocyclic compounds. In the derivatives of N-cyclopropylanilines, substrates with para-fluoro and meta-fluoro substitutions are also amenable to this method. Finally, a preliminary mechanistic investigation was conducted, proposing a plausible reaction mechanism pathway initiating from the intermediate N-cyclopropylanilines with chiral phosphoric acid. Full article