Beilstein Journal of Organic Chemistry最新文献

We have streamlined a dipolar cycloaddition approach to assemble the core of malayamycin A and other related uracil nucleosides possessing the common bicyclic perhydrofuropyran framework. The latent functionality strategy employing oxazoline to unmask the 1,2-hydroxyamine moiety proves feasible, eliminating the need for alkene functionalization required in previous endeavours. This current strategy provides a reliable platform for accessing diverse uracil nucleosides and their derivatives, facilitating the development of potent fungicides.

Calix[n]arenes are polyphenolic macrocycles known for their remarkable synthetic versatility, which supports their broad application in various areas, including drug discovery. Their unique conformational features, functionality, and low toxicity make calixarene derivatives valuable drug candidates against cancer. The aim of the present study was the synthesis and characterization of a calix[4]arene derivative in which known anticancer isothiouronium groups were clustered on a calix[4]arene scaffold bearing long C12 alkyl chains at the lower rim. The resulting amphiphilic calix[4]arene derivative 3 spontaneously self-assembled into nanoscale aggregates in aqueous medium, as demonstrated by dynamic light scattering analysis. The cytotoxicity of compound 3 towards cancer cells was assessed using human renal carcinoma cells (786-O cells) and compared with that in non-malignant fibroblast cells (SW1 cells). Compound 3 showed a significantly greater antiproliferative effect on cancer cells (IC₅₀ 37.4 µM) than on normal fibroblasts (517 µM). The importance of the isothiouronium moieties in the observed cytoxic effect was confirmed by comparison with the calix[4]arene precursor (1) lacking these functional units. The selective antiproliferative profile of compound 3 highlights its potential as a lead anticancer agent. Moreover, compound 3 holds promise for further development in combination multidrug therapy due to the potential to load drug molecules in the bioactive nanoassembled structure.

A series of pentacyclic aromatic heterocycles representing functionalized phenanthridines, naphthyridines, and phenanthrolines were prepared via Pd-catalyzed annulation of 1,5-diaryl-1,2,3-triazoles. Analogs with triazole N1-connected ortho-bromobenzene subunits successfully underwent annulation under microwave irradiation in yields of 31-90%. In contrast, annulations of triazole C1-connected ortho-bromobenzene subunit analogs failed under microwave irradiation but were successful using conventional thermal heating in yields of 31-65%. The expanded nature of the aromatic ring system following annulation was reflected by the downfield shifting of aromatic ¹H NMR signals and the red-shifting of UV-visible absorbance signals relative to their non-annulated counterparts. Structural rigidity of annulated systems compared to non-annulated counterparts was reflected by emission signals with increased intensity and decreased Stokes shifts. Five benzotriazolophenanthroline regioisomers sharing structural similarity regarding N center placement showed antimicrobial activity, as measured by minimum inhibitory concentration assays. MIC values of 2-16 μM towards Gram-positive bacteria Staphylococcus epidermidis and Bacillus subtilis and 8-16 μM towards Saccharomyces cerevisiae yeast were observed for these annulated molecules, while their analogous non-annulated control compounds were not bioactive.

Non-coding ribonucleic acid (RNA) impacts many biological processes; however, the complexities of its many roles are not completely understood. Therefore, designing tools for molecular recognition is of paramount importance. Peptide nucleic acids (PNA) show promise as a tool for selective recognition of double helical regions of RNA. We herein report the synthesis and binding studies of new isoorotamide-based PNA monomers that target uridine-adenosine base pairs via a distal base recognition strategy. Monomers were designed with an arylisoorotamide core attached to a linker aimed at bypassing the uridine in a U-A pair and ultimately forming Hoogsteen hydrogen bonds with adenosine. Three new monomers were prepared and incorporated into PNAs that were screened against matched RNA hairpins using UV thermal melting and isothermal titration calorimetry experiments. Two of the three PNA oligonucleotides that contained distal binding monomers (Db) demonstrated slightly higher affinity for A-U base pairs while one demonstrated slightly higher affinity for the G-C base pair. These results provide insight into the nature of PNA monomer design particularly around linker design and rigidity.

This study investigated a rotaxane featuring azobenzene photoswitches in its macrocycle and its ability to modulate membrane permeability in large unilamellar vesicles (LUVs) of varying lipid compositions. Upon photoisomerization, the rotaxane significantly enhanced the release of the hydrophilic dye sulforhodamine B in vesicles composed of EYPC/Chol 8:2, with release increasing from 29% (non-irradiated) to 59% (irradiated). Moreover, gel-phase DPPC bilayers also exhibited an increase in release from 7% to 14%. On the contrary, highly fluid pure EYPC bilayers showed high baseline release upon rotaxane incorporation (64%), with photoswitching producing only a slight increase (70%), as most dye was released within the first minutes of rotaxane insertion. Likewise, azobenzene photoswitching did not induce permeabilization in the more rigid and thicker EYPC/Chol 6:4 bilayers, which showed minimal release (5%). Furthermore, we discovered that when the unthreaded axle is irradiated with light, an unknown, irreversible photochemical process occurs, which triggers the release from only the vesicles containing EYPC. These findings underscore the significance of both the physical and chemical properties of the bilayer in enabling effective light-triggered cargo release through rotaxane activation.

A versatile synthetic route to thieno[3,2-b]thiophenes was elaborated from dimethyl 3-nitrothiophene-2,5-dicarboxylate. Nucleophilic substitution of the nitro group with sulfur nucleophiles, including thioacetate or disulfide anions as well as thioacetamide, yielded bis(thiophen-3-yl)disulfide and sulfide derivatives. The disulfide served as a suitable precursor for the preparation of 3-alkylthio-substituted thiophene-2,5-dicarboxylates by its one-pot reduction-alkylation using NaBH₄ in DMF followed by an alkylating agent. Base-promoted cyclization of electron-deficient 3-alkylthio derivatives furnished 2-aryl-, 2-aroyl-, and 2-cyano-substituted thieno[3,2-b]thiophenes, bearing a 3-hydroxy group. This protocol broadens access to functionalized thieno[3,2-b]thiophenes with potential applications in pharmaceutical and materials chemistry.

Natural products with topologically complex architectures are important sources in drug discovery. The pursuit of conciseness and efficiency in the total synthesis of natural products promotes continuous innovation and the development of new reactions and strategies. In this work, a PET-initiated cationic radical-derived interrupted [2 + 2]/retro-Mannich reaction of N-substituted cyclobutenone provided a facile approach to the direct construction of the ABCE tetracyclic framework of Aspidosperma alkaloids. DFT calculations showed that the rate-determining step of the key PET reaction involved C19-C12 bond formation and C19-C3 bond cleavage. Investigation of the bond length changes along the IRC path, spin density, and NBO analysis indicated that this process is neither strictly concerted nor stepwise, but falls in between, and involves a formal 1,3-C shift.

Carbazoles are ubiquitous and privileged heterocyclic scaffolds in various functional organic materials and naturally occurring products. Although extensive efforts have focused on developing synthetic strategies toward carbazole derivatives, direct regioselective functionalization of the carbazole core remains challenging due to the inherently higher reactivity at the C3/C6 positions. In this study, we report a palladium-catalyzed, directing group-assisted, regioselective C1-H nitration of carbazoles. The protocol features a removable directing group and is amenable to gram-scale synthesis. This strategy provides a valuable platform for the selective functionalization of carbazoles, offering potential applications in optoelectronics, functional organic materials, and related areas while contributing to the advancement of C-H activation methodologies.

Furanoside derivatives are broadly present in the antigenic structures of pathogenic microorganisms and play a key role in their recognition by the host immune system. Despite the high demand for vaccine and diagnostic development, their chemical synthesis remains challenging. During the development of a new methodology for the synthesis of galactofuranoside building blocks, we encountered an unexpected predominance of the furanoside form in the equilibrium mixture of benzoylated β-galactosides. Since the furanoside form is typically less stable and is usually present only in minor amounts, we turned to computational studies to elucidate the driving force of this pyranoside-into-furanoside isomerisation. The DFT B3LYP-D3 approach was employed for this task with additional validation of its results at DLPNO-CCSD(T) level for the lowest energy conformers. The results demonstrate that the van-der-Waals interactions between phenyl rings of the benzoate substituents are crucial for the stabilization of the furanoside isomer. This outcome could not be rationalized within the framework of conventional carbohydrate chemistry, as the key intramolecular interactions determining the equilibrium lie outside the carbohydrate ring system. Consideration of such effects is essential to rationalize the reactivity of structurally complex and densely protected carbohydrate compounds.

The synthesis of fluorinated haloacetimidates relies on the access to the corresponding fluoroacetonitriles, which are toxic gaseous molecules difficult to store and handle. In this work we develop a safe two-chamber method for the ex-situ generation of these reagents in one chamber and their subsequent reaction with O-nucleophiles in the second chamber. The method is easy to setup, control and gives access to new haloacetimidates under mild conditions, similar to the ones used for the synthesis of the more commonly used trichloroacetimidates.