The synthesis and structural characterization of new brassinosteroid (BR) analogs, in which substituents with different electronegativities and molecular sizes have been attached to a C-22 benzoate function, are described. The biological activities of all new compounds were evaluated by using the rice lamina inclination test (RLIT) and inhibition of root growth of Arabidopsis thaliana. The RLIT data is compared with those previously reported for two series of compounds having the same substitution pattern at C-22 but different structure in ring A. This comparison revealed that a 2α,3α-dihydroxy configuration is more active than a 3-carbonyl or 3β-hydroxy function in this ring. Additionally, the accumulation of the dephosphorylated form of the BES1 protein, which is part of the BRs signaling pathway and control their activity, has been evaluated as well. The results are analyzed in terms of BR analog's structure and compared with binding energies obtained from a docking study. In this way, it is intended to assess the effect of chemical structure on the initial and one intermediate step, and on the final plant response. Our results show that the binding of BR analogs to the active site, which initiate the signaling process, and dephosphorylation of BES1 depend on the structure of BR analogs in a similar way. However, the relationship between the BR analog's structure and the final plant response is different. The dependence on unknown factors which are able to activate or repress genes associated with growth and development is discussed.
Depressin (1) is a soft coral-derived diterpenoid containing the typical bicyclo[12.1.0]pentadecane casbane skeleton and a C5-keto group. Key strategies for the synthesis of depressin, as well as its casbene skeleton reported so far focused on the formation of the challenging 14-membered ring system. Cryptomeridiol (2) and 4-epi-cryptomeridiol (3) are two eudesmane-type sesquiterpene diols produced by a variety of different plants with broad biological activity. Most of the syntheses focused on the transformation of chiral pool substrates into their trans-6/6-fused ring system. We herein report the synthesis of compounds 1-3 by taking advantage of an expanded chiral pool strategy, in which the terpenoid skeletons including casbene (4) and germacrene A (5) were produced by an Escherichia coli-based heterologous host harboring the isopentenol utilization pathway and corresponding terpene cyclases. Two allylic oxidations of both C13 and C5 positions of the casbene skeleton followed by deoxygenation of C13 hydroxy group allowed the synthesis of compound 1 from 4 in nine steps. Selective acid-mediated 5,10-transannular cyclization of 5 followed by hydration reaction furnished both products 2 and 3 in two steps.
In addition to new acetophenones and 2H-chromenes, the dichlormethane extract from leaves of Melicope barbigera A. Gray (Rutaceae) afforded a mixture of the isomeric melifoliones A (1) and B (2) as well as an oxidation product of 2, whose structure was elucidated as the para-quinol 4. For an independent synthesis of 4 and its possible isomer 3, the required compounds 1 and 2 were synthesized as a mixture of the isomers starting from chromene 5, briefly heated in a closed microwave apparatus with catalytic amounts of acetic acid. Forced heating of 5 in acetic acid or use of stronger acids lead to the benzoxocin derivatives 6 and 7. Oxidation of melifoliones 1 and 2 under a great variety of oxidants and conditions failed to give 3 and 4. Iodine-containing oxidants yielded the products 8, 9, and 10. Combined oxidation with hydrogen peroxide and ferricyanide in alkaline solution resulted in an unexpected contraction of the acetyl phenol to a furanone ring, forming the derivatives 11 and 12, whose structures were confirmed by X-ray analysis. A hypothetical mechanism for the oxidative ring contraction is proposed. 11 and 12 are the first representatives of new heterocyclic ring systems that have not previously been described in the literature.
This study aimed to develop a novel degrader capable of selectively degrading fibroblast growth factor receptor 2 (FGFR2) to overcome the issues of drug resistance and adverse reactions associated with traditional inhibitors in the treatment of FGFR2-driven tumors. Erdafitinib was employed as the targeting ligand, and its aliphatic amine site was conjugated with a CRBN E3 ligase ligand to design and synthesize a series of PROTAC molecules with different linkers. Screening was performed in KATO III cells with high FGFR2 expression, leading to the identification of LC-JD-6 as a potent degrader. Experimental results demonstrated that LC-JD-6 effectively induced FGFR2 protein degradation with a half-maximal degrading concentration (DC50) of 121.4 nM, and this effect exhibited time- and concentration-dependence. Assessed at the cellular level, LC-JD-6 has a half-maximal inhibitory concentration in the KATO III (IC50) of 96.0 nM and showed low inhibitory activity in normal cells. Selectivity analysis revealed that LC-JD-6 specifically degraded FGFR2 with minimal impact on other FGFR subtypes. Further studies confirmed that LC-JD-6 also efficiently reduced the expression of FGFR2 on the cell membrane surface. In conclusion, this study successfully developed LC-JD-6, a novel FGFR2-selective degrader, and for the first time confirmed its ability to degrade the membrane-bound form of FGFR2. This work provides an innovative targeted protein degradation strategy for the treatment of FGFR2-driven tumors and holds significant potential for clinical application.
6,6'-Dibromoindigo is the major component of a historic pigment, famous since ancient times, known as Tyrian purple. In this work, we report a new strategy for the synthesis of 6,6'-dibromoindigo in four steps from p-bromotoluene in 14.5% overall yield. A key improvement in the reported synthesis is the oxidation of the benzylic methyl group of 4-bromo-2-nitrotoluene to 4-bromo-2-nitrobenzaldehyde, which is accomplished by benzylic bromination followed by a Kornblum oxidation. This gentle oxidation avoids the need for chromium trioxide-mediated or nitrone-based methods. While other published syntheses of 6,6'-dibromoindigo have resulted in higher overall yields, our approach offers the advantages of inexpensive starting reagents, operationally simple reactions, and minimal purification of intermediates. Moreover, this work reports the successful sulfonation of 6,6'-dibromoindigo, producing water-soluble derivatives of this historically relevant dye.
Rotational correlation time is a key parameter for organic radical contrast agents (ORCA) for magnetic resonance imaging (MRI). Design of polycyclic systems with incorporated nitroxide moieties in which rotation of the radical separately from the framework is impossible is one of the ways to improve properties of ORCA. Feasibility of the synthesis of rigid 3b,4,5,6,6a,7-hexahydropyrrolo[2',3':3,4]pyrrolo[1,2-c][1,2,3]triazole and 3b,4,5,6,6a,7-hexahydropyrrolo[2',3':3,4]pyrrolo[1,2-b]pyrazole ring systems with incorporated nitroxide moiety from 2-alkynyl-substituted pyrrolidine nitroxides was studied. These nitroxides have been prepared via intramolecular Huisgen cycloaddition or intramolecular alkylation in 2-pyrazolyl derivatives prepared by Michael addition-cyclocondensation of the corresponding alkynones with hydrazine. The reduction kinetics by ascorbate showed that the formation of the rigid tricyclic framework does not lead to a significant increase in stability of the radical center to chemical reduction.
Phytic acid is a phosphorus-rich molecule, which is produced by plants using water-soluble phosphates absorbed from soil. It can potentially serve as a phosphorus source in the syntheses of organic phosphates; however, this approach has not been utilized for the preparation of phosphate esters. In this study, we report the first successful synthesis of phosphate esters using phytic acid as a phosphorus source. Crude products of phosphate diesters were obtained through the reactions of commercially available phytic acid and aromatic alcohols with 31P nuclear magnetic resonance yields up to 83%. We also isolated a portion of the reaction substrates with yields up to 60%. Next, we extracted phytic acid from rice bran with a recovery of 4.2% and then conducted an esterification reaction using the extracted phytic acid and phenol. As a result, diphenyl phosphate with a yield of 44% was obtained. This work can facilitate the development of an environmentally friendly method for producing phosphate esters that does not rely on phosphate rock but instead uses biomass as a phosphorus source.
This review focuses on new directions in (3 + 2) cycloaddition of azomethine ylides to alkenes, resulting in the formation of fused or spiro-fused pyrrolidine derivatives with multiple chiral centers under high regio- and stereocontrol. Currently, strategies using azomethine ylides based on imino esters or α-amino acids with a variety of cyclic and acyclic carbonyl compounds dominate. Enantioselective (3 + 2) cycloaddition reactions of azomethine ylides obtained from imino esters, catalyzed by chiral Cu(I,II) and Ag(I) complexes, are widely used. Reactions using α-amino acids proceed, in most cases, without the use of catalysts, with high yields and high stereoselectivity. Electrophilic alkenes of various structures, (hetero)aromatic olefins and benzofulvenes, cyclic and acyclic unsaturated substrates, and fullerenes are useful dipolarophiles. This reaction method allows for the single-step creation of a wide variety of complex polyheterocyclic systems that may be useful for practical applications.
The regioselective methanolysis of new azido-4-nitrobenzoate epoxycyclooctane isomers and the characterization of the resulting products are described herein. Firstly, treatment of key compound 8-azidocyclooct-4-en-1-ol with 4-nitrobenzoyl chloride followed by an epoxidation reaction and then methanolysis of the epoxide ring and acetylation resulted in the formation of two corresponding chloro-acetate isomers. The structure of one of the chloro-acetate isomers was determined via crystallographic analysis and the other by 1D and 2D NMR spectroscopy. DFT computations confirm the regioselectivity of the methanolysis process, highlighting its precision and efficiency.
We present HAlator, a fully automated quantum chemistry (QM) workflow for computing C-H hydricities and explore its potential in predicting the regioselectivity of electron-rich C-H functionalisation reactions. The workflow was benchmarked against 35 experimentally determined C-H hydricities in DMSO, yielding a mean absolute error (MAE) of 4.43 kcal/mol and a root mean squared error (RMSE) of 5.45 kcal/mol. Leveraging this approach, we generated a dataset of 3278 C-H sites across 740 molecules to train a machine learning (ML) model based on CM5 atomic charge descriptors, achieving an MAE of 2.30 kcal/mol and an RMSE of 3.74 kcal/mol relative to QM-computed hydricities. The method was further applied to 250 hydride transfer-like reactions, including C-N, C-C, and C-X bond formations, carbene insertions, and oxidative transformations. Comparative analysis with ALFABET, a bond dissociation energy (BDE)-based ML model, reveals that hydricity predictions, when combined with steric accessibility, correctly identify the reactive site in eight out of ten representative reactions, surpassing BDEs in most cases. These findings highlight hydricity as a complementary and, in some cases, superior descriptor for guiding regioselectivity predictions in electron-rich C-H functionalisation. The model is made available at regioselect.org, together with a host of other reactivity predictors.
Many cancer cells require extracellular glutamine to meet the energetic, biosynthetic, and redox demands of the proliferative state. Glutaminases catalyze the hydrolysis of glutamine to glutamate, which supports the biosynthesis of amino acids, lipids, and glutathione and can also be oxidatively deaminated to α-ketoglutarate and enter the citric acid cycle. The "glutamine addiction" of cancer cells has made glutaminase an attractive anticancer drug target. Compound 968 is a glutaminase inhibitor that is widely used to probe cancer cells' dependence on glutaminase activity. Here, we show by NMR spectroscopy and X-ray crystallography that the reported benzo[c]phenanthridine structure of compound 968 is incorrect; its true structure is the isomeric benzo[c]acridine. The structural reassignment of compound 968 will aid the medicinal chemistry development of this important compound.
The amide bond is one of the most fundamental and widely utilized functional groups in organic chemistry, central to the structures of pharmaceuticals, bioactive molecules, and advanced materials. However, its exceptional resonance stabilization renders the C-N bond highly inert, posing a persistent synthetic challenge for its transformation. While twisted amides with distorted C-N bonds have offered useful reactivity enhancements, the selective activation of conventional, non-activated amides remains far more difficult. This review summarizes recent advances over the past decade in the activation and cleavage of non-activated amide C-N bonds for their conversion into diverse carboxylic acid derivatives. Key strategies covered include transition-metal catalysis, electrophilic activation, strong base-counter-cation systems, and N-based activating groups that enable chemoselective bond cleavage. Together, these developments provide powerful tools for amide functionalization and offer new opportunities for efficient, practical, and selective syntheses.
Efficient approaches have been developed for the synthesis of heteromultifunctional cone calix[4]arenes containing four amino groups at the wide rim and one, two or four propargyl or 2-azidoethyl groups at the narrow rim of the macrocycle, which can be used for expanding functionalization of the calixarene core in the well-known amine acylation (or similar reactions) and CuAAC 'click' reactions. Two different strategies were implemented to obtain propargylated and 2-azidoethylated p-aminocalixarenes. In the case of propargylated calixarenes, sterically crowding silyl protection was introduced into the alkyne groups of p-tert-butylcalix[4]arene (multiple) propargyl ethers, and the resulting compounds were ipso-nitrated followed by reduction of the nitro groups. To prepare 2-azidoethylated macrocycles, the ipso-nitration/reduction sequence was applied to p-tert-butylcalix[4]arenes containing 2-tosyloxyethyl groups at the narrow rims followed by replacement of the tosyloxy groups with azide ones. In all cases, p-aminocalix[4]arenes were obtained as the readily cleavable tert-butoxycarbonyl (Boc) derivatives, which was crucial for certain transformation and purification steps. To confirm the functionalization capabilities of the five obtained multifunctional calixarenes, they were reacted with excess benzyl azide or phenylacetylene, taken as representatives, under copper(I) catalysis, resulting in the narrow-rim triazolated macrocycles. By removing the Boc protecting groups and involving the free amino groups in reactions with p-tolyl isocyanate, a series of narrow-rim triazolated tetraureacalix[4]arenes was obtained. Examination of the 1H NMR spectra of the tetraureas in CDCl3 showed that in most cases triazole heterocycles do not intervene the formation of homo- and heterodimeric capsules by these compounds. Thus, considering the synthetic value of CuAAC and amine transformations, p-aminocalix[4]arenes enriched with alkyne or azide functionalities can be readily used as multifunctional platforms to obtain even higher functionalized macrocycles. As an example, they can be used for the preparation of sophisticated supramolecular assemblies with homo- or heterodimeric calixarene cores and virtually any functional units attached to them via triazole groups.
The contamination of water by uranium poses a serious threat to ecosystems and human health, creating a need for efficient and selective remediation strategies. Supramolecular materials, with their pre-organized structures, offer a promising route for uranium removal. Phenoxycalix[4]pyrroles (PCP) are well-known supramolecular scaffolds capable of selective metal binding, making them attractive candidates for designing uranium extractants. Here, we report the design and synthesis of PCP HA, a phenoxycalix[4]pyrrole scaffold functionalized with four hydroxamic acid (HA) groups, and evaluate its uranium(VI) extraction potential. PCP HA was synthesized from its ester precursor (PCP E) via hydroxyaminolysis using KOH, achieving a 95% yield. Its structure was confirmed by 1H NMR, 13C NMR, and HRMS. The uranium(VI) extraction efficiency of PCP HA was evaluated by solid-liquid extraction experiments, using uranyl acetate as the uranium source, with measurements performed by gamma spectroscopy. PCP HA demonstrated good performance, removing up to 95% of uranyl(VI) from aqueous solutions (1 mM) at acidic pH, likely due to the strong coordination provided by its hydroxamic acid groups. Further studies revealed that the extraction efficiency also depends on the ligand-to-metal molar ratio. These findings establish PCP HA as a promising supramolecular material for the removal of uranyl from aqueous media.
Difluoromethylornithine (DFMO, eflornithine) is a fluorinated analogue of ornithine that serves both as an inhibitor of ornithine decarboxylase and as a therapeutic agent against African trypanosomiasis. Beyond its pharmacological importance, DFMO provides a valuable model for examining how fluorine substitution governs molecular conformation. A comprehensive quantum-chemical study was performed to elucidate the origins of DFMO's conformational stability. High-level DLPNO-CCSD(T)/CBS calculations revealed that type-I conformers - those maximizing gauche interactions between C-F and C-N bonds - dominate the equilibrium population, confirming the presence of the fluorine gauche effect. natural bond orbital (NBO) analysis showed that this preference arises primarily from hyperconjugative stabilization, particularly the σCH → σ*CN interaction, while steric effects modulate the relative stability among low-energy conformers. The gauche effect is intensified in the zwitterionic form due to electrostatic interactions. In contrast, the bioconformation observed in crystallographic data corresponds to a type-II structure, imposed by strong hydrogen bonding of the amino and carboxyl groups with surrounding residues. Thus, DFMO's intrinsic conformational preferences are dictated by stereoelectronic effects, but these can be overridden by specific intermolecular interactions in biological environments. This study clarifies the electronic origin of DFMO's gauche effect and provides insight into how local electronic factors determine the structure of fluorinated amino acid derivatives.
Class I histone deacetylases (HDACs 1-3) serve as catalytic subunits within seven multiprotein co-repressor complexes, each of which has distinct functions in the cell. We report the synthesis of a HDAC inhibitor-nanogold probe, derived from the class I HDAC inhibitor CI-994, for cryo-electron microscopy (cryo-EM) visualization of the HDAC catalytic domain within class I HDAC co-repressor complexes. The nanogold probe retained HDAC inhibitory activity comparable to CI-994 against the HDAC1-LSD1-CoREST complex in vitro. In cryo-EM studies, 2D class averages revealed the bi-lobed architecture of the CoREST complex and partial localization of the gold nanoparticle probe to the CoREST complex. However, the probe was not observed in classes showing the side-view of the CoREST complex, limiting unambiguous identification and positioning of the HDAC catalytic domain within the CoREST complex.
The synthesis of racemic trans-taxifolin (trans-(±)-taxifolin) and its derivatives and subsequent chiral separation is the most prevalent chemical method to obtain enantiomerically pure taxifolin and its derivatives. The development of an economical and practical synthetic route to trans-(±)-taxifolin, a key precursor to the enantiomerically pure trans-taxifolin, is therefore of great importance and significance. In this work, we developed a new synthetic method for trans-(±)-taxifolin and its derivatives with 2,4,6-trihydroxyacetophenone as a starting material undergoing hydroxy protection, α-bromination, construction of α,β-epoxy carbonyl products via the Darzens reaction, acid-mediated deprotection, and cyclization to afford the target compounds. This method is highlighted by satisfactory overall yields (20-41%) and proceeds without the use of explosive peroxides (such as H2O2), which are commonly employed in methods reported earlier. The avoidance of explosive peroxides in the present method enables safe operation, easy scale-up, and also the synthesis of taxifolin derivatives with oxidant-sensitive groups, largely expanding the substituent scope compared with the previous method.
Klebsiella pneumoniae ST512 is an emerging multidrug-resistant pathogen whose capsular polysaccharide represents a prime target for vaccine development. Here, we report the first total synthesis of the branched hexasaccharide repeating unit of the K. pneumoniae ST512 CPS, together with four structurally related oligosaccharide analogues. Key synthetic challenges including the stereoselective construction of the 1,2-cis glycosidic linkage on the galacturonic acid core and the inherently low reactivity of elongated oligosaccharide intermediates were addressed employing orthogonally protected building blocks. The resulting library of conjugation-ready oligosaccharides, equipped with aminopentyl linkers, enables glycan microarray-based identification of minimal immunogenic epitopes. This work establishes a robust chemical foundation for the rational development of semi-synthetic glycoconjugate vaccines targeting K. pneumoniae ST512.
The Australian endemic plant genus Eremophila has long been recognized for its unique chemical diversity, with numerous novel and bioactive compounds reported. In this study, we chemically investigated the seeds of Eremophila maculata for the first time, which led to the isolation and characterization of two known plant metabolites, (+)-salicifoliol and (+)-pinoresinol. Due to the reported biological properties of the lignan natural product (+)-pinoresinol and its high abundance from the seeds of E. maculata, we synthesized five analogues for biological evaluations. Preliminary cytotoxicity evaluations of the semisynthetic pinoresinol-based library against two human glioblastoma cell lines, U251MG and KNS42, showed (+)-4,4'-di(3,3-dimethylbutanoyl)pinoresinol had slight cytotoxicity at 10 µM. A transwell anti-invasive assay on the same compound showed a reduction in the invasion of adult U251MG cells by 50% and pediatric KNS42 cells by 30%, with IC50 values of 0.26 and 0.40 µM, respectively.