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1.
Chirality ; 36(6): e23681, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38839280

RESUMO

An N-centered epimeric mixture of chlorophyll-a derivatives methylated at the inner nitrogen atom was separated by reverse-phase high-performance liquid chromatography. Circular dichroism (CD) spectroscopic analyses of the epimerically pure N22-methyl-chlorins revealed that the minor first-eluted and major second-eluted stereoisomers were (22S)- and (22R)-configurations, respectively. Their visible absorption and CD spectra in solution were dependent on the N22-stereochemistry. The epimer-dependent spectral changes were independent of the substituents at the peripheral 3-position of the core chlorin chromophore.


Assuntos
Clorofila A , Clorofila , Dicroísmo Circular , Estereoisomerismo , Clorofila/química , Metilação , Clorofila A/química , Cromatografia Líquida de Alta Pressão/métodos , Nitrogênio/química
2.
Anal Chim Acta ; 1314: 342791, 2024 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-38876520

RESUMO

BACKGROUND: Innovations in computer hardware and software capabilities have paved the way for advances in molecular modelling techniques and methods, leading to an unprecedented expansion of their potential applications. In contrast to the docking technique, which usually identifies the most stable selector-selectand (SO-SA) complex for each enantiomer, the molecular dynamics (MD) technique enables the consideration of a distribution of the SO-SA complexes based on their energy profile. This approach provides a more truthful representation of the processes occurring within the column. However, benchmark procedures and focused guidelines for computational treatment of enantioselectivity at the molecular level are still missing. RESULTS: Twenty-eight molecular dynamics simulations were performed to study the enantiorecognition mechanisms of seven N-3,5-dinitrobenzoylated α- and ß-amino acids (DNB-AAs), occurring with the two quinine- and quinidine-based (QN-AX and QD-AX) chiral stationary phases (CSPs), under polar-ionic conditions. The MD protocol was optimized in terms of box size, simulation run time, and frame recording frequency. Subsequently, all the trajectories were analyzed by calculating both the type and amount of the interactions engaged by the selectands (SAs) with the two chiral selectors (SOs), as well as the conformational and interaction energy profiles of the formed SA-SO associates. All the MDs were in strict agreement with the experimental enantiomeric elution order and allowed to establish (i) that salt-bridge and H-bond interactions play a pivotal role in the enantiorecognition mechanisms, and (ii) that the π-cation and π-π interactions are the discriminant chemical features between the two SOs in ruling the chiral recognition mechanism. SIGNIFICANCE: The results of this work clearly demonstrate the high contribution given by MD simulations in the comprehension of the enantiorecognition mechanism with Cinchona alkaloid-based CSPs. However, from this research endeavor it clearly emerged that the MD protocol optimization is crucial for the quality of the produced results.


Assuntos
Aminoácidos , Alcaloides de Cinchona , Simulação de Dinâmica Molecular , Alcaloides de Cinchona/química , Estereoisomerismo , Aminoácidos/química , Dinitrobenzenos/química
3.
Chem Pharm Bull (Tokyo) ; 72(6): 547-558, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38866476

RESUMO

Iridoids, which are a class of monoterpenoids, are attractive synthetic targets due to their diversely substituted cis-fused cyclopenta[c]pyran skeletons. Additionally, various biological activities of iridoids raise the value of synthetic studies on this class of compounds. Here, our synthetic efforts toward 11-noriridoids; (±)-umbellatolide B (6), (±)-10-O-benzoylglobularigenin (9) and 1-O-pentenylaucubigenin (34) are described. For the efficient synthesis of target compounds, common synthetic intermediates (tricyclic enones 17 and 26) were prepared by the Pauson-Khand reaction. The cleavage of the acetal bond on the tricyclic enones and 1,2-reduction introduced the two hydroxy groups on the cyclopentane ring of the core scaffold. Furthermore, the C3-C4 olefin part was constructed by the syn-elimination of a thiocarbonate moiety to obtain 34. The developed synthetic routes for 6, 9, and 34 will be useful for the preparation of iridoid analogs that have a polyfunctionalized core skeleton.


Assuntos
Iridoides , Iridoides/síntese química , Iridoides/química , Estrutura Molecular , Estereoisomerismo
4.
J Med Chem ; 67(11): 9227-9259, 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38833507

RESUMO

The marine metabolite diazonamide A exerts low nanomolar cytotoxicity against a range of tumor cell lines; however, its highly complex molecular architecture undermines the therapeutic potential of the natural product. We demonstrate that truncation of heteroaromatic macrocycle in natural diazonamide A, combined with the replacement of the challenging-to-synthesize tetracyclic hemiaminal subunit by oxindole moiety leads to considerably less complex analogues with improved drug-like properties and nanomolar antiproliferative potency. The structurally simplified macrocycles are accessible in 12 steps from readily available indolin-2-one and tert-leucine with excellent diastereoselectivity (99:1 dr) in the key macrocyclization step. The most potent macrocycle acts as a tubulin assembly inhibitor and exerts similar effects on A2058 cell cycle progression and induction of apoptosis as does marketed microtubule-targeting agent vinorelbine.


Assuntos
Antineoplásicos , Apoptose , Microtúbulos , Moduladores de Tubulina , Humanos , Moduladores de Tubulina/farmacologia , Moduladores de Tubulina/química , Moduladores de Tubulina/síntese química , Linhagem Celular Tumoral , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Relação Estrutura-Atividade , Proliferação de Células/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Produtos Biológicos/farmacologia , Produtos Biológicos/química , Produtos Biológicos/síntese química , Ensaios de Seleção de Medicamentos Antitumorais , Estereoisomerismo , Tubulina (Proteína)/metabolismo , Tubulina (Proteína)/química , Indóis/química , Indóis/farmacologia , Indóis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis , Oxazóis
5.
Nat Commun ; 15(1): 4925, 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38858373

RESUMO

Terpene synthesis stands at the forefront of modern synthetic chemistry and represents the state-of-the-art in the chemist's toolbox. Notwithstanding, these endeavors are inherently tied to the current availability of natural cyclic building blocks. Addressing this limitation, the stereocontrolled cyclization of abundant unbiased linear terpenes emerges as a valuable tool, which is still difficult to achieve with chemical catalysts. In this study, we showcase the remarkable capabilities of squalene-hopene cyclases (SHCs) in the chemoenzymatic synthesis of head-to-tail-fused terpenes. By combining engineered SHCs and a practical reaction setup, we generate ten chiral scaffolds with >99% ee and de, at up to decagram scale. Our mechanistic insights suggest how cyclodextrin encapsulation of terpenes may influence the performance of the membrane-bound enzyme. Moreover, we transform the chiral templates to valuable (mero)-terpenes using interdisciplinary synthetic methods, including a catalytic ring-contraction of enol-ethers facilitated by cooperative iodine/lipase catalysis.


Assuntos
Biocatálise , Terpenos , Ciclização , Terpenos/metabolismo , Terpenos/química , Estereoisomerismo , Transferases Intramoleculares/metabolismo , Transferases Intramoleculares/genética , Transferases Intramoleculares/química , Ciclodextrinas/química , Ciclodextrinas/metabolismo
6.
Carbohydr Res ; 541: 109167, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38823063

RESUMO

This paper describes a mild and efficient catalytic deprotection method for isopropylidene ketals and benzylidene acetals using AcOH/H2O/DME(1,2-Dimethoxyethane). The method effectively removes ketal and acetal protecting groups from 2-deoxyglycosides which are prone to hydrolysis under acidic conditions. Moreover, it enables the selective removal of the terminal ketal over an internal one.


Assuntos
Glicosídeos , Glicosídeos/química , Glicosídeos/síntese química , Água/química , Estereoisomerismo , Cetonas/química , Catálise , Acetais/química , Estrutura Molecular
7.
Sci Rep ; 14(1): 12825, 2024 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-38834643

RESUMO

Cyclic tetrapeptides c(Pro-Phe-Pro-Phe) obtained by the mechanosynthetic method using a ball mill were isolated in a pure stereochemical form as a homochiral system (all L-amino acids, sample A) and as a heterochiral system with D configuration at one of the stereogenic centers of Phe (sample B). The structure and stereochemistry of both samples were determined by X-ray diffraction studies of single crystals. In DMSO and acetonitrile, sample A exists as an equimolar mixture of two conformers, while only one is monitored for sample B. The conformational space and energetic preferences for possible conformers were calculated using DFT methods. The distinctly different conformational flexibility of the two samples was experimentally proven by Variable Temperature (VT) and 2D EXSY NMR measurements. Both samples were docked to histone deacetylase HDAC8. Cytotoxic studies proved that none of the tested cyclic peptide is toxic.


Assuntos
Peptídeos Cíclicos , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Humanos , Cristalografia por Raios X , Histona Desacetilases/metabolismo , Histona Desacetilases/química , Simulação de Acoplamento Molecular , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Estereoisomerismo , Solventes/química
8.
Amino Acids ; 56(1): 38, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38844708

RESUMO

Biomarkers that accurately reflect renal function are essential in management of chronic kidney diseases (CKD). However, in children, age/physique and medication often alter established renal biomarkers. We studied whether amino acid enantiomers in body fluids correlate with renal function and whether they are influenced by physique or steroid medication during development. We conducted a prospective study of children 2 to 18 years old with and without CKD. We analyzed associations of serine/asparagine enantiomers in body fluids with major biochemical parameters as well as physique. To study consequences of kidney dysfunction and steroids on serine/asparagine enantiomers, we generated juvenile mice with uninephrectomy, ischemic reperfusion injury, or dexamethasone treatment. We obtained samples from 27 children, of which 12 had CKD due to congenital (n = 7) and perinatal (n = 5) causes. Plasma D-asparagine and the D/L-serine ratio had robust, positive linear associations with serum creatinine and cystatin C, and detected CKD with high sensitivity and specificity, uninfluenced by body size or biochemical parameters. In the animal study, kidney dysfunction increased plasma D-asparagine and the D/L-serine ratio, but dexamethasone treatment did not. Thus, plasma D-asparagine and the D/L-serine ratio can be useful markers for renal function in children.


Assuntos
Asparagina , Biomarcadores , Insuficiência Renal Crônica , Serina , Criança , Animais , Humanos , Asparagina/sangue , Asparagina/metabolismo , Insuficiência Renal Crônica/sangue , Pré-Escolar , Serina/sangue , Camundongos , Masculino , Feminino , Adolescente , Biomarcadores/sangue , Estudos Prospectivos , Dexametasona , Estereoisomerismo , Creatinina/sangue , Rim/metabolismo
9.
J Nanobiotechnology ; 22(1): 337, 2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38886712

RESUMO

BACKGROUND: Molybdenum disulfide (MoS2) has excellent physical and chemical properties. Further, chiral MoS2 (CMS) exhibits excellent chiroptical and enantioselective effects, and the enantioselective properties of CMS have been studied for the treatment of neurodegenerative diseases. Intriguingly, left- and right-handed materials have different effects on promoting the differentiation of neural stem cells into neurons. However, the effect of the enantioselectivity of chiral materials on peripheral nerve regeneration remains unclear. METHODS: In this study, CMS@bacterial cellulose (BC) scaffolds were fabricated using a hydrothermal approach. The CMS@BC films synthesized with L-2-amino-3-phenyl-1-propanol was defined as L-CMS. The CMS@BC films synthesized with D-2-amino-3-phenyl-1-propanol was defined as D-CMS. The biocompatibility of CMS@BC scaffolds and their effect on Schwann cells (SCs) were validated by cellular experiments. In addition, these scaffolds were implanted in rat sciatic nerve defect sites for three months. RESULTS: These chiral scaffolds displayed high hydrophilicity, good mechanical properties, and low cytotoxicity. Further, we found that the L-CMS scaffolds were superior to the D-CMS scaffolds in promoting SCs proliferation. After three months, the scaffolds showed good biocompatibility in vivo, and the nerve conducting velocities of the L-CMS and D-CMS scaffolds were 51.2 m/s and 26.8 m/s, respectively. The L-CMS scaffolds showed a better regenerative effect than the D-CMS scaffolds. Similarly, the sciatic nerve function index and effects on the motor and electrophysiological functions were higher for the L-CMS scaffolds than the D-CMS scaffolds. Finally, the axon diameter and myelin sheath thickness of the regenerated nerves were improved in the L-CMS group. CONCLUSION: We found that the CMS@BC can promote peripheral nerve regeneration, and in general, the L-CMS group exhibited superior repair performance. Overall, the findings of this study reveal that CMS@BC can be used as a chiral nanomaterial nerve scaffold for peripheral nerve repair.


Assuntos
Celulose , Dissulfetos , Molibdênio , Regeneração Nervosa , Células de Schwann , Alicerces Teciduais , Regeneração Nervosa/efeitos dos fármacos , Animais , Ratos , Alicerces Teciduais/química , Dissulfetos/química , Dissulfetos/farmacologia , Células de Schwann/efeitos dos fármacos , Molibdênio/química , Molibdênio/farmacologia , Celulose/química , Celulose/farmacologia , Celulose/análogos & derivados , Ratos Sprague-Dawley , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/fisiologia , Proliferação de Células/efeitos dos fármacos , Engenharia Tecidual/métodos , Masculino , Traumatismos dos Nervos Periféricos , Estereoisomerismo
10.
Int J Mol Sci ; 25(11)2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38891794

RESUMO

The chiral H8-BINOL derivatives R-1 and R-2 were efficiently synthesized via a Suzuki coupling reaction, and they can be used as novel dialdehyde fluorescent probes for the enantioselective recognition of R/S-2-amino-1-phenylethanol. In addition, R-1 is much more effective than R-2. Scanning electron microscope images and X-ray analyses show that R-1 can form supramolecular vesicles through the self-assembly effect of the π-π force and strong hydrogen bonding. As determined via analysis, the fluorescence of the probe was significantly enhanced by mixing a small amount of S-2-amino-1-phenylethanol into R-1, with a redshift of 38 nm, whereas no significant fluorescence response was observed in R-2-amino-1-phenylethanol. The enantioselective identification of S-2-amino-1-phenylethanol by the probe R-1 was further investigated through nuclear magnetic titration and fluorescence kinetic experiments and DFT calculations. The results showed that this mechanism was not only a simple reactive probe but also realized object recognition through an ICT mechanism. As the intramolecular hydrogen bond activated the carbonyl group on the probe R-1, the carbonyl carbon atom became positively charged. As a strong nucleophile, the amino group of S-2-amino-1-phenylethanol first transferred the amino electrons to a carbonyl carbocation, resulting in a significantly enhanced fluorescence of the probe R-1 and a 38 nm redshift. Similarly, S-2-amino-1-phenylethanol alone caused severe damage to the self-assembled vesicle structure of the probe molecule itself due to its spatial structure, which made R-1 highly enantioselective towards it.


Assuntos
Amino Álcoois , Ligação de Hidrogênio , Estereoisomerismo , Amino Álcoois/química , Corantes Fluorescentes/química , Cinética , Estrutura Molecular , Modelos Moleculares , Naftóis
11.
Pharmazie ; 79(6): 98-100, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38877684

RESUMO

Urticaria is induced by the histamine released from mast cells which develops wheals (edema) as a visual feature. In clinical practice, second-generation histamine H1 -receptor blockers are routinely used as the first-line symptomatic treatment for urticaria. Nevertheless, not much research has directly examined the second-generation histamine H1-receptor blockers' ability to reduce edema. In this study, we directly evaluated the anti-edematous activities of three second-generation histamine H1-receptor blockers available in the market (epinastine hydrochloride, cetirizine hydrochloride, and levocetirizine hydrochloride) using a λ-carrageenan-induced footpad edema model. One hour before the induction of edema with 1% λ -carrageenan injection, all second-generation histamine H1 -receptor blockers (5, 10, 50 and 100 mg/kg) were subcutaneously administered to rats. At 0.5 and 3 hours after λ -carrageenan administration, the edema volume was evaluated using a Plethysmometer. Epinastine hydrochloride significantly suppressed the edema growth in a dose-dependent manner. Cetirizine hydrochloride showed a slight anti-edematous effect, while levocetirizine significantly inhibited the development of edema in a dose-dependent manner. On the other hand, dextrocetirizine did not prevent edema from growing. In summary, second-generation histamine H1 -receptor blockers, at least those examined in this study, may be able to reduce the clinical symptoms of urticaria associated with edema. Levocetirizine hydrochloride is also anticipated to have stronger anti-edematous effects than cetirizine hydrochloride because levocetirizine is responsible for cetirizine's anti-edematous activity.


Assuntos
Carragenina , Cetirizina , Edema , Animais , Cetirizina/farmacologia , Edema/tratamento farmacológico , Edema/induzido quimicamente , Ratos , Masculino , Estereoisomerismo , Antagonistas dos Receptores Histamínicos H1/farmacologia , Antagonistas não Sedativos dos Receptores H1 da Histamina/farmacologia , Relação Dose-Resposta a Droga , Ratos Wistar , Imidazóis/farmacologia , Ratos Sprague-Dawley , Dibenzazepinas
12.
J Sep Sci ; 47(12): e2400190, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38894562

RESUMO

An efficient method for the continuous separation of Voriconazole enantiomers was developed using sulfobutyl ether-ß-cyclodextrin (SBE-ß-CD) as a chiral selector in high-speed countercurrent chromatography (HSCCC) with different types. The separation was performed using a two-phase solvent system consisting of n-hexane/ethyl acetate/100 mmol/L phosphate buffer solution (pH = 3.0, containing 50 mmol/L SBE-ß-CD) (1.5:0.5:2, v/v/v). A fast and predictable scale-up process was achieved using an analytical DE HSCCC instrument. The optimized parameters were subsequently applied to a preparative Tauto HSCCC instrument, resulting in consistent separation time and enantiomeric purity, with throughput boosted by a remarkable 11-fold. Preparative HSCCC successfully separated 506 mg of the racemate, delivering enantiomers exceeding 99% purity as confirmed by high-performance liquid chromatography analysis. This investigation presents an effective methodology for forecasting the HSCCC scale-up process and attaining continuous separation of chiral drugs.


Assuntos
Distribuição Contracorrente , Voriconazol , Distribuição Contracorrente/métodos , Estereoisomerismo , Voriconazol/química , Voriconazol/isolamento & purificação , Cromatografia Líquida de Alta Pressão , beta-Ciclodextrinas/química
13.
Chem Pharm Bull (Tokyo) ; 72(6): 559-565, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38880627

RESUMO

Biosynthetic intermediates of siderophore vibrioferrin (VF), O-citryl-L-serine, 2-aminoethyl citrate, and alanine-2-amidoethyl citrate were respectively synthesized as a mixture of stereoisomers. These compounds were used as substrates for enzyme reactions using recombinant PvsA, PvsB, and PvsE proteins as corresponding enzyme equivalents. The results of our study show that each enzyme reacts with a respective substrate and produces VF along the proposed biosynthetic pathway. Furthermore, the results of this study will contribute to the understanding of VF biosynthetic enzymes and may help in the development of antimicrobial drugs by inhibiting siderophore biosynthetic enzymes.


Assuntos
Sideróforos , Estereoisomerismo , Sideróforos/biossíntese , Sideróforos/química , Sideróforos/metabolismo , Especificidade por Substrato , Estrutura Molecular , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/química , Serina/biossíntese , Serina/química , Serina/metabolismo
14.
Int J Mol Sci ; 25(11)2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38892193

RESUMO

The DNA building blocks 2'-deoxynucleotides are enantiomeric, with their natural ß-D-configuration dictated by the sugar moiety. Their synthetic ß-L-enantiomers (ßLdNs) can be used to obtain L-DNA, which, when fully substituted, is resistant to nucleases and is finding use in many biosensing and nanotechnology applications. However, much less is known about the enzymatic recognition and processing of individual ßLdNs embedded in D-DNA. Here, we address the template properties of ßLdNs for several DNA polymerases and the ability of base excision repair enzymes to remove these modifications from DNA. The Klenow fragment was fully blocked by ßLdNs, whereas DNA polymerase κ bypassed them in an error-free manner. Phage RB69 DNA polymerase and DNA polymerase ß treated ßLdNs as non-instructive but the latter enzyme shifted towards error-free incorporation on a gapped DNA substrate. DNA glycosylases and AP endonucleases did not process ßLdNs. DNA glycosylases sensitive to the base opposite their cognate lesions also did not recognize ßLdNs as a correct pairing partner. Nevertheless, when placed in a reporter plasmid, pyrimidine ßLdNs were resistant to repair in human cells, whereas purine ßLdNs appear to be partly repaired. Overall, ßLdNs are unique modifications that are mostly non-instructive but have dual non-instructive/instructive properties in special cases.


Assuntos
Dano ao DNA , Reparo do DNA , Humanos , DNA/química , DNA/metabolismo , Nucleotídeos/química , Nucleotídeos/metabolismo , Conformação de Ácido Nucleico , DNA Polimerase beta/metabolismo , DNA Polimerase beta/química , DNA Polimerase Dirigida por DNA/metabolismo , DNA Polimerase Dirigida por DNA/química , Estereoisomerismo
15.
Chemosphere ; 361: 142530, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38851511

RESUMO

Chiroptical sensing with real-time colorimetrical detection has been emerged as quantifiable properties, enantioselective responsiveness, and optical manipulation in environmental monitoring, food safety and other trace identification fields. However, the sensitivity of chiroptical sensing materials remains an immense challenge. Here, we report a dynamically crosslinking strategy to facilitate highly sensitive chiroptical sensing material. Chiral nematic cellulose nanocrystals (CNC) were co-assembled with amino acid by a two-step esterification, of which a precisely tunable helical pitch, a unique spiral conformation with hierarchical and numerous active sites in sensing performance could be trigged by dynamic covalent bond on amines. Such a CNC/amino acid chiral optics features an ultra-trace amount of 0.08 mg/m3 and a high sensitivity of 60 nm/(mg/m3) for formaldehyde gas at a molecule level detection, which is due to the three synergistic adsorption enhancement of dynamic covalent bonded interaction, hydrogen bonded interaction and van der Waals interaction. Meanwhile, an enhancement hierarchical adsorption of CNC/amino acid chiral materials can be readily representative to the precise helical pitch and colorimetrical switch for sensitive visualization reorganization.


Assuntos
Celulose , Nanopartículas , Compostos Orgânicos Voláteis , Celulose/química , Compostos Orgânicos Voláteis/análise , Compostos Orgânicos Voláteis/química , Nanopartículas/química , Monitoramento Ambiental/métodos , Aminoácidos/análise , Aminoácidos/química , Colorimetria/métodos , Estereoisomerismo , Formaldeído/química , Formaldeído/análise , Adsorção
16.
Anal Chem ; 96(24): 9994-10002, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38855895

RESUMO

Therapeutic oligonucleotides (ONs) commonly incorporate phosphorothioate (PS) modifications. These introduce chiral centers and generate ON diastereomers. The increasing number of ONs undergoing clinical trials and reaching the market has led to a growing interest to better characterize the ON diastereomer composition, especially for small interfering ribonucleic acids (siRNAs). In this study, and for the first time, we identify higher-order structures as the major cause of ON diastereomer separation in hydrophilic interaction chromatography (HILIC). We have used conformational predictions and melting profiles of several representative full-length ONs to first analyze ON folding and then run mass spectrometry and HILIC to underpin the link between their folding and diastereomer separation. On top, we show how one can either enhance or suppress diastereomer separation depending on chromatographic settings, such as column temperature, pore size, stationary phase, mobile-phase ionic strength, and organic modifier. This work will significantly facilitate future HILIC-based characterization of PS-containing ONs; e.g., enabling monitoring of batch-to-batch diastereomer distributions in full-length siRNAs, a complex task that is now for the first time shown as possible on this delicate class of therapeutic double-stranded ONs.


Assuntos
Interações Hidrofóbicas e Hidrofílicas , Estereoisomerismo , Oligonucleotídeos/química , Oligonucleotídeos/isolamento & purificação , RNA Interferente Pequeno/química , RNA Interferente Pequeno/isolamento & purificação , Conformação de Ácido Nucleico , Cromatografia Líquida/métodos
17.
Int J Biol Macromol ; 270(Pt 2): 132471, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38763235

RESUMO

Enantioselective antibodies have emerged as great potential biomaterials in the fields of immunoassays and chiral separation. However, cross-reactivity of antibodies to the distomer may severely restrict the application. Comprehending the interaction mechanism between antibodies and enantiomers could be beneficial to produce superior enantioselective antibodies. In this study, a pair of recombinant antibodies (RAbs) against metolachlor enantiomers at chiral carbon (αSS-MET and αSR-MET) were generated and characterized. The αSS-MET-RAb and αSR-MET-RAb showed comparable sensitivity and specificity to the parental monoclonal antibodies by icELISA, with IC50 values of 3.45 and 223.77 ng/mL, respectively. Moreover, the complex structures of RAbs and corresponding eutomer were constructed and analyzed, and site-specific mutagenesis was utilized to verify the reliability of the enantioselective mechanism elucidated. It demonstrated that the strength of the interaction between the chiral center region of eutomer and the antibody was the key factor for the enantioselectivity of antibody. Increasing this interaction could limit the conformational adjustment of the distomer in a specific chiral recognition cavity, thus decreasing the affinity of the antibody to the distomer. This work provided the in-depth analysis of enantioselective mechanism for two RAbs and paved the way to regulate antibody enantioselective performance for immunoassays of chiral compounds.


Assuntos
Acetamidas , Herbicidas , Estereoisomerismo , Herbicidas/química , Acetamidas/química , Anticorpos Monoclonais/química , Animais , Proteínas Recombinantes/química
18.
Org Biomol Chem ; 22(22): 4420-4435, 2024 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-38775347

RESUMO

Over past decades, chiral amides and peptides have emerged as powerful and versatile compounds due to their various biological activities and interesting molecular architectures. Although some chiral condensation reagents have been applied successfully for their synthesis, the introduction of racemization-free methods of amino acid activation have shown lots of advantages in terms of their low cost and low toxicity. In this review, advancements in amide and peptide synthesis using racemization-free coupling reagents over the last 10 years are summarized. Various racemization-free coupling reagents have been applied in the synthesis of enantioselective amides and peptides, including ynamides, allenones, HSi[OCH(CF3)2]3, Ta(OMe)5, Nb(OEt)5, Ta(OEt)5, TCFH-NMI, water-removable ynamides, DBAA, DATB, o-NosylOXY, TCBOXY, Boc-Oxyma, NDTP, 9-silafluorenyl dichlorides, the Mukaiyama reagent, EDC and T3P. The racemization-free reagents described in this review provide an alternative greener option for the asymmetric synthesis of chiral amides and peptides. We hope that this review will inspire further studies and developments in this field.


Assuntos
Amidas , Peptídeos , Amidas/química , Amidas/síntese química , Peptídeos/química , Peptídeos/síntese química , Estereoisomerismo , Técnicas de Química Sintética/métodos , Indicadores e Reagentes/química , Estrutura Molecular
19.
Anal Methods ; 16(23): 3714-3719, 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38808520

RESUMO

The burgeoning interest in rapid, simultaneous multi-target detection has propelled advancements in chiral electrochemiluminescence (ECL) assays. This study presents the design and implementation of a potential-resolved dual-color ECL sensor, engineered for the concurrent detection of aspartic acid (Asp) and phenylalanine (Phe) enantiomers. The sensor array was meticulously constructed by amalgamating anodic chiral ECL probe Ru(phen)2(L-Cys) nanocrystals with cathodic ECL probe ZnO nanoflowers (ZnO NFs). This research explored the potential of executing multianalyte assays via a potential-resolved ECL strategy, contributing to the advancements in the field of chiral ECL assays.


Assuntos
Ácido Aspártico , Técnicas Eletroquímicas , Medições Luminescentes , Fenilalanina , Fenilalanina/química , Fenilalanina/análise , Ácido Aspártico/química , Ácido Aspártico/análise , Estereoisomerismo , Medições Luminescentes/métodos , Técnicas Eletroquímicas/métodos , Óxido de Zinco/química
20.
J Org Chem ; 89(11): 8120-8130, 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38810272

RESUMO

Herein, the execution of synthetic strategies solving scalability issues observed in the original route is reported, increasing the total yield by 50% compared to the previously disclosed synthesis. A notable restructuring of the route's initial steps to reach a common allylic alcohol intermediate employs a highly stereoselective epoxidation method and avoids superfluous protecting group manipulations while limiting dependence on kinetic resolution in establishing stereochemistry for four of the six chiral centers in (+)-desmethylxestospongin B. Different protecting group strategies to avoid problems with their subsequent removal were considered and enacted; to this end, material was retained as byproducts were suppressed. While the lactam semireduction under Birch conditions requires further investigation, the updated synthesis of (+)-desmethylxestospongin B reported here made it more scalable, affording 0.37 g of this natural product for continued biological studies.


Assuntos
Produtos Biológicos , Estereoisomerismo , Estrutura Molecular , Produtos Biológicos/síntese química , Produtos Biológicos/química
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