RESUMO
5N-Acylation of 1N-methyl-1,5-benzodiazepin-2-ones with (S)-2-phenylpropanoyl and (S)-2-phenylbutanoyl chlorides afforded the (a1S,a2S,S)-atropisomer (I) diastereoselectively over the (a1R,a2R,S)-isomer (II) in the ratio of 1:0.06-0.15. The preferential formation of I may be explained by the thermodynamically preferable π-π stacking interaction between two benzene rings in the benzodiazepine ring and the acyl chloride during the reaction. Analysis using ab initio calculations (RI-MP2/6-31+G(d) level of theory) for the acylation reaction indicated the π-π stacking interaction in the transition state. Furthermore, isomer I was shown to be thermodynamically more stable than II. The higher stability of I may be caused by the folded form of the two benzene rings, which was revealed by NMR, X-ray, and computational analyses.
Assuntos
Benzodiazepinas , Cloretos , Benzeno/química , AcilaçãoRESUMO
The goal of drug design is to discover molecular structures that have suitable pharmacological properties in vast chemical space. In recent years, the use of deep generative models (DGMs) is getting a lot of attention as an effective method of generating new molecules with desired properties. However, most of the properties do not have three-dimensional (3D) information, such as shape and pharmacophore. In drug discovery, pharmacophores are valuable clues in finding active compounds. In this study, we propose a computational strategy based on deep reinforcement learning for generating molecular structures with a desired pharmacophore. In addition, to extract selective molecules against a target protein, chemical genomics-based virtual screening (CGBVS) is used as post-processing method of deep reinforcement learning. As an example study, we have employed this strategy to generate molecular structures of selective TIE2 inhibitors. This strategy can be adopted into general use for generating selective molecules with a desired pharmacophore.
Assuntos
Aprendizado Profundo , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Estrutura Molecular , Ligação ProteicaRESUMO
The 5N-arylsulfonyl-1,5-benzodiazepin-2-ones with antiproliferative activity were prepared and successfully separated into the (a1R,a2R)- and (a1S,a2S)-atropisomers with extraordinary stability (ΔG⧧ = â¼130 kJ/mol) by freezing the conformation around the sp2-sp2 axis in an Ar-N(SO2) moiety with a C6-methyl group. Also, by introducing a C3-methyl group (central chirality) into the 1,5-benzodiazepine nucleus, the stereochemistry at the axis was biased to take solely one diastereomer with a relative stereochemistry of (a1R*,a2R*,3R*). The (a1S) stereochemistry was crucial for exerting the antiproliferative activity.
Assuntos
Antineoplásicos/farmacologia , Benzodiazepinas/farmacologia , Sulfonamidas/farmacologia , Células A549 , Antineoplásicos/síntese química , Antineoplásicos/química , Benzodiazepinas/síntese química , Benzodiazepinas/química , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Humanos , Modelos Moleculares , Conformação Molecular , Estereoisomerismo , Sulfonamidas/síntese química , Sulfonamidas/química , TermodinâmicaRESUMO
The syn (aR*,5R*) and anti (aS*,5R*) diastereomers of N-benzoyl-C5-substituted-1-benzazepines originating in the chiralities at C5 and the Ar-N(CâO) axis were first stereoselectively synthesized by biasing the conformation with a substituent at C6 and C9, respectively. Detailed examination of the stereochemistry (i.e., conformation and configuration) of these N-benzoyl-1-benzazepines by X-ray crystallographic analysis, VT NMR, and DFT calculations revealed new physicochemical aspects of these heterocycles including revision of the stereochemistry previously reported.
RESUMO
Brassinolide (BL) is a plant steroid hormone that is necessary for stem elongation and cell division. To date more than 70 steroidal BL-like compounds, which are collectively named as brassinosteroids, have been identified. However, non-steroidal compounds that mimic BL have not been reported yet, which can be used as plant growth regulators. Twenty-two non-steroidal compounds were screened from the database containing about 5 million compound structures using a pharmacophore-based in silico screening method. The crystal structure (PDB: 4LSX) of the BL receptor was used to generate a pharmacophore model required for in silico screening. Among 22 hit compounds, 15 compounds that are thought to be physicochemically acceptable were submitted to the in vivo rice lamina inclination assay. Although no compound showed BL like activity, three compounds were detected as BL antagonist. The most potent compound was an ester derivative of 1,4-diphenlenedimethanol and isoxazole-4-carboxylic acid, and the other two compounds contain 2-phenylfuran and pyrimidin-2(1H)-one moieties bridged by an ethenyl substructure. The 50% effective doses (ED50) for the antagonistic activity were in a range of 0.6-5nmol per plant. The inhibition of the lamina inclination by the most potent agonist was recovered by the co-application of BL in a dose-dependent manner.
Assuntos
Derivados de Benzeno/química , Brassinosteroides/agonistas , Brassinosteroides/antagonistas & inibidores , Isoxazóis/química , Metanol/química , Oryza/crescimento & desenvolvimento , Reguladores de Crescimento de Plantas/química , Esteroides Heterocíclicos/agonistas , Esteroides Heterocíclicos/antagonistas & inibidores , Derivados de Benzeno/farmacologia , Simulação por Computador , Isoxazóis/farmacologia , Metanol/farmacologia , Modelos Moleculares , Oryza/efeitos dos fármacos , Reguladores de Crescimento de Plantas/farmacologiaRESUMO
The atropisomeric and conformational properties of 1,5-benzodiazepines with an N-sulfonyl (p-tosyl/mesyl) group (IIa/b) were investigated by comparison with those of the N-benzoyl congeners (I). Similar to I, when the Ar-N(SO2) axis was frozen by a C9-substitution in the molecules, IIa/b were separated into the (aR)- and (aS)-atropisomers. The conformation of IIa/b revealed that the substituent (p-tolyl/methyl group) in the sulfonyl moiety occupies the position over the diazepine ring (folded form) in both the solid and solution states [e.g., (+)-(aR)-N-p-tosyl-1,5-benzodiazepin-2-one (IIa-2)], whereas that of I is anti to the diazepine ring [e.g., (-)-(aR)-N-benzoyl-1,5-benzodiazepin-2-one (I-2)], which was further supported by a computational study. The stereochemical stability also differed between the two congeners (e.g., ΔG(): 104 kJ/mol for I-2 and 132 kJ/mol for IIa-2).
Assuntos
Benzodiazepinas/química , Compostos de Tosil/química , Benzodiazepinas/síntese química , Cristalografia por Raios X , Conformação Molecular , Técnicas de Síntese em Fase Sólida , Estereoisomerismo , Relação Estrutura-Atividade , Compostos de Tosil/síntese químicaRESUMO
In recent years, synthetic opioids have emerged as a predominant cause of drug-overdose-related fatalities, causing the "opioid crisis." To design safer therapeutic agents, we accidentally discovered µ-opioid receptor (MOR) antagonists based on fentanyl with a relatively uncomplicated chemical composition that potentiates structural modifications. Here, we showed the development of novel atropisomeric fentanyl analogues that exhibit more potent antagonistic activity against MOR than naloxone, a morphinan MOR antagonist. Derivatives displaying stable axial chirality were synthesized based on the amide structure of fentanyl. The aS- and aR-enantiomers exerted antagonistic and agonistic effects on the MOR, respectively, and each atropisomer interacted with the MOR by assuming a distinct binding mode through molecular docking. These findings suggest that introducing atropisomerism into fentanyl may serve as a key feature in the molecular design of future MOR antagonists to help mitigate the opioid crisis.
Assuntos
Fentanila , Receptores Opioides mu , Receptores Opioides mu/antagonistas & inibidores , Receptores Opioides mu/metabolismo , Fentanila/farmacologia , Fentanila/análogos & derivados , Fentanila/química , Estereoisomerismo , Humanos , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Animais , Antagonistas de Entorpecentes/química , Antagonistas de Entorpecentes/farmacologia , Conformação Molecular , Analgésicos Opioides/farmacologia , Analgésicos Opioides/química , Analgésicos Opioides/síntese química , Células CHO , CricetulusRESUMO
Both natural viral infections and therapeutic interventions using viral vectors pose significant risks of malignant transformation. Monitoring for clonal expansion of infected cells is important for detecting cancer. Here we developed a novel method of tracking clonality via the detection of transgene integration sites. RAISING (Rapid Amplification of Integration Sites without Interference by Genomic DNA contamination) is a sensitive, inexpensive alternative to established methods. Its compatibility with Sanger sequencing combined with our CLOVA (Clonality Value) software is critical for those without access to expensive high throughput sequencing. We analyzed samples from 688 individuals infected with the retrovirus HTLV-1, which causes adult T-cell leukemia/lymphoma (ATL) to model our method. We defined a clonality value identifying ATL patients with 100% sensitivity and 94.8% specificity, and our longitudinal analysis also demonstrates the usefulness of ATL risk assessment. Future studies will confirm the broad applicability of our technology, especially in the emerging gene therapy sector.
Assuntos
Vírus Linfotrópico T Tipo 1 Humano , Leucemia-Linfoma de Células T do Adulto , Adulto , Sequenciamento de Nucleotídeos em Larga Escala , Vírus Linfotrópico T Tipo 1 Humano/genética , Humanos , Leucemia-Linfoma de Células T do Adulto/genética , Leucemia-Linfoma de Células T do Adulto/patologia , Leucemia-Linfoma de Células T do Adulto/terapia , Transgenes , Integração Viral/genéticaRESUMO
Discoidin domain receptor 1 (DDR1) inhibitors with a desired pharmacophore were designed using deep generative models (DGMs). DDR1 is a receptor tyrosine kinase activated by matrix collagens and implicated in diseases such as cancer, fibrosis and hypoxia. Herein we describe the synthesis and inhibitory activity of compounds generated from DGMs. Three compounds were found to have sub-micromolar inhibitory activity. The most potent of which, compound 3 (N-(4-chloro-3-((pyridin-3-yloxy)methyl)phenyl)-3-(trifluoromethyl)benzamide), had an IC50 value of 92.5â nM. Furthermore, these compounds were predicted to interact with DDR1, which have a desired pharmacophore derived from a known DDR1 inhibitor. The results of synthesis and experiments indicated that our de novo design strategy is practical for hit identification and scaffold hopping.
Assuntos
Benzamidas/farmacologia , Receptor com Domínio Discoidina 1/antagonistas & inibidores , Desenho de Fármacos , Inibidores de Proteínas Quinases/farmacologia , Benzamidas/síntese química , Benzamidas/química , Receptor com Domínio Discoidina 1/metabolismo , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-AtividadeRESUMO
The stereochemistry of N-benzoyl-1,5-benzothiazepine and its S-oxide derivatives as vasopressin receptor ligands was examined in detail by freezing the conformation with a methyl group at the C6 or C9 of 1,5-benzothiazepine. It was revealed that the active forms recognized by the receptors are (cis,aS) for 1,5-benzothiazepine (5-7)-II and (cis,1S,aS) (syn) for its S-oxide (8-10)-II. The C9-methyl derivative of 1,5-benzothiazepine S-oxide (10-II) was designed and synthesized, achieving the putative active syn-isomer.
Assuntos
Receptores de Vasopressinas/metabolismo , Tiazepinas/farmacologia , Técnicas de Química Sintética , Cristalografia por Raios X , Humanos , Ligantes , Conformação Molecular , Óxidos/química , Estereoisomerismo , Relação Estrutura-Atividade , Tiazepinas/químicaRESUMO
2',6'-Disubstituted N-benzoylated carbazole derivatives were found to exhibit atropisomerism. The bulky substituents restricted rotation about the N-C7' and C7'-C1' bonds to separate four atropisomers, in which rotation about the C7'-C1' bond was in perfect concert with rotation about the N-C7' bond. Complete geared rotation without slippage at 37 °C for 7 days was observed for the first time. Conformational analysis clarified the preference for the gear system over other internal conversion pathways.