RESUMO
A diversity-oriented synthesis (DOS) strategy was developed for the synthesis of stereochemically diverse fused-ring systems containing a pyran moiety. Each scaffold contains an amine and methyl ester for further diversification via amine capping and amide coupling. Scaffold diversity was evaluated in comparison to previously prepared scaffolds by a shape-based principal moments of inertia (PMI) analysis.
Assuntos
Glicosídeos/síntese química , Glicosídeos/química , Conformação Molecular , Piranos/química , EstereoisomerismoRESUMO
The synthesis and diversification of a densely functionalized azetidine ring system to gain access to a wide variety of fused, bridged, and spirocyclic ring systems is described. The in vitro physicochemical and pharmacokinetic properties of representative library members are measured in order to evaluate the use of these scaffolds for the generation of lead-like molecules to be used in targeting the central nervous system. The solid-phase synthesis of a 1976-membered library of spirocyclic azetidines is also described.
Assuntos
Azetidinas/farmacocinética , Sistema Nervoso Central/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/farmacocinética , Compostos de Espiro/síntese química , Compostos de Espiro/farmacocinética , Animais , Azetidinas/sangue , Azetidinas/síntese química , Células CACO-2 , Permeabilidade da Membrana Celular/efeitos dos fármacos , Sistema Nervoso Central/citologia , Células Endoteliais/efeitos dos fármacos , Humanos , Camundongos , Estrutura Molecular , Solubilidade , Compostos de Espiro/sangue , EstereoisomerismoRESUMO
[This corrects the article DOI: 10.7759/cureus.20123.].
RESUMO
An efficient build/couple/pair approach to diversity-oriented synthesis was employed to access several structurally complex macrolactams. In this paper, we describe the successful evaluation of ring-closing metathesis toward the systematic generation of skeletal diversity. By appropriately varying the nature and chain length of the alkenol fragment, a diverse collection of 13- to 18-membered macrolactams were obtained.
Assuntos
Técnicas de Química Sintética/métodos , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/síntese química , Aldeídos/química , EstereoisomerismoRESUMO
The Stanford Department of Emergency Medicine joined forces with Digital Medic to create educational materials to teach global healthcare providers how to evaluate patients via telemedicine in the setting of COVID-19. Users then asked for additional education on best practices surrounding the use of telemedicine as a communication medium. Here, we describe our experience in the creation of this additional module and provide some basic feedback received from end-users. We scripted, filmed, and edited a video module for this application over the course of 14 weeks. It was subsequently deployed as part of the larger COVID-19 educational program. To date, the course has had over 28,000 participants. Each was asked to take a pre- and post-test to assess the knowledge of telemedicine best practices before and after the video module; 19,412 elected to take the pre-test and 19,364 took the post-test with overall scores of 84% and 95%, respectively. Anecdotal feedback has been positive. Telemedicine systems have proliferated rapidly around the world, but best practices for physician-to-patient interactions have not been similarly disseminated. We conclude that video modules can be used to fill this educational need quickly and economically.
RESUMO
An aldol-based build/couple/pair (B/C/P) strategy was applied to generate a collection of stereochemically and skeletally diverse small molecules. In the build phase, a series of asymmetric syn- and anti-aldol reactions were performed to produce four stereoisomers of a Boc-protected γ-amino acid. In addition, both stereoisomers of O-PMB-protected alaninol were generated to provide a chiral amine coupling partner. In the couple step, eight stereoisomeric amides were synthesized by coupling the chiral acid and amine building blocks. The amides were subsequently reduced to generate the corresponding secondary amines. In the pair phase, three different reactions were employed to enable intramolecular ring-forming processes: nucleophilic aromatic substitution (S(N)Ar), Huisgen [3+2] cycloaddition, and ring-closing metathesis (RCM). Despite some stereochemical dependencies, the ring-forming reactions were optimized to proceed with good to excellent yields, providing a variety of skeletons ranging in size from 8- to 14-membered rings. Scaffolds resulting from the RCM pairing reaction were diversified on the solid phase to yield a 14 400-membered library of macrolactams. Screening of this library led to the discovery of a novel class of histone deacetylase inhibitors, which display mixed enzyme inhibition, and led to increased levels of acetylation in a primary mouse neuron culture. The development of stereo-structure/activity relationships was made possible by screening all 16 stereoisomers of the macrolactams produced through the aldol-based B/C/P strategy.
Assuntos
Aldeídos/química , Descoberta de Drogas/métodos , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/farmacologia , Animais , Produtos Biológicos/síntese química , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Inibidores de Histona Desacetilases/química , Compostos Macrocíclicos/química , Camundongos , Modelos Moleculares , Conformação Molecular , Estereoisomerismo , Especificidade por SubstratoRESUMO
Synthesis and preliminary biological evaluation of a 35-member library of bistramide A stereoisomers are reported. All eight stereoisomers of the C1-C13 tetrahydropyran fragment of the molecule were prepared utilizing crotylsilane reagents 9 and 10 in our [4+2]-annulation methodology. In addition, the four isomers of the C14-C18 gamma-amino acid unit were accessed via a Lewis acid mediated crotylation reaction with use of both enantiomers of organosilane 11. The spiroketal subunit of bistramide A was modified at the C39-alcohol to give another point of stereochemical diversification. The fragments were coupled by using a standard peptide coupling protocol to provide 35 stereoisomers of the natural product. These stereochemical analogues were screened for their effects on cellular actin and cytotoxicity against cancer cell lines (UO-31 renal and SF-295 CNS). The results of these assays identified one analogue, 1.21, with enhanced potency relative to the natural product, bistramide A.
Assuntos
Acetamidas/síntese química , Acetamidas/farmacologia , Actinas/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Piranos/síntese química , Piranos/farmacologia , Acetamidas/química , Actinas/química , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Conformação Molecular , Piranos/química , Compostos de Espiro/síntese química , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
An asymmetric synthesis of the marine metabolite bistramide A is reported. The synthesis relies on the utility of three different organosilane reagents to construct all principle fragments and 8 of the 11 stereogenic centers of the natural product. [structure: see text].
Assuntos
Acetamidas/síntese química , Piranos/síntese química , Acetamidas/química , Conformação Molecular , Piranos/química , Compostos de Espiro/síntese química , Compostos de Espiro/química , EstereoisomerismoRESUMO
[reaction: see text]. New chiral crotylsilanes that bear a (Z)-olefin geometry were synthesized in high enantiopurity. The reagents participate in [4 + 2]-annulations with aldehydes to give stereochemically complementary pyrans (relative to (E)-crotylsilanes) bearing 2,6-cis-5,6-cis and 2,6-trans-5,6-cis relationships of peripheral functionalities. A stereoselective synthesis of the C1-C13 fragment of bistramide A is also described highlighting this annulation strategy.
Assuntos
Acetamidas/síntese química , Técnicas de Química Combinatória , Piranos/síntese química , Silanos/síntese química , Acetamidas/química , Estrutura Molecular , Piranos/química , Silanos/química , Compostos de Espiro/síntese química , Compostos de Espiro/química , EstereoisomerismoRESUMO
[reaction: see text] Development of new organosilane reagents bearing C-centered chirality where the stereocenter is fully substituted, and their use in the stereocontrolled synthesis of cis- and trans-dihydropyrans containing a trisubstituted olefin is described. The reagents participate in Lewis acid promoted [4+2]-annulations providing useful levels of selectivity with both aliphatic and aromatic aldehydes. A stereoselective synthesis of the C1a-C10 fragment of kendomycin (1) is also described.
Assuntos
Piranos/química , Rifabutina/análogos & derivados , Silanos/química , Estrutura Molecular , Rifabutina/síntese química , Silanos/síntese química , EstereoisomerismoRESUMO
A total synthesis of the natural product 6-deoxypladienolide D (1) has been achieved. Two noteworthy attributes of the synthesis are (1) a late-stage allylic oxidation which proceeds with full chemo-, regio-, and diastereoselectivity and (2) the development of a scalable and cost-effective synthetic route to support drug discovery efforts. 6-Deoxypladienolide D (1) demonstrates potent growth inhibition in a mutant SF3B1 cancer cell line, high binding affinity to the SF3b complex, and inhibition of pre-mRNA splicing.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral/química , Linhagem Celular Tumoral/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Compostos de Epóxi/síntese química , Compostos de Epóxi/metabolismo , Macrolídeos/síntese química , Macrolídeos/metabolismo , Fosfoproteínas/antagonistas & inibidores , Fosfoproteínas/química , Splicing de RNA/efeitos dos fármacos , Ribonucleoproteína Nuclear Pequena U2/antagonistas & inibidores , Ribonucleoproteína Nuclear Pequena U2/química , Antineoplásicos/química , Sítios de Ligação , Compostos de Epóxi/química , Humanos , Macrolídeos/química , Fatores de Processamento de RNARESUMO
We have implemented an aldol-based "build/couple/pair" (B/C/P) strategy for the synthesis of stereochemically diverse 8-membered lactam and sultam scaffolds via S(N)Ar cycloetherification. Each scaffold contains two handles, an amine and aryl bromide, for solid-phase diversification via N-capping and Pd-mediated cross coupling. A sparse matrix design strategy that achieves the dual objective of controlling physicochemical properties and selecting diverse library members was implemented. The production of two 8000-membered libraries is discussed including a full analysis of library purity and property distribution. Library diversity was evaluated in comparison to the Molecular Library Small Molecule Repository (MLSMR) through the use of a multifusion similarity (MFS) map and principal component analysis (PCA).
Assuntos
Técnicas de Química Combinatória/métodos , Lactamas/síntese química , Bibliotecas de Moléculas Pequenas/síntese química , Descoberta de Drogas/métodos , Compostos Macrocíclicos/síntese química , Modelos Químicos , EstereoisomerismoRESUMO
Enantioenriched allenylsilanes are used in three-component propargylation reactions with aldehydes and silyl ethers to form syn-homopropargylic ethers that contain an imbedded azide. These materials then undergo thermally induced intramolecular 1,3-dipolar cycloaddition reactions, resulting in unique fused ring systems containing 1,2,3-triazoles. The ability to modify all three components of the reaction allows for expedient access to compounds containing significant structural and stereochemical variation.
Assuntos
Alcinos/síntese química , Azidas/síntese química , Aldeídos/química , Alcinos/química , Azidas/química , Ciclização , Éteres/química , Conformação Molecular , EstereoisomerismoRESUMO
An enantioselective synthesis of (-)-kendomycin is described and is based on the application of the organosilane-based [4 + 2]-annulation strategy for the assembly of the C1a-C10 fragment. An underutilized samarium(II) iodide-assisted cyclization (intramolecular Barbier-type reaction) is employed to afford the protected macrocycle.
Assuntos
Rifabutina/análogos & derivados , Ciclização , Iodetos/química , Rifabutina/síntese química , Samário/química , EstereoisomerismoRESUMO
A multigram scale synthesis of the four stereoisomers of methyl 3-silylglycidates (epoxysilanes) with high enantiopurity is described. Key reactions include a Sharpless asymmetric epoxidation (SAE) of a trans-vinylsilane and an enzymatic resolution of a racemic cis-epoxysilane to establish the desired configurations. Few chromatographic separations (5 columns out of 13 steps) are required for purification, establishing a convenient reaction sequence for both the trans- and cis-isomers.