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1.
Nat Chem ; 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38951616

RESUMO

The selective hetero-dihalogenation of alkenes provides useful building blocks for a broad range of chemical applications. Unlike homo-dihalogenation, selective hetero-dihalogenation reactions, especially fluorohalogenation, are underdeveloped. Current approaches combine an electrophilic halogen source with a nucleophilic halogen source, which necessarily leads to anti-addition, and regioselectivity has only been achieved using highly activated alkenes. Here we describe an alternative, nucleophile-nucleophile approach that adds chloride and fluoride ions over unactivated alkenes in a highly regio-, chemo- and diastereoselective manner. A curious switch in the reaction mechanism was discovered, which triggers a complete reversal of the diastereoselectivity to promote either anti- or syn-addition. The conditions are demonstrated on an array of pharmaceutically relevant compounds, and detailed mechanistic studies reveal the selectivity and the switch between the syn- and anti-diastereomers are based on different active iodanes and which of the two halides adds first.

2.
J Med Chem ; 67(12): 10464-10489, 2024 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-38866424

RESUMO

The bromodomain and extra terminal (BET) family of bromodomain-containing proteins are important epigenetic regulators that elicit their effect through binding histone tail N-acetyl lysine (KAc) post-translational modifications. Recognition of such markers has been implicated in a range of oncology and immune diseases and, as such, small-molecule inhibition of the BET family bromodomain-KAc protein-protein interaction has received significant interest as a therapeutic strategy, with several potential medicines under clinical evaluation. This work describes the structure- and property-based optimization of a ligand and lipophilic efficient pan-BET bromodomain inhibitor series to deliver candidate I-BET787 (70) that demonstrates efficacy in a mouse model of inflammation and suitable properties for both oral and intravenous (IV) administration. This focused two-phase explore-exploit medicinal chemistry effort delivered the candidate molecule in 3 months with less than 100 final compounds synthesized.


Assuntos
Administração Intravenosa , Animais , Administração Oral , Camundongos , Relação Estrutura-Atividade , Humanos , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo , Estrutura Molecular
3.
Org Lett ; 26(14): 2697-2701, 2024 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-37204455

RESUMO

Tertiary C-F bonds are important structural designs; however, they suffer from challenging synthesis. Current methodologies use corrosive amine-HF salts or expensive and hazardous catalysts and reagents. Our group recently introduced collidinium tetrafluoroborate as an efficient fluorinating agent for anodic decarboxyfluorination reactions. Nevertheless, tertiary carboxylic acids are less readily available and more challenging to prepare than their alcohol analogues. Herein we report a practical, mild, and cheap electrochemical method to achieve deoxyfluorination of hindered carbon centers.

4.
Chemistry ; 30(12): e202304070, 2024 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-38117748

RESUMO

Bicyclo[1.1.1]pentane (BCP) derivatives have attracted significant recent interest in drug discovery as alkyne, tert-butyl and arene bioisosteres, where their incorporation is frequently associated with increased compound solubility and metabolic stability. While strategies for functionalisation of the bridgehead (1,3) positions are extensively developed, platforms allowing divergent substitution at the bridge (2,4,5) positions remain limited. Recent reports have introduced 1-electron strategies for arylation and incorporation of a small range of other substituents, but are limited in terms of scope, yields or practical complexity. Herein, we show the synthesis of diverse 1,2,3-trifunctionalised BCPs through lithium-halogen exchange of a readily accessible BCP bromide. When coupled with medicinally relevant product derivatisations, our developed 2-electron "late stage" approach provides rapid and straightforward access to unprecedented BCP structural diversity (>20 hitherto-unknown motifs reported). Additionally, we describe a method for the synthesis of enantioenriched "chiral-at-BCP" bicyclo[1.1.1]pentanes through a novel stereoselective bridgehead desymmetrisation.

5.
J Am Chem Soc ; 145(39): 21623-21629, 2023 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-37738304

RESUMO

sulfinamides, sulfonamides, and sulfonimidamides are in-demand motifs in medicinal chemistry, yet methods for the synthesis of alkyl variants that start from simple, readily available feedstocks are scarce. In addition, bespoke syntheses of each class of molecules are usually needed. In this report, we detail the synthesis of these three distinct sulfur functional groups, using readily available and structurally diverse alkyl carboxylic acids as the starting materials. The method harnesses alkyl radical generation from carboxylic acids using acridine photocatalysts and 400 nm light with subsequent radical addition to sulfinylamine reagents, delivering sulfinamide products. Using the N-alkoxy sulfinylamine reagent t-BuO-NSO as the radical trap provides common N-alkoxy sulfinamide intermediates, which can be converted in a divergent manner to either sulfonamides or sulfonimidamides, by treatment with sodium hydroxide, or an amine, respectively. The reactions are scalable, tolerate a broad range of functional groups, and can be used for the diversification of complex biologically active compounds.

6.
Angew Chem Int Ed Engl ; 62(38): e202309563, 2023 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-37540528

RESUMO

Hydrogenation reactions are staple transformations commonly used across scientific fields to synthesise pharmaceuticals, natural products, and various functional materials. However, the vast majority of these reactions require the use of a toxic and costly catalyst leading to unpractical, hazardous and often functionally limited conditions. Herein, we report a new, general, practical, efficient, mild and high-yielding hydrogen-free electrochemical method for the reduction of alkene, alkyne, nitro and azido groups. Finally, this method has been applied to deuterium labelling.

7.
Org Lett ; 25(9): 1353-1358, 2023 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-36856464

RESUMO

A practical electrochemical method for the rapid, safer, and mild synthesis of tertiary hindered alkyl fluorides from carboxylic acids has been developed without the need for hydrofluoric acid salts or non-glass reactors. In this anodic fluorination, collidinium tetrafluoroborate acts as both the supporting electrolyte and fluoride donor. A wide range of functional groups has been shown to be compatible, and the possibility of scale-up using flow electrochemistry has also been demonstrated.

8.
Org Lett ; 25(12): 2053-2057, 2023 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-36929825

RESUMO

Herein, we report the decarboxylative Minisci heteroarylation of bicyclo[1.1.1]pentane (BCP) and 2-oxabicyclo[2.1.1]hexane (oBCH) derivatives at the bridge positions. In an operationally simple, photocatalyst-free process, free bridge carboxylic acids are directly coupled with nonprefunctionalized heteroarenes to provide rare examples of polysubstituted BCP and oBCH derivatives in synthetically useful yields. Additionally, the impact of the BCP core on the physicochemical properties of a representative example compared to those of its all-aromatic ortho- and meta-substituted analogues is evaluated.

9.
Org Lett ; 25(7): 1147-1150, 2023 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-36787535

RESUMO

Isothiocyanates are ubiquitous building blocks used across the fields. Nevertheless, their classical syntheses very often rely on the use of toxic and expensive reagents. Herein, we report a new practical, mild, high-yielding, and supporting-electrolyte-free electrochemical method for the preparation of aliphatic and aromatic isothiocyanates from amine and carbon disulfide.

10.
Angew Chem Int Ed Engl ; : e202218195, 2023 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-36705627

RESUMO

We report a general procedure for the direct mono- and di-hydrodefluorination of ArCF3 compounds. Exploiting the tunability of electrochemistry and the selectivity enabled by a Ni cathode, the deep reduction garners high selectivity with good to excellent yields up to gram scale. The late-stage peripheral editing of CF3 feedstocks to construct fluoromethyl moieties will aid the rapid diversification of lead-compounds and compound libraries.

11.
Org Lett ; 25(4): 614-618, 2023 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-36688518

RESUMO

A simple method for the C-4 alkylation of isoquinolines is described using benzoic acid as a nucleophilic reagent and vinyl ketones as an electrophile. The reaction shows tolerance for substitution at C-3, and C-5-C-8 positions as well as allowing some variation of the vinyl ketone electrophiles. The products contain a carbonyl that can act as a synthetic handle for further manipulations giving esters, amines, or simple alkyl products.

13.
J Med Chem ; 65(22): 15174-15207, 2022 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-36378954

RESUMO

The bromodomain and extra terminal (BET) family of proteins are an integral part of human epigenome regulation, the dysregulation of which is implicated in multiple oncology and inflammatory diseases. Disrupting the BET family bromodomain acetyl-lysine (KAc) histone protein-protein interaction with small-molecule KAc mimetics has proven to be a disease-relevant mechanism of action, and multiple molecules are currently undergoing oncology clinical trials. This work describes an efficiency analysis of published GSK pan-BET bromodomain inhibitors, which drove a strategic choice to focus on the identification of a ligand-efficient KAc mimetic with the hypothesis that lipophilic efficiency could be drastically improved during optimization. This focus drove the discovery of the highly ligand-efficient and structurally distinct benzoazepinone KAc mimetic. Following crystallography to identify suitable growth vectors, the benzoazepinone core was optimized through an explore-exploit structure-activity relationship (SAR) approach while carefully monitoring lipophilic efficiency to deliver I-BET432 (41) as an oral candidate quality molecule.


Assuntos
Lisina , Fatores de Transcrição , Humanos , Lisina/metabolismo , Ligantes , Domínios Proteicos , Histonas/metabolismo
14.
Sci Rep ; 12(1): 4595, 2022 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-35302062

RESUMO

Most cases of cystic fibrosis (CF) are caused by class 2 mutations in the cystic fibrosis transmembrane regulator (CFTR). These proteins preserve some channel function but are retained in the endoplasmic reticulum (ER). Partial rescue of the most common CFTR class 2 mutant, F508del-CFTR, has been achieved through the development of pharmacological chaperones (Tezacaftor and Elexacaftor) that bind CFTR directly. However, it is not clear whether these drugs will rescue all class 2 CFTR mutants to a medically relevant level. We have previously shown that the nonsteroidal anti-inflammatory drug (NSAID) ibuprofen can correct F508del-CFTR trafficking. Here, we utilized RNAi and pharmacological inhibitors to determine the mechanism of action of the NSAID glafenine. Using cellular thermal stability assays (CETSAs), we show that it is a proteostasis modulator. Using medicinal chemistry, we identified a derivative with a fourfold increase in CFTR corrector potency. Furthermore, we show that these novel arachidonic acid pathway inhibitors can rescue difficult-to-correct class 2 mutants, such as G85E-CFTR > 13%, that of non-CF cells in well-differentiated HBE cells. Thus, the results suggest that targeting the arachidonic acid pathway may be a profitable way of developing correctors of certain previously hard-to-correct class 2 CFTR mutations.


Assuntos
Fibrose Cística , Glafenina , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Ácido Araquidônico , Ciclo-Oxigenase 2/metabolismo , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Glafenina/uso terapêutico , Humanos , Mutação
15.
Chemistry ; 28(13): e202103728, 2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-35076117

RESUMO

An electrochemical method for the green and practical synthesis of a broad range of substituted isoxazoline cores is presented. Both aryl and more challenging alkyl aldoximes are converted to the desired isoxazoline in an electrochemically enabled regio- and diastereoselective reaction with electron-deficient alkenes. Additionally, in-situ reaction monitoring methods compatible with electrochemistry equipment have been developed in order to probe the reaction pathway. Supporting analyses from kinetic (time-course) modelling and density functional theory support a stepwise, radical-mediated mechanism, and discounts hypothesised involvement of closed shell [3+2] cycloaddition pathways.


Assuntos
Alcenos , Isoxazóis , Reação de Cicloadição , Elétrons , Oximas
16.
Chem Sci ; 12(40): 13392-13397, 2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34777757

RESUMO

Through the use of model studies, an approach was conceived towards the synthesis of the taiwanschirin family of natural products. These are structurally complex compounds which represent highly challenging and biologically active targets for total synthesis. This work describes a successful synthesis of the complex taiwanschirin fused [8,6,5] core through a novel alkynylation reaction coupled with an intramolecular Heck reaction used to construct the 8-membered ring.

17.
J Org Chem ; 86(22): 16095-16103, 2021 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-34766770

RESUMO

The 3-substituted chromane core is found in several bioactive natural products. Herein, we describe a route to 3-fluorinated chromanes from allylic phenol ethers. Our external oxidant-free approach takes advantage of an electrochemical generation of a hypervalent iodine species, difluoro-λ3-tolyl iodane, which mediates the alkene fluoroarylation. High yields and selectivity for this transformation are achieved for electron poor substrates. The redox chemistry has been characterized for the electrochemical generation of the iodane in the presence of fluoride, and insights into the mechanism are given. The transformation has been demonstrated on gram scales, which indicates the potential broader utility of the process.


Assuntos
Alcenos , Iodo , Éteres , Oxirredução , Fenóis
18.
Org Lett ; 23(21): 8488-8493, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34648294

RESUMO

Synthetically versatile alkyl sulfinates can be prepared from readily available amines, using Katritzky pyridinium salt intermediates. In a catalyst-free procedure, primary, secondary, and benzylic alkyl radicals are generated by photoinduced or thermally induced single-electron transfer (SET) from an electron donor-acceptor (EDA) complex, and trapped by SO2 to generate sulfonyl radicals. Hydrogen atom transfer (HAT) from Hantzsch ester gives alkyl sulfinate products, which are used to prepare a selection of medicinal chemistry relevant sulfonyl-containing motifs.

19.
Angew Chem Int Ed Engl ; 60(47): 24754-24769, 2021 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-34151501

RESUMO

"Escaping from flatland", by increasing the saturation level and three-dimensionality of drug-like compounds, can enhance their potency, selectivity and pharmacokinetic profile. One approach that has attracted considerable recent attention is the bioisosteric replacement of aromatic rings, internal alkynes and tert-butyl groups with bicyclo[1.1.1]pentane (BCP) units. While functionalisation of the tertiary bridgehead positions of BCP derivatives is well-documented, functionalisation of the three concyclic secondary bridge positions remains an emerging field. The unique properties of the BCP core present considerable synthetic challenges to the development of such transformations. However, the bridge positions provide novel vectors for drug discovery and applications in materials science, providing entry to novel chemical and intellectual property space. This Minireview aims to consolidate the major advances in the field, serving as a useful reference to guide further work that is expected in the coming years.

20.
J Med Chem ; 63(2): 714-746, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31904959

RESUMO

The bromodomain and extraterminal (BET) family of bromodomain-containing proteins are important regulators of the epigenome through their ability to recognize N-acetyl lysine (KAc) post-translational modifications on histone tails. These interactions have been implicated in various disease states and, consequently, disruption of BET-KAc binding has emerged as an attractive therapeutic strategy with a number of small molecule inhibitors now under investigation in the clinic. However, until the utility of these advanced candidates is fully assessed by these trials, there remains scope for the discovery of inhibitors from new chemotypes with alternative physicochemical, pharmacokinetic, and pharmacodynamic profiles. Herein, we describe the discovery of a candidate-quality dimethylpyridone benzimidazole compound which originated from the hybridization of a dimethylphenol benzimidazole series, identified using encoded library technology, with an N-methyl pyridone series identified through fragment screening. Optimization via structure- and property-based design led to I-BET469, which possesses favorable oral pharmacokinetic properties, displays activity in vivo, and is projected to have a low human efficacious dose.


Assuntos
Ensaios de Triagem em Larga Escala/métodos , Proteínas/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacologia , Benzimidazóis/química , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Quimiocina CCL2/biossíntese , Cristalografia por Raios X , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Humanos , Interleucina-6/antagonistas & inibidores , Leucócitos/efeitos dos fármacos , Masculino , Camundongos , Modelos Moleculares , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas
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