RESUMO
Enzyme-mediated damage repair or mitigation, while common for nucleic acids, is rare for proteins. Examples of protein damage are elimination of phosphorylated Ser/Thr to dehydroalanine/dehydrobutyrine (Dha/Dhb) in pathogenesis and aging. Bacterial LanC enzymes use Dha/Dhb to form carbon-sulfur linkages in antimicrobial peptides, but the functions of eukaryotic LanC-like (LanCL) counterparts are unknown. We show that LanCLs catalyze the addition of glutathione to Dha/Dhb in proteins, driving irreversible C-glutathionylation. Chemo-enzymatic methods were developed to site-selectively incorporate Dha/Dhb at phospho-regulated sites in kinases. In human MAPK-MEK1, such "elimination damage" generated aberrantly activated kinases, which were deactivated by LanCL-mediated C-glutathionylation. Surveys of endogenous proteins bearing damage from elimination (the eliminylome) also suggest it is a source of electrophilic reactivity. LanCLs thus remove these reactive electrophiles and their potentially dysregulatory effects from the proteome. As knockout of LanCL in mice can result in premature death, repair of this kind of protein damage appears important physiologically.
Assuntos
Alanina/análogos & derivados , Aminobutiratos/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Ligação a Fosfato/metabolismo , Proteoma , Receptores Acoplados a Proteínas G/metabolismo , Alanina/metabolismo , Animais , Peptídeos Catiônicos Antimicrobianos/metabolismo , Feminino , Glutationa/metabolismo , Células HEK293 , Humanos , MAP Quinase Quinase 1/metabolismo , Masculino , Proteínas de Membrana/química , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Proteínas de Ligação a Fosfato/química , Proteínas de Ligação a Fosfato/genética , Fosforilação , Domínios Proteicos , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/genética , Sulfetos/metabolismoRESUMO
The modulation of protein surface physicochemistry through single point mutations can trigger polymerization, which is facilitated by subunit repetition within a homomeric complex. Furthermore, monogenic disorders may result from aberrant supramolecular assemblies caused by missense mutations that modify the protein surface. Noteworthy from a therapeutic perspective, small molecules have been shown to not only mediate and enhance polymerization, analogous to a surface residue perturbation, but also bind and stabilize the repeating unit to inhibit the self-assembly event. We exemplify pharmacological manipulation of polymeric protein assemblies using some recently reported studies. The aim of this Viewpoint is to highlight opportunities to rationally control protein polymerization for therapeutic benefit.
Assuntos
Polímeros , PolimerizaçãoRESUMO
Diazirines are widely used in photoaffinity labeling (PAL) to trap noncovalent interactions with biomolecules. However, design and interpretation of PAL experiments is challenging without a molecular understanding of the reactivity of diazirines with protein biomolecules. Herein, we report a systematic evaluation of the labeling preferences of alkyl and aryl diazirines with individual amino acids, single proteins, and in the whole cell proteome. We find that alkyl diazirines exhibit preferential labeling of acidic amino acids in a pH-dependent manner that is characteristic of a reactive alkyl diazo intermediate, while the aryl-fluorodiazirine labeling pattern reflects reaction primarily through a carbene intermediate. From a survey of 32 alkyl diazirine probes, we use this reactivity profile to rationalize why alkyl diazirine probes preferentially enrich highly acidic proteins or those embedded in membranes and why probes with a net positive charge tend to produce higher labeling yields in cells and in vitro. These results indicate that alkyl diazirines are an especially effective chemistry for surveying the membrane proteome and will facilitate design and interpretation of biomolecular labeling experiments with diazirines.
Assuntos
Compostos de Diazônio/química , Marcadores de Fotoafinidade/química , Proteínas/química , Aminoácidos/análise , Aminoácidos/química , Sítios de Ligação , Diazometano/química , Humanos , Concentração de Íons de Hidrogênio , Conformação Proteica , Proteínas/análise , Proteoma/análise , Proteoma/química , Canal de Ânion 1 Dependente de Voltagem/químicaRESUMO
Myotonic dystrophy Type 1 (DM1) is a rare genetic disease caused by the expansion of CTG trinucleotide repeats ((CTG)exp) in the 3' untranslated region of the DMPK gene. The repeat transcripts sequester the RNA binding protein Muscleblind-like protein 1 (MBNL1) and hamper its normal function in pre-mRNA splicing. Overexpressing exogenous MBNL1 in the DM1 mouse model has been shown to rescue the splicing defects and reverse myotonia. Although a viable therapeutic strategy, pharmacological modulators of MBNL1 expression have not been identified. Here, we engineered a ZsGreen tag into the endogenous MBNL1 locus in HeLa cells and established a flow cytometry-based screening system to identify compounds that increase MBNL1 level. The initial screen of small molecule compound libraries identified more than thirty hits that increased MBNL1 expression greater than double the baseline levels. Further characterization of two hits revealed that the small molecule HDAC inhibitors, ISOX and vorinostat, increased MBNL1 expression in DM1 patient-derived fibroblasts and partially rescued the splicing defect caused by (CUG)exp repeats in these cells. These findings demonstrate the feasibility of this flow-based cytometry screen to identify both small molecule compounds and druggable targets for MBNL1 upregulation.
Assuntos
Distrofia Miotônica/tratamento farmacológico , Distrofia Miotônica/metabolismo , Miotonina Proteína Quinase/genética , Proteínas de Ligação a RNA/biossíntese , Proteínas de Ligação a RNA/genética , Bibliotecas de Moléculas Pequenas/farmacologia , Regiões 3' não Traduzidas , Processamento Alternativo , Éxons , Citometria de Fluxo/métodos , Células HeLa , Humanos , Distrofia Miotônica/genética , Miotonina Proteína Quinase/metabolismo , Precursores de RNA/metabolismo , Splicing de RNA/efeitos dos fármacos , Proteínas de Ligação a RNA/metabolismo , Expansão das Repetições de Trinucleotídeos , Repetições de TrinucleotídeosRESUMO
Chemogenomics expedites the discovery of therapeutically-relevant targets from phenotypic screens. However, the vast majority of proteins in the proteome lack selective pharmacological modulators, necessitating the development of new technologies that significantly expand chemogenomic space. Chemoproteomics has emerged as a robust platform to map small molecule-protein interactions in cells using functionalized chemical probes in conjunction with mass spectrometry analysis. Exploration of the ligandable proteome in this manner has led to the development of new pharmacological modulators of diverse proteins. Opportunities to further enhance the impact of chemoproteomics using medicinal chemical biology are described.
Assuntos
Proteínas/química , Proteínas/genética , Proteômica , Bibliotecas de Moléculas Pequenas/química , Relação Dose-Resposta a Droga , Humanos , Espectrometria de Massas , Estrutura Molecular , Proteínas/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-AtividadeRESUMO
The reaction of small-molecule chemical probes with proteins has been harnessed to develop covalent inhibitor drugs and protein-profiling technologies. This Essay discusses some of the recent enhancements to the chemical biology toolkit that are enabling the study of previously unchartered areas of chemoproteomic space. An analysis of the kinome is used to illustrate the potential for these approaches enable the pursuit of new targets using reactive chemical probes.
Assuntos
Cisteína/antagonistas & inibidores , Lisina/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/metabolismo , Cisteína/metabolismo , Humanos , Lisina/química , Espectrometria de Massas , Conformação Molecular , Inibidores de Proteínas Quinases/química , ProteômicaRESUMO
Protein kinases comprise a large family of structurally related enzymes. A major goal in kinase-inhibitor development is to selectively engage the desired kinase while avoiding myriad off-target kinases. However, quantifying inhibitor interactions with multiple endogenous kinases in live cells remains an unmet challenge. Here, we report the design of sulfonyl fluoride probes that covalently label a broad swath of the intracellular kinome with high efficiency. Protein crystallography and mass spectrometry confirmed a chemoselective reaction between the sulfonyl fluoride and a conserved lysine in the ATP binding site. Optimized probe 2 (XO44) covalently modified up to 133 endogenous kinases, efficiently competing with high intracellular concentrations of ATP. We employed probe 2 and label-free mass spectrometry to quantify intracellular kinase engagement by the approved drug, dasatinib. The data revealed saturable dasatinib binding to a small subset of kinase targets at clinically relevant concentrations, highlighting the utility of lysine-targeted sulfonyl fluoride probes in demanding chemoproteomic applications.
Assuntos
Modelos Biológicos , Sondas Moleculares/química , Proteínas Quinases/química , Ácidos Sulfínicos/química , Trifosfato de Adenosina/química , Sítios de Ligação , Células Cultivadas , Dasatinibe/química , Dasatinibe/farmacologia , Sistemas de Liberação de Medicamentos , Lisina/química , Espectrometria de Massas , Estrutura MolecularRESUMO
The discovery and selection of a highly potent and selective NaV1.7 inhibitor PF-06456384, designed specifically for intravenous infusion, is disclosed. Extensive in vitro pharmacology and ADME profiling followed by in vivo preclinical PK and efficacy model data are discussed. A proposed protein-ligand binding mode for this compound is also provided to rationalise the high levels of potency and selectivity over inhibition of related sodium channels. To further support the proposed binding mode, potent conjugates are described which illustrate the potential for development of chemical probes to enable further target evaluation.
Assuntos
Canal de Sódio Disparado por Voltagem NAV1.7/química , Piperidinas/química , Piridinas/química , Sulfonamidas/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Animais , Sítios de Ligação , Cães , Meia-Vida , Hepatócitos/metabolismo , Humanos , Infusões Intravenosas , Concentração Inibidora 50 , Camundongos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Dor/tratamento farmacológico , Dor/patologia , Piperidinas/farmacocinética , Piperidinas/uso terapêutico , Ligação Proteica , Estrutura Terciária de Proteína , Piridinas/farmacocinética , Piridinas/uso terapêutico , Ratos , Relação Estrutura-Atividade , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapêutico , Tiadiazóis , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacocinética , Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêuticoRESUMO
Sulfonyl fluoride (SF)-based activity probes have become important tools in chemical biology. Herein, exploiting the relative chemical stability of SF to carry out a number of unprecedented SF-sparing functional group manipulations, we report the chemoselective synthesis of a toolbox of highly functionalized aryl SF monomers that we used to quickly prepare SF chemical biology probes. In addition to SF, the monomers bear an embedded click handle (a terminal alkyne that can perform copper(I)-mediated azide-alkyne cycloaddition). The monomers can be used either as fragments to prepare clickable SF analogues of drugs (biologically active compounds) bearing an aryl ring or, alternatively, attached to drugs as minimalist clickable aryl SF substituents.
Assuntos
Sondas Moleculares/síntese química , Ácidos Sulfínicos/síntese química , Química Click , Modelos Moleculares , Sondas Moleculares/química , Estrutura Molecular , Ácidos Sulfínicos/químicaRESUMO
BACKGROUND: Exacerbations of asthma and COPD are triggered by rhinoviruses. Uncontrolled inflammatory pathways, pathogenic bacterial burden and impaired antiviral immunity are thought to be important factors in disease severity and duration. Macrolides including azithromycin are often used to treat the above diseases, but exhibit variable levels of efficacy. Inhaled corticosteroids are also readily used in treatment, but may lack specificity. Ideally, new treatment alternatives should suppress unwanted inflammation, but spare beneficial antiviral immunity. METHODS: In the present study, we screened 225 novel macrolides and tested them for enhanced antiviral activity against rhinovirus, as well as anti-inflammatory activity and activity against Gram-positive and Gram-negative bacteria. Primary bronchial epithelial cells were grown from 10 asthmatic individuals and the effects of macrolides on rhinovirus replication were also examined. Another 30 structurally similar macrolides were also examined. RESULTS: The oleandomycin derivative Mac5, compared with azithromycin, showed superior induction (up to 5-fold, EC50â=â5-11 µM) of rhinovirus-induced type I IFNß, type III IFNλ1 and type III IFNλ2/3 mRNA and the IFN-stimulated genes viperin and MxA, yet had no effect on IL-6 and IL-8 mRNA. Mac5 also suppressed rhinovirus replication at 48 h, proving antiviral activity. Mac5 showed antibacterial activity against Gram-positive Streptococcus pneumoniae; however, it did not have any antibacterial properties compared with azithromycin when used against Gram-negative Escherichia coli (as a model organism) and also the respiratory pathogens Pseudomonas aeruginosa and non-typeable Haemophilus influenzae. Further non-toxic Mac5 derivatives were identified with various anti-inflammatory, antiviral and antibacterial activities. CONCLUSIONS: The data support the idea that macrolides have antiviral properties through a mechanism that is yet to be ascertained. We also provide evidence that macrolides can be developed with anti-inflammatory, antibacterial and antiviral activity and show surprising versatility depending on the clinical need.
Assuntos
Antibacterianos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Antivirais/química , Antivirais/farmacologia , Descoberta de Drogas , Interferons/imunologia , Macrolídeos/farmacologia , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antibacterianos/uso terapêutico , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/isolamento & purificação , Anti-Inflamatórios não Esteroides/uso terapêutico , Antivirais/isolamento & purificação , Antivirais/uso terapêutico , Asma/tratamento farmacológico , Brônquios/citologia , Brônquios/efeitos dos fármacos , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos , Células Epiteliais/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Haemophilus influenzae/efeitos dos fármacos , Humanos , Interferon beta/imunologia , Interferons/biossíntese , Interleucina-6/imunologia , Interleucina-6/metabolismo , Interleucina-8/imunologia , Interleucina-8/metabolismo , Macrolídeos/química , Macrolídeos/uso terapêutico , Proteínas de Resistência a Myxovirus/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-CH , Proteínas/genética , Pseudomonas aeruginosa/efeitos dos fármacos , Rhinovirus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacosRESUMO
Many adverse drug reactions are caused by the cytochrome P450 (CYP)-dependent activation of drugs into reactive metabolites. In order to reduce attrition due to metabolism-induced toxicity and to improve the safety of drug candidates, we developed a simple cell viability assay by combining a bioactivation system (human CYP3A4, CYP2D6 and CYP2C9) with Hep3B cells. We screened a series of drugs to explore structural motifs that may be responsible for CYP450-dependent activation caused by reactive metabolite formation, which highlighted specific liabilities regarding certain phenols and anilines.
Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Preparações Farmacêuticas/metabolismo , Trifosfato de Adenosina/metabolismo , Benzobromarona/análogos & derivados , Benzobromarona/metabolismo , Benzobromarona/toxicidade , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cromanos/metabolismo , Cromanos/toxicidade , Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP3A/metabolismo , Humanos , Tiazolidinedionas/metabolismo , Tiazolidinedionas/toxicidade , TroglitazonaRESUMO
New advances in synthetic methodologies that allow rapid access to a wide variety of functionalized heterocyclic compounds are of critical importance to the medicinal chemist as it provides the ability to expand the available drug-like chemical space and drive more efficient delivery of drug discovery programs. Furthermore, the development of robust synthetic routes that can readily generate bulk quantities of a desired compound help to accelerate the drug development process. While established synthetic methodologies are commonly utilized during the course of a drug discovery program, the development of innovative heterocyclic syntheses that allow for different bond forming strategies are having a significant impact in the pharmaceutical industry. This review will focus on recent applications of new methodologies in C-H activation, photoredox chemistry, borrowing hydrogen catalysis, multicomponent reactions, regio- and stereoselective syntheses, as well as other new, innovative general syntheses for the formation and functionalization of heterocycles that have helped drive project delivery. Additionally, the importance and value of collaborations between industry and academia in shaping the development of innovative synthetic approaches to functionalized heterocycles that are of greatest interest to the pharmaceutical industry will be highlighted.
Assuntos
Técnicas de Química Sintética/métodos , Descoberta de Drogas/métodos , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Humanos , Oxirredução , Processos Fotoquímicos , EstereoisomerismoRESUMO
Proof of drug-target engagement in physiologically-relevant contexts is a key pillar of successful therapeutic target validation. We developed two orthogonal technologies, the cellular thermal shift assay (CETSA) and a covalent chemical probe reporter approach (harnessing sulfonyl fluoride tyrosine labeling and subsequent click chemistry) to measure the occupancy of the mRNA-decapping scavenger enzyme DcpS by a small molecule inhibitor in live cells. Enzyme affinity determined using isothermal dose response fingerprinting (ITDRFCETSA) and the concentration required to occupy 50% of the enzyme (OC50) using the chemical probe reporter assay were very similar. In this case, the chemical probe method worked well due to the long offset kinetics of the reversible inhibitor (determined using a fluorescent dye-tagged probe). This work suggests that CETSA could become the first choice assay to determine in-cell target engagement due to its simplicity.
Assuntos
Endorribonucleases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Corantes Fluorescentes/química , Quinazolinas/farmacologia , Temperatura , Química Click , Relação Dose-Resposta a Droga , Endorribonucleases/metabolismo , Inibidores Enzimáticos/química , Células HEK293 , Humanos , Estrutura Molecular , Quinazolinas/química , Ácidos Sulfínicos/química , Tirosina/químicaRESUMO
A 1,2,4-triazole motif was employed as a bioisostere for the ester commonly used in muscarinic antagonists, and subsequent integrative conjugation to a ß2 agonist quinolinone furnished a new class of bifunctional MABAs for the treatment of COPD. Medicinal chemistry optimization using the principles of 'inhalation by design' furnished a clinical candidate with desirable pharmacological, pharmacokinetic and biopharmaceutical properties.
Assuntos
Agonistas de Receptores Adrenérgicos beta 2/síntese química , Broncodilatadores/síntese química , Antagonistas Muscarínicos/síntese química , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Triazóis/síntese química , Agonistas de Receptores Adrenérgicos beta 2/farmacocinética , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Animais , Disponibilidade Biológica , Broncoconstrição/efeitos dos fármacos , Broncodilatadores/farmacocinética , Broncodilatadores/farmacologia , Células CHO , Cricetulus , Cães , Humanos , Ipratrópio/farmacologia , Antagonistas Muscarínicos/farmacocinética , Antagonistas Muscarínicos/farmacologia , Ratos , Receptor Muscarínico M3/antagonistas & inibidores , Xinafoato de Salmeterol/farmacologia , Brometo de Tiotrópio/farmacologia , Triazóis/farmacocinética , Triazóis/farmacologiaRESUMO
Through a "tag-and-modify" protein chemical modification strategy, we site-selectively phosphorylated the activation loop of protein kinase p38α. Phosphorylation at natural (180) and unnatural (172) sites created two pure phospho-forms. p38α bearing only a single phosphocysteine (pCys) as a mimic of pThr at 180 was sufficient to switch the kinase to an active state, capable of processing natural protein substrate ATF2; 172 site phosphorylation did not. In this way, we chemically recapitulated triggering of a relevant segment of the MAPK-signaling pathway in vitro. This allowed detailed kinetic analysis of global and stoichiometric phosphorylation events catalyzed by p38α and revealed that site 180 is a sufficient activator alone and engenders dominant mono-phosphorylation activity. Moreover, a survey of kinase inhibition using inhibitors with different (Type I/II) modes (including therapeutically relevant) revealed unambiguously that Type II inhibitors inhibit phosphorylated p38α and allowed discovery of a predictive kinetic analysis based on cooperativity to distinguish Type I vs II.
Assuntos
Proteína Quinase 14 Ativada por Mitógeno/síntese química , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Fator 2 Ativador da Transcrição/metabolismo , Sítios de Ligação , Cisteína/química , Ativação Enzimática , Cinética , Sistema de Sinalização das MAP Quinases , Proteína Quinase 14 Ativada por Mitógeno/química , Proteína Quinase 14 Ativada por Mitógeno/genética , Modelos Moleculares , Fosforilação , Conformação Proteica , Especificidade por SubstratoRESUMO
Molecular glues and bifunctional small molecules, such as targeted protein degraders, induce protein proximity to mediate gain-of-function pharmacology. Emerging technologies that synthetically manipulate protein surfaces to create neoproteins, and the development of covalent chemical probes for intra- and inter-protein surface labeling are described. Ligand-directed protein surface modification strategies have the potential to enhance the induced-proximity pharmacology toolkit and expand the druggable proteome, and this Opinion considers the opportunities and challenges that lie ahead.
RESUMO
In small molecule organic chemistry, the heuristic insight into ring-forming processes that was enabled by Baldwin's rules some 50 years ago proved a step-change in the role of mechanistically guided synthesis. It created a lens upon and marker of fundamental stereoelectronic and conformation-guided chemical processes. However, despite the widespread role of stereoelectronics and conformational control in Biology, no equivalent coherent exploitation of trapped, ring-forming processes yet exists in biomolecules. In the development of a minimal ring-closing process in intact proteins that might prove suitable in a coherent rule-set, we have tested endo-trig ring-closing conjugate thioether lanthionine (Lan) -CH2-S-CH2- formation as a limiting cyclization. Spontaneous Lan formation in proteins is rare if not non-existent and when found in natural product cyclic peptides it requires the mediation of corresponding biosynthetic enzymes as well as productive reactive conformations to guide it. Here, we show that within a conformationally flexible and functionally important protein loop - the MAPK kinase phosphorylation-targeted activation loop - Lan ring-closing is possible. Ring-closing proves to be critically dependent on the location of a trig electrophilic site in just one of two regioisomeric potential precursors to allow phosphosite-to-phosphosite 'stapling'. This first example of spontaneous protein thioether ring-closing/'stapling' and its accessibility from just one precursor (despite the potential for both to form an identical 'staple') now reveals the potential for Lan formation not only as an accessible form of minimal stapling in proteins but also as an exquisitely sensitive probe of associated protein geometries. We suggest that the use of this (as well as the development of other such, intramolecular protein traps that are dependent on inherent protein-controlled reactivity rather than forced crosslinking) may allow the broader trapping and mapping of relevant, even minor, protein states. In this way, protein ring formation may enable a form of extended 'bio-Baldwin's rules' that help to delineate relevant protein conformational space.
RESUMO
Sulfonyl fluoride EM12-SF was developed previously to covalently engage a histidine residue in the sensor loop of cereblon (CRBN) in the E3 ubiquitin ligase complex CRL4CRBN. Here, we further develop the structure-activity relationships of additional sulfonyl fluoride containing ligands that possess a range of cereblon binding potencies in cells. Isoindoline EM364-SF, which lacks a key hydrogen bond acceptor present in CRBN molecular glues, was identified as a potent binder of CRBN. This led to the development of the reversible molecular glue CPD-2743, that retained cell-based binding affinity for CRBN and degraded the neosubstrate IKZF1 to the same extent as EM12, but unlike isoindolinones, lacked SALL4 degradation activity (a target linked to teratogenicity). CPD-2743 had high permeability and lacked efflux in Caco-2 cells, in contrast to the isoindolinone iberdomide. Our methodology expands the repertoire of sulfonyl exchange chemical biology via the advancement of medicinal chemistry design strategies.
RESUMO
Bromomaleimides are useful building blocks in synthesis and powerful reagents for the selective chemical modification of proteins. A mild new synthesis of these reagents is described, along with the convenient transferability of the approach to dithiomaleimides and bromopyridazinediones.