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1.
J Am Chem Soc ; 145(6): 3330-3334, 2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-36745524

RESUMO

Due to burgeoning interest in the pharmaceutical industry in exploiting optically active α-aminoboronic derivatives as bioisosteres of α-amino acid derivatives, the discovery of methods for their catalytic asymmetric synthesis is an important challenge. Herein, we establish that a chiral copper catalyst (generated in situ from commercially available components) can achieve the enantioselective synthesis of α-aminoboronic derivatives via the coupling of two readily available partners, a carbamate and a racemic α-chloroboronate ester. Furthermore, we describe mechanistic studies that played a key role in the development of this new method and that provide insight into the optimized process.

2.
ACS Med Chem Lett ; 13(11): 1755-1762, 2022 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-36385927

RESUMO

The synthesis of all N-Me and N-H analogues of ent-verticilide is described, enabling a structure-activity relationship study based on cardiac ryanodine receptor (RyR2) calcium ion channel inhibition. The use of permeabilized cardiomyocytes allowed us to correlate the degree of N-methylation with activity without concern for changes in passive membrane permeability that these modifications can cause. A key hypothesis was that the minimal pharmacophore may be repeated in this cyclic oligomeric octadepsipeptide (a 24-membered macrocycle), opening the possibility that target engagement will not necessarily be lost with a single N-Me → N-H modification. The effect in the corresponding 18-membered ring oligomer (ent-verticilide B1) was also investigated. We report here that a high degree of N-methyl amide content is critical for activity in the ent-verticilide series but not entirely so for the ent-verticilide B1 series.

4.
Circ Res ; 128(3): 321-331, 2021 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-33297863

RESUMO

RATIONALE: The class Ic antiarrhythmic drug flecainide prevents ventricular tachyarrhythmia in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), a disease caused by hyperactive RyR2 (cardiac ryanodine receptor) mediated calcium (Ca) release. Although flecainide inhibits single RyR2 channels in vitro, reports have claimed that RyR2 inhibition by flecainide is not relevant for its mechanism of antiarrhythmic action and concluded that sodium channel block alone is responsible for flecainide's efficacy in CPVT. OBJECTIVE: To determine whether RyR2 block independently contributes to flecainide's efficacy for suppressing spontaneous sarcoplasmic reticulum Ca release and for preventing ventricular tachycardia in vivo. METHODS AND RESULTS: We synthesized N-methylated flecainide analogues (QX-flecainide and N-methyl flecainide) and showed that N-methylation reduces flecainide's inhibitory potency on RyR2 channels incorporated into artificial lipid bilayers. N-methylation did not alter flecainide's inhibitory activity on human cardiac sodium channels expressed in HEK293T cells. Antiarrhythmic efficacy was tested utilizing a Casq2 (cardiac calsequestrin) knockout (Casq2-/-) CPVT mouse model. In membrane-permeabilized Casq2-/- cardiomyocytes-lacking intact sarcolemma and devoid of sodium channel contribution-flecainide, but not its analogues, suppressed RyR2-mediated Ca release at clinically relevant concentrations. In voltage-clamped, intact Casq2-/- cardiomyocytes pretreated with tetrodotoxin to inhibit sodium channels and isolate the effect of flecainide on RyR2, flecainide significantly reduced the frequency of spontaneous sarcoplasmic reticulum Ca release, while QX-flecainide and N-methyl flecainide did not. In vivo, flecainide effectively suppressed catecholamine-induced ventricular tachyarrhythmias in Casq2-/- mice, whereas N-methyl flecainide had no significant effect on arrhythmia burden, despite comparable sodium channel block. CONCLUSIONS: Flecainide remains an effective inhibitor of RyR2-mediated arrhythmogenic Ca release even when cardiac sodium channels are blocked. In mice with CPVT, sodium channel block alone did not prevent ventricular tachycardia. Hence, RyR2 channel inhibition likely constitutes the principal mechanism of antiarrhythmic action of flecainide in CPVT.


Assuntos
Antiarrítmicos/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Flecainida/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Canal de Liberação de Cálcio do Receptor de Rianodina/efeitos dos fármacos , Retículo Sarcoplasmático/efeitos dos fármacos , Taquicardia Ventricular/prevenção & controle , Potenciais de Ação , Animais , Sinalização do Cálcio , Calsequestrina/genética , Calsequestrina/metabolismo , Modelos Animais de Doenças , Feminino , Células HEK293 , Humanos , Masculino , Camundongos Knockout , Miócitos Cardíacos/metabolismo , Fosforilação , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Retículo Sarcoplasmático/metabolismo , Carneiro Doméstico , Taquicardia Ventricular/genética , Taquicardia Ventricular/metabolismo , Taquicardia Ventricular/fisiopatologia , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia
5.
Proc Natl Acad Sci U S A ; 116(11): 4810-4815, 2019 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-30792355

RESUMO

Ca2+ leak via ryanodine receptor type 2 (RyR2) can cause potentially fatal arrhythmias in a variety of heart diseases and has also been implicated in neurodegenerative and seizure disorders, making RyR2 an attractive therapeutic target for drug development. Here we synthesized and investigated the fungal natural product and known insect RyR antagonist (-)-verticilide and several congeners to determine their activity against mammalian RyR2. Although the cyclooligomeric depsipeptide natural product (-)-verticilide had no effect, its nonnatural enantiomer [ent-(+)-verticilide] significantly reduced RyR2-mediated spontaneous Ca2+ leak both in cardiomyocytes from wild-type mouse and from a gene-targeted mouse model of Ca2+ leak-induced arrhythmias (Casq2-/-). ent-(+)-verticilide selectively inhibited RyR2-mediated Ca2+ leak and exhibited higher potency and a distinct mechanism of action compared with the pan-RyR inhibitors dantrolene and tetracaine and the antiarrhythmic drug flecainide. ent-(+)-verticilide prevented arrhythmogenic membrane depolarizations in cardiomyocytes without significant effects on the cardiac action potential and attenuated ventricular arrhythmia in catecholamine-challenged Casq2-/- mice. These findings indicate that ent-(+)-verticilide is a potent and selective inhibitor of RyR2-mediated diastolic Ca2+ leak, making it a molecular tool to investigate the therapeutic potential of targeting RyR2 hyperactivity in heart and brain pathologies. The enantiomer-specific activity and straightforward chemical synthesis of (unnatural) ent-(+)-verticilide provides a compelling argument to prioritize ent-natural product synthesis. Despite their general absence in nature, the enantiomers of natural products may harbor unprecedented activity, thereby leading to new scaffolds for probe and therapeutic development.


Assuntos
Antiarrítmicos/química , Antiarrítmicos/farmacologia , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacologia , Cálcio/metabolismo , Depsipeptídeos/química , Depsipeptídeos/farmacologia , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Animais , Antiarrítmicos/uso terapêutico , Arritmias Cardíacas/tratamento farmacológico , Arritmias Cardíacas/fisiopatologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Depsipeptídeos/uso terapêutico , Dimerização , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Rianodina/metabolismo , Estereoisomerismo
6.
J Am Chem Soc ; 140(13): 4560-4568, 2018 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-29565576

RESUMO

The ion-mediated Mitsunobu macrocyclooligomerization (M-MCO) reaction of hydroxy acid depsipeptides provides small collections of cyclic depsipeptides with good mass recovery. The approach can produce good yields of a single macrocycle or provide rapid access to multiple oligomeric macrocycles in good overall yield. While Lewis acidic alkali metal salts are known to play a role in the outcome of MCO reactions, it is unclear whether their effect is due to an organizational (e.g., templating) mechanism. Isothermal titration calorimetry (ITC) was used to study macrocycle-metal ion binding interactions, and this report correlates these thermodynamic measurements to the (kinetically determined) size distributions of depsipeptides formed during a Mitsunobu-based macrocyclooligomerization (MCO). Key trends have been identified in quantitative metal ion-cyclic depsipeptide binding affinity ( Ka), enthalpy of binding (Δ H), and stoichiometry of complexation across discrete series of macrocycles, and they provide the first analytical platform to rationally select a metal-ion template for a targeted size regime of cyclic oligomeric depsipeptides.


Assuntos
Depsipeptídeos/química , Calorimetria , Ciclização , Cinética , Estrutura Molecular , Termodinâmica
7.
Proc Natl Acad Sci U S A ; 113(52): 14893-14897, 2016 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-27974608

RESUMO

Macrocyclic small molecules are attractive tools in the development of sensors, new materials, and therapeutics. Within early-stage drug discovery, they are increasingly sought for their potential to interact with broad surfaces of peptidic receptors rather than within their narrow folds and pockets. Cyclization of linear small molecule precursors is a straightforward strategy to constrain conformationally mobile motifs, but forging a macrocycle bond typically becomes more difficult at larger ring sizes. We report the development of a general approach to discrete collections of oligomeric macrocyclic depsipeptides using an oligomerization/macrocyclization process governed by a series of Mitsunobu reactions of hydroxy acid monomers. Ring sizes of 18, 24, 30, and 36 are formed in a single reaction from a didepsipeptide, whereas sizes of 24, 36, and 60 result from a tetradepsipeptide. The ring-size selectivity inherent to the approach can be modulated by salt additives that enhance the formation of specific ring sizes. Use of chemical synthesis to prepare the monomers suggests broad access to functionally and stereochemically diverse collections of natural product-like oligodepsipeptide macrocycles. Two cyclodepsipeptide natural products were prepared along with numerous unnatural oligomeric congeners to provide rapid access to discrete collections of complex macrocyclic small molecules from medium (18) to large (60) ring sizes.


Assuntos
Depsipeptídeos/química , Depsipeptídeos/síntese química , Compostos Macrocíclicos/química , Ciclização/fisiologia , Compostos Macrocíclicos/síntese química , Conformação Molecular , Estrutura Molecular , Estereoisomerismo
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