Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 11 de 11
Filtrar
Más filtros

Banco de datos
Tipo del documento
País de afiliación
Intervalo de año de publicación
1.
Nature ; 603(7901): 439-444, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-35296845

RESUMEN

The introduction of molecular complexity in an atom- and step-efficient manner remains an outstanding goal in modern synthetic chemistry. Artificial biosynthetic pathways are uniquely able to address this challenge by using enzymes to carry out multiple synthetic steps simultaneously or in a one-pot sequence1-3. Conducting biosynthesis ex vivo further broadens its applicability by avoiding cross-talk with cellular metabolism and enabling the redesign of key biosynthetic pathways through the use of non-natural cofactors and synthetic reagents4,5. Here we describe the discovery and construction of an enzymatic cascade to MK-1454, a highly potent stimulator of interferon genes (STING) activator under study as an immuno-oncology therapeutic6,7 (ClinicalTrials.gov study NCT04220866 ). From two non-natural nucleotide monothiophosphates, MK-1454 is assembled diastereoselectively in a one-pot cascade, in which two thiotriphosphate nucleotides are simultaneously generated biocatalytically, followed by coupling and cyclization catalysed by an engineered animal cyclic guanosine-adenosine synthase (cGAS). For the thiotriphosphate synthesis, three kinase enzymes were engineered to develop a non-natural cofactor recycling system in which one thiotriphosphate serves as a cofactor in its own synthesis. This study demonstrates the substantial capacity that currently exists to use biosynthetic approaches to discover and manufacture complex, non-natural molecules.


Asunto(s)
Guanosina , Nucleotidiltransferasas , Adenosina , Animales , Interferones , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Nucleotidiltransferasas/metabolismo , Transducción de Señal
2.
J Am Chem Soc ; 146(23): 16306-16313, 2024 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-38804633

RESUMEN

Transaminases are choice biocatalysts for the synthesis of chiral primary amines, including amino acids bearing contiguous stereocenters. In this study, we employ lysine as a "smart" amine donor in transaminase-catalyzed dynamic kinetic resolution reactions to access ß-branched noncanonical arylalanines. Our mechanistic investigation demonstrates that, upon transamination, the lysine-derived ketone byproduct readily cyclizes to a six-membered imine, driving the equilibrium in the desired direction and thus alleviating the need to load superstoichiometric quantities of the amine donor or deploy a multienzyme cascade. Lysine also shows good overall compatibility with a panel of wild-type transaminases, a promising hint of its application as a smart donor more broadly. Indeed, by this approach, we furnished a broad scope of ß-branched arylalanines, including some bearing hitherto intractable cyclopropyl and isopropyl substituents, with high yields and excellent selectivities.


Asunto(s)
Aminas , Aminoácidos , Lisina , Transaminasas , Transaminasas/metabolismo , Transaminasas/química , Aminas/química , Lisina/química , Aminoácidos/química , Aminoácidos/síntesis química , Biocatálisis , Estructura Molecular
3.
Mol Pharm ; 21(3): 1182-1191, 2024 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-38323546

RESUMEN

The chemical structure of excipients molecularly mixed in an amorphous solid dispersion (ASD) has a significant impact on properties of the ASD including dissolution behavior, physical stability, and bioavailability. Polymers used in ASDs require a balance between hydrophobic and hydrophilic functionalities to ensure rapid dissolution of the amorphous dispersion as well as sustained supersaturation of the drug in solution. This work demonstrates the use of postpolymerization functionalization of poly(vinylpyridine) excipients to elucidate the impact of polymer properties on the dissolution behavior of amorphous dispersions containing posaconazole. It was found that N-oxidation of pyridine functionalities increased the solubility of poly(vinylpyridine) derivatives in neutral aqueous conditions and allowed for nanoparticle formation which supplied posaconazole into solution at concentrations exceeding those achieved by more conventional excipients such as hydroxypropyl methylcellulose acetate succinate (HPMCAS) or Eudragit E PO. By leveraging these functional modifications of the parent poly(vinylpyridine) excipient to increase polymer hydrophilicity and minimize the effect of polymer on pH, a new polymeric excipient was optimized for rapid dissolution and supersaturation maintenance for a model compound.


Asunto(s)
Excipientes , Óxidos , Triazoles , Excipientes/química , Solubilidad , Polímeros/química , Metilcelulosa
4.
Angew Chem Int Ed Engl ; 63(13): e202316133, 2024 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-38279624

RESUMEN

Biocatalytic oxidations are an emerging technology for selective C-H bond activation. While promising for a range of selective oxidations, practical use of enzymes catalyzing aerobic hydroxylation is presently limited by their substrate scope and stability under industrially relevant conditions. Here, we report the engineering and practical application of a non-heme iron and α-ketoglutarate-dependent dioxygenase for the direct stereo- and regio-selective hydroxylation of a non-native fluoroindanone en route to the oncology treatment belzutifan, replacing a five-step chemical synthesis with a direct enantioselective hydroxylation. Mechanistic studies indicated that formation of the desired product was limited by enzyme stability and product overoxidation, with these properties subsequently improved by directed evolution, yielding a biocatalyst capable of >15,000 total turnovers. Highlighting the industrial utility of this biocatalyst, the high-yielding, green, and efficient oxidation was demonstrated at kilogram scale for the synthesis of belzutifan.


Asunto(s)
Indenos , Oxigenasas de Función Mixta , Oxidación-Reducción , Hidroxilación , Biocatálisis
5.
J Am Chem Soc ; 144(13): 5855-5863, 2022 04 06.
Artículo en Inglés | MEDLINE | ID: mdl-35333525

RESUMEN

As practitioners of organic chemistry strive to deliver efficient syntheses of the most complex natural products and drug candidates, further innovations in synthetic strategies are required to facilitate their efficient construction. These aspirational breakthroughs often go hand-in-hand with considerable reductions in cost and environmental impact. Enzyme-catalyzed reactions have become an impressive and necessary tool that offers benefits such as increased selectivity and waste limitation. These benefits are amplified when enzymatic processes are conducted in a cascade in combination with novel bond-forming strategies. In this article, we report a highly diastereoselective synthesis of MK-1454, a potent agonist of the stimulator of interferon gene (STING) signaling pathway. The synthesis begins with the asymmetric construction of two fluoride-bearing deoxynucleotides. The routes were designed for maximum convergency and selectivity, relying on the same benign electrophilic fluorinating reagent. From these complex subunits, four enzymes are used to construct the two bridging thiophosphates in a highly selective, high yielding cascade process. Critical to the success of this reaction was a thorough understanding of the role transition metals play in bond formation.


Asunto(s)
Productos Biológicos , Productos Biológicos/química , Catálisis
6.
J Am Chem Soc ; 138(2): 587-93, 2016 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-26744765

RESUMEN

A recent trend in homogeneous gold catalysis has been the development of oxidative transformations relying on Au(I)/Au(III) redox cycling. Typically, phosphine-supported Au(I) precatalysts are used in the presence of strong oxidants to presumably generate phosphine Au(III) intermediates. Herein, we disclose that such Au(III) complexes can undergo facile C(aryl)-P reductive elimination to afford phosphonium salts, which have been spectroscopically and crystallographically characterized. Mechanistic studies indicate that this process occurs from cationic species at temperatures as low as -20 °C but can be accelerated in the presence of nucleophiles, such as acetonitrile and phosphines, via a five-coordinate intermediate. Importantly, this study highlights that irreversible C(aryl)-P reductive elimination is a feasible decomposition or activation pathway for phosphine-supported Au(III) catalysts and should not be ignored in future reaction development.


Asunto(s)
Carbono/química , Oro/química , Fósforo/química , Oxidación-Reducción
7.
Inorg Chem ; 55(11): 5534-9, 2016 Jun 06.
Artículo en Inglés | MEDLINE | ID: mdl-27219499

RESUMEN

We have synthesized a rare example of a uranium(IV) stannyl (κ(4)-N(CH2CH2NSi((i)Pr)3)3U(SnMe3), 1) via transmetalation with LiSnMe3. This complex has been characterized crystallographically and shown to have a U-Sn bond length of 3.3130(3) Å, substantially longer than the only other crystallographically observed U-Sn bond (3.166 Å). Computational studies suggest that the U-Sn bond in 1 is highly polarized, with significant charge transfer to the stannylate ligand. We briefly discuss plausible mechanistic scenarios for the formation of 1, which may be relevant to other transmetalation processes involving heavy main group atoms. Furthermore, we demonstrate the reducing ability of [SnMe3](-) in the absence of strongly donating ligands on U(IV).

8.
J Am Chem Soc ; 137(24): 7921-8, 2015 Jun 24.
Artículo en Inglés | MEDLINE | ID: mdl-26065722

RESUMEN

Two unique organometallic halide series (Ph3P)Au(4-Me-C6H4)(CF3)(X) and (Cy3P)Au(4-F-C6H4)(CF3)(X) (X = I, Br, Cl, F) have been synthesized. The PPh3-supported complexes can undergo both C(aryl)-X and C(aryl)-CF3 reductive elimination. Mechanistic studies of thermolysis at 122 °C reveal a dramatic reactivity and kinetic selectivity dependence on halide ligand. For X = I or F, zero-order kinetic behavior is observed, while for X = Cl or Br, kinetic studies implicate product catalysis. The selectivity for C(aryl)-CF3 bond formation increases in the order X = I < Br < Cl < F, with exclusively C(aryl)-I bond formation when X = I, and exclusively C(aryl)-CF3 bond formation when X = F. Thermodynamic measurements show that Au(III)-X bond dissociation energies increase in the order X = I < Br < Cl, and that ground state Au(III)-X bond strength ultimately dictates selectivities for C(aryl)-X and C(aryl)-CF3 reductive elimination.


Asunto(s)
Halógenos/química , Compuestos Orgánicos de Oro/química , Bromuros/química , Cloruros/química , Fluoruros/química , Calor , Yoduros/química , Ligandos , Modelos Moleculares , Oxidación-Reducción , Termodinámica
9.
J Am Chem Soc ; 136(21): 7777-82, 2014 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-24836526

RESUMEN

Herein we report the mechanism of oxidative addition of CF3I to Au(I), and remarkably fast Caryl-CF3 bond reductive elimination from Au(III) cations. CF3I undergoes a fast, formal oxidative addition to R3PAuR' (R = Cy, R' = 3,5-F2-C6H4, 4-F-C6H4, C6H5, 4-Me-C6H4, 4-MeO-C6H4, Me; R = Ph, R' = 4-F-C6H4, 4-Me-C6H4). When R' = aryl, complexes of the type R3PAu(aryl)(CF3)I can be isolated and characterized. Mechanistic studies suggest that near-ultraviolet light (λmax = 313 nm) photoinitiates a radical chain reaction by exciting CF3I. Complexes supported by PPh3 undergo reversible phosphine dissociation at 110 °C to generate a three-coordinate intermediate that undergoes slow reductive elimination. These processes are quantitative and heavily favor Caryl-I reductive elimination over Caryl-CF3 reductive elimination. Silver-mediated halide abstraction from all complexes of the type R3PAu(aryl)(CF3)I results in quantitative formation of Ar-CF3 in less than 1 min at temperatures as low as -10 °C.


Asunto(s)
Compuestos de Oro/química , Luz , Enlace de Hidrógeno , Modelos Moleculares , Estructura Molecular , Oxidación-Reducción , Temperatura
10.
Angew Chem Int Ed Engl ; 51(39): 9822-4, 2012 Sep 24.
Artículo en Inglés | MEDLINE | ID: mdl-22945030

RESUMEN

A bench-stable, hydroxy-bridged α-diimine-Pd dimer can self-activate to an olefin oligomerization and isomerization catalyst in the presence of substrate. A cationic Pd-hydride is generated principally through a Wacker oxidation of olefin to ketone, and with C(4+) olefins, lesser amounts of allylic C-H activation, ß-H transfer, and release of diene products are observed.

11.
Nat Chem ; 6(2): 159-64, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24451593

RESUMEN

Reductive elimination of carbon-carbon bonds occurs in numerous metal-catalysed reactions. This process is well documented for a variety of transition metal complexes. However, carbon-carbon bond reductive elimination from a limited number of Au(III) complexes has been shown to be a slow and prohibitive process that generally requires elevated temperatures. Herein we show that oxidation of a series of mono- and bimetallic Au(I) aryl complexes at low temperature generates observable Au(III) and Au(II) intermediates. We also show that aryl-aryl bond reductive elimination from these oxidized species is not only among the fastest observed for any transition metal, but is also mechanistically distinct from previously studied alkyl-alkyl and aryl-alkyl reductive eliminations from Au(III).


Asunto(s)
Carbono/química , Oro/química , Catálisis , Complejos de Coordinación/química , Cinética , Oxidación-Reducción , Fosfinas/química , Elementos de Transición/química
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA