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1.
J Med Chem ; 66(15): 10715-10733, 2023 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-37486969

RESUMO

While STING agonists have proven to be effective preclinically as anti-tumor agents, these promising results have yet to be translated in the clinic. A STING agonist antibody-drug conjugate (ADC) could overcome current limitations by improving tumor accessibility, allowing for systemic administration as well as tumor-localized activation of STING for greater anti-tumor activity and better tolerability. In line with this effort, a STING agonist ADC platform was identified through systematic optimization of the payload, linker, and scaffold based on multiple factors including potency and specificity in both in vitro and in vivo evaluations. The platform employs a potent non-cyclic dinucleotide STING agonist, a cleavable ester-based linker, and a hydrophilic PEG8-bisglucamine scaffold. A tumor-targeted ADC built with the resulting STING agonist platform induced robust and durable anti-tumor activity and demonstrated high stability and favorable pharmacokinetics in nonclinical species.


Assuntos
Antineoplásicos , Imunoconjugados , Neoplasias , Humanos , Imunoconjugados/farmacocinética , Anticorpos Monoclonais , Antineoplásicos/farmacocinética , Neoplasias/tratamento farmacológico
2.
Chem Sci ; 9(30): 6440-6445, 2018 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-30310574

RESUMO

This report describes the development of a novel C-H amination strategy using both a Cu(ii) Lewis acid and an organic hydrogen atom transfer catalyst to activate benzylic C-H bonds adjacent to aromatic N-heterocycles. This simple methodology demonstrates very high selectivity towards azaheterocycles without using exogenous directing groups and affords excellent site selectivity in substrates with more than one reactive position. A wide range of heterocyclic structures not compatible with previously reported catalytic systems have proven to be amenable to this approach. Mechanistic investigations strongly support a radical-mediated H-atom abstraction, which explains the observed contrast to known closed-shell Lewis acid catalyzed processes.

3.
J Am Chem Soc ; 139(5): 1758-1761, 2017 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-28128945

RESUMO

Pyridoxal-5'-phosphate (PLP) is introduced to a biomimetic indicator displacement assay for simultaneous determination of the absolute configuration, enantiomeric composition and concentration of unprotected amino acids, amino alcohols and amines. The chiroptical assay is based on fast imine metathesis with a PLP aryl imine probe to capture the target compound for circular dichroism and fluorescence sensing analysis. The substrate binding yields characteristic Cotton effects that provide information about the target compound ee and the synchronous release of the indicator results in a nonenantioselective off-on fluorescence response that is independent of the enantiomeric sample composition and readily correlated to the total analyte concentration.

4.
Nat Commun ; 7: 12539, 2016 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-27549926

RESUMO

Molecular recognition, activation and dynamic self-assembly with Brønsted and Lewis acids play a central role across the chemical sciences including catalysis, crystal engineering, supramolecular architectures and drug design. Despite this general advance, the utilization of the corresponding binding motifs for fast and robust quantitative chemosensing of chiral compounds in a complicate matrix has remained challenging. Here we show that a stereodynamic probe carrying complementary boronic acid and urea units achieves this goal with hydroxy carboxylic acids. Synergistic dual-site binding and instantaneous chirality imprinting result in characteristic ultraviolet and CD readouts that allow instantaneous determination of the absolute configuration, enantiomeric excess and concentration of the target compound even in complex mixtures. The robustness and practicality of this strategy for high-throughput screening purposes is demonstrated. Comprehensive sensing of only 0.5 mg of a crude reaction mixture of an asymmetric reduction eliminates cumbersome work-up protocols and minimizes analysis time, labour and waste production.

5.
Sci Adv ; 2(2): e1501162, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26933684

RESUMO

High-throughput experimentation (HTE) has emerged as a widely used technology that accelerates discovery and optimization processes with parallel small-scale reaction setups. A high-throughput screening (HTS) method capable of comprehensive analysis of crude asymmetric reaction mixtures (eliminating product derivatization or isolation) would provide transformative impact by matching the pace of HTE. We report how spontaneous in situ construction of stereodynamic metal probes from readily available, inexpensive starting materials can be applied to chiroptical chemosensing of the total amount, enantiomeric excess (ee), and absolute configuration of a wide variety of amines, diamines, amino alcohols, amino acids, carboxylic acids, α-hydroxy acids, and diols. This advance and HTS potential are highlighted with the analysis of 1 mg of crude reaction mixtures of a catalytic asymmetric reaction. This operationally simple assay uses a robust mix-and-measure protocol, is amenable to microscale platforms and automation, and provides critical time efficiency and sustainability advantages over traditional serial methods.

6.
J Org Chem ; 81(3): 1185-91, 2016 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-26756165

RESUMO

Molecular hosts capable of chiroptical sensing of complexed guest molecules offer an attractive alternative to conventional methods for the analysis of the absolute configuration and enantiopurity. Sensors based on the Pfeiffer effect rely on complexation-driven asymmetric transformation of the first kind and can produce a chiroptical signal against an otherwise null background. To be most effective, the wavelength of the induced chiroptical sensor readout should be free and clear of interfering signals coming from the sample under investigation. In this study, we report the introduction of stereodynamic zinc complexes of antenna biphenols, a new class of sensors bearing antenna-like appendages that can extend the wavelength of the chiroptical signal while also improving enantioselective guest recognition.

7.
J Org Chem ; 81(1): 89-99, 2016 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-26656940

RESUMO

The conformational preference of 2,2'-bisanilides was investigated by variable-temperature NMR spectroscopy, NMR titration and diffusion experiments, IR spectroscopy, computational analysis, and X-ray crystallography. The formation of a conformation having the two amide moieties linked by an intramolecular hydrogen bond was detected at low temperatures. The interconversion kinetics of the two conformational species of bisanilide 2 were determined by NMR line shape analysis. The formation of a supramolecule linked by intermolecular hydrogen bonds was ruled out by means of DMSO titration, DOSY experiments, and steric considerations.

8.
Chirality ; 27(10): 700-7, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26299373

RESUMO

Two bidentate ligands consisting of a fluxional polyarylacetylene framework with terminal phenol groups were synthesized. Reaction with diethylzinc gives stereodynamic complexes that undergo distinct asymmetric transformation of the first kind upon binding of chiral amines and amino alcohols. The substrate-to-ligand chirality imprinting at the zinc coordination sphere results in characteristic circular dichroism signals that can be used for direct enantiomeric excess (ee) analysis. This chemosensing approach bears potential for high-throughput ee screening with small sample amounts and reduced solvent waste compared to traditional high-performance liquid chromatography methods.

9.
J Org Chem ; 79(14): 6517-31, 2014 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-24936934

RESUMO

The attachment of a salicylaldehyde ring and a cofacial aryl or heteroaryl N-oxide chromophore onto a naphthalene scaffold affords stereodynamic probes designed to rapidly bind amines, amino alcohols, or amino acids and to translate this binding event via substrate-to-receptor chirality amplification into a dual (chir)optical response. 1-(3'-Formyl-4'-hydroxyphenyl)-8-(9'-anthryl)naphthalene (1) was prepared via two consecutive Suzuki cross-coupling reactions, and the three-dimensional structure and racemization kinetics were studied by crystallography and dynamic HPLC. This probe proved successful for chirality sensing of several compounds, but in situ IR monitoring of the condensation reaction between the salicylaldehyde moiety in 1 and phenylglycinol showed that the imine formation takes 2 h. Optimization of the substrate binding rate and the circular dichroism (CD) and fluorescence readouts led to the replacement of anthracene with smaller fluorophores capable of intramolecular hydrogen bonding. 1-(3'-Formyl-4'-methoxyphenyl)-8-(4'-isoquinolyl)naphthalene N-oxide (2) and its pyridyl analogue 3 combine fast substrate binding with distinctive chiral amplification. This asymmetric transformation of the first kind prompts CD and fluorescence responses that can be used for in situ determination of the absolute configuration, ee, and total concentration of many compounds. The general utility of the three chemosensors was successfully tested on 18 substrates.

10.
J Org Chem ; 79(8): 3725-30, 2014 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-24673491

RESUMO

The relative stabilities of three conformational isomers of 2,2'-binaphthalene-1,1'-diol diisobutyrate and the energy barriers to rotation about the pivotal aryl-aryl bond and the two aryl-oxygen bonds were investigated by variable-temperature NMR spectroscopy in conjunction with DFT computations. The experimental and calculated data were found to be in very good agreement and provide new insights into the dynamic stereochemistry of BINOL-derived tropos ligands.

11.
J Am Chem Soc ; 135(48): 18052-5, 2013 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-24261969

RESUMO

A stereodynamic probe for determination of the absolute configuration and enantiomeric composition of chiral amines, diamines, amino alcohols, amino acids, and α-hydroxy carboxylic acids is described. The chirality sensing is based on spontaneous asymmetric transformation of the first kind with stereolabile binaphtholate boron and zinc complexes. The substrate binding and chiral amplification processes yield a distinctive chiroptical sensor output at high wavelength that can be used for rapid and accurate ee detection of minute sample amounts.


Assuntos
Aminas/química , Aminoácidos/química , Amino Álcoois/química , Diaminas/química , Hidroxiácidos/química , Boro/química , Complexos de Coordenação/química , Modelos Moleculares , Estereoisomerismo , Zinco/química
12.
J Am Chem Soc ; 135(33): 12200-3, 2013 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-23909867

RESUMO

A stereodynamic chemosensor having a parallel arrangement of a substrate-binding salicylaldehyde unit and an adjacent pyridyl N-oxide fluorophore undergoes rapid condensation with chiral amino alcohols and subsequent asymmetric transformation of the first kind toward a single rotamer. Crystallographic analysis shows that the concomitant central-to-axial chirality imprinting is controlled by minimization of steric repulsion and by intramolecular hydrogen bonding between the bound amino alcohol and the proximate N-oxide group. The substrate binding event results in strong CD effects and characteristic fluorescence changes which can be used for instantaneous in situ determination of the absolute configuration, enantiomeric composition and total concentration of a variety of chiral amino alcohols. This chemosensing approach avoids time-consuming workup and purification steps, and it is applicable to minute sample amounts which reduces the use of solvents and limits waste production.


Assuntos
Técnicas de Química Analítica/instrumentação , Aldeídos/química , Amino Álcoois/química , Dicroísmo Circular , Ligação de Hidrogênio , Modelos Moleculares , Conformação Molecular , Espectrometria de Fluorescência , Estereoisomerismo
13.
Chem Soc Rev ; 42(12): 5408-24, 2013 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-23482984

RESUMO

Circular dichroism (CD) spectroscopy is one of the most useful techniques for the stereochemical analysis of chiral biopolymers and fine chemicals. It has become invaluable for the assignment of the absolute configuration, the study of conformational isomers, and the determination of racemization kinetics of CD active chiral compounds. Molecular interactions between a nonracemic chiral substrate and a chromophoric, CD-silent probe that is achiral or exists as a racemic mixture of rapidly interconverting enantiomeric conformations or configurations can induce a strong, characteristic chiroptical readout. A covalent or noncovalent binding event that coincides with a well-defined asymmetric induction process can effectively imprint the chiral information of the substrate on the stereodynamic sensor and thus generate intense Cotton effects in the UV region of the latter. The probe can thus function as a stereochemical reporter unit and analysis of the CD spectrum often provides accurate information about the absolute configuration and enantiomeric composition of the substrate used. In this review, recent developments in circular dichroism analysis of chiral compounds with stereodynamic probes are described and particular emphasis is given to sensor design, chiral induction processes and applications scope.

14.
Chirality ; 24(7): 584-9, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22628254

RESUMO

Enantioselective induced circular dichroism analysis of amino alcohols has been accomplished using a conformationally flexible arylacetylene-based probe exhibiting two terminal aldehyde groups. The chirality of the amino alcohol substrates is imprinted on the stereodynamic receptor upon [1 + 2] condensation, which ultimately generates a strong chiroptical response. The distinct induced circular dichroism effects of the diimines obtained can be used for enantioselective sensing and enantiomeric excess determination of a wide range of substrates.

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