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1.
Chem Soc Rev ; 50(18): 10403-10421, 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34320043

RESUMO

There has been a significant push in recent years to deploy fundamental knowledge and methods of photochemistry toward biological ends. Photoreactive groups have enabled chemists to activate biological function using the concept of photocaging. By granting spatiotemporal control over protein activation, these photocaging methods are fundamental in understanding biological processes. Peptides and proteins are an important group of photocaging targets that present conceptual and technical challenges, requiring precise chemoselectivity in complex polyfunctional environments. This review focuses on recent advances in photocaging techniques and methodologies, as well as their use in living systems. Photocaging methods include genetic and chemical approaches that require a deep understanding of structure-function relationships based on subtle changes in primary structure. Successful implementation of these ideas can shed light on important spatiotemporal aspects of living systems.


Assuntos
Fenômenos Biológicos , Proteínas , Peptídeos , Fotoquímica
2.
Org Biomol Chem ; 18(27): 5110-5114, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32519726

RESUMO

Light is a uniquely powerful tool for spatiotemporal control of molecular structure, necessitating the development of new photocaging approaches. This communication describes the design, synthesis, and reactivity of two new photoreactive boronic acid reagents for backbone N-H modification and subsequent photocleavage.

3.
Org Biomol Chem ; 18(17): 3288-3296, 2020 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-32286579

RESUMO

Recurrence and drug resistance are major challenges in the treatment of acute myeloid leukemia (AML) that spur efforts to identify new clinical targets and active agents. STAT3 has emerged as a potential target in resistant AML, but inhibiting STAT3 function has proven challenging. This paper describes synthetic studies and biological assays for a naphthalene sulfonamide inhibitor class of molecules that inhibit G-CSF-induced STAT3 phosphorylation in cellulo and induce apoptosis in AML cells. We describe two different approaches to inhibitor design: first, variation of substituents on the naphthalene sulfonamide core allows improvements in anti-STAT activity and creates a more thorough understanding of anti-STAT SAR. Second, a novel approach involving hybrid sulfonamide-rhodium(ii) conjugates tests our ability to use cooperative organic-inorganic binding for drug development, and to use SAR studies to inform metal conjugate design. Both approaches have produced compounds with improved binding potency. In vivo and in cellulo experiments further demonstrate that these approaches can also lead to improved activity in living cells, and that compound 3aa slows disease progression in a xenograft model of AML.


Assuntos
Antineoplásicos/química , Leucemia Mieloide Aguda/tratamento farmacológico , Naftalenos/química , Inibidores de Proteínas Quinases/química , Fator de Transcrição STAT3/antagonistas & inibidores , Sulfonamidas/química , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Modelos Moleculares , Terapia de Alvo Molecular , Neoplasias Experimentais , Oxirredução , Ligação Proteica , Inibidores de Proteínas Quinases/farmacologia , Fator de Transcrição STAT3/genética , Relação Estrutura-Atividade
4.
Blood Adv ; 3(24): 4215-4227, 2019 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-31856268

RESUMO

Atovaquone, a US Food and Drug Administration-approved antiparasitic drug previously shown to reduce interleukin-6/STAT3 signaling in myeloma cells, is well tolerated, and plasma concentrations of 40 to 80 µM have been achieved with pediatric and adult dosing. We conducted preclinical testing of atovaquone with acute myeloid leukemia (AML) cell lines and pediatric patient samples. Atovaquone induced apoptosis with an EC50 <30 µM for most AML lines and primary pediatric AML specimens. In NSG mice xenografted with luciferase-expressing THP-1 cells and in those receiving a patient-derived xenograft, atovaquone-treated mice demonstrated decreased disease burden and prolonged survival. To gain a better understanding of the mechanism of atovaquone, we performed an integrated analysis of gene expression changes occurring in cancer cell lines after atovaquone exposure. Atovaquone promoted phosphorylation of eIF2α, a key component of the integrated stress response and master regulator of protein translation. Increased levels of phosphorylated eIF2α led to greater abundance of the transcription factor ATF4 and its target genes, including proapoptotic CHOP and CHAC1. Furthermore, atovaquone upregulated REDD1, an ATF4 target gene and negative regulator of the mechanistic target of rapamycin (mTOR), and caused REDD1-mediated inhibition of mTOR activity with similar efficacy as rapamycin. Additionally, atovaquone suppressed the oxygen consumption rate of AML cells, which has specific implications for chemotherapy-resistant AML blasts that rely on oxidative phosphorylation for survival. Our results provide insight into the complex biological effects of atovaquone, highlighting its potential as an anticancer therapy with novel and diverse mechanisms of action, and support further clinical evaluation of atovaquone for pediatric and adult AML.


Assuntos
Atovaquona/farmacologia , Leucemia Mieloide Aguda/metabolismo , Fosforilação Oxidativa/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Fator 4 Ativador da Transcrição/metabolismo , Adolescente , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Criança , Pré-Escolar , Modelos Animais de Doenças , Feminino , Humanos , Lactente , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Camundongos , Camundongos Knockout , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Chem Commun (Camb) ; 55(19): 2841-2844, 2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30768093

RESUMO

S-Arylation of cysteine residues is an increasingly powerful tool for site-specific modification of proteins, providing novel structure and electronic perturbation. The present work demonstrates an operationally-simple cysteine arylation reaction 2-nitro-substituted arylboronic acids, promoted by a simple nickel(ii) salt. The process exhibits strikingly fast reaction rates under physiological conditions in purely aqueous media with excellent selectivity toward cysteine residues. Cysteine arylation of natural proteins and peptides allows attachment of useful reactive handles for stapling, imaging, or further conjugation.

6.
J Am Chem Soc ; 140(27): 8401-8404, 2018 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-29924590

RESUMO

Side-chain modifications that respond to external stimuli provide a convenient approach to control macromolecular structure and function. Responsive modification of backbone amide structure represents a direct and powerful alternative to impact folding and function. Here, we describe a new photocaging method using histidine-directed backbone modification to selectively modify peptides and proteins at the amide N-H bond. A new vinylogous photocleavage method allows photorelease of the backbone modification and, with it, restoration of function.

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