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1.
Int J Mol Sci ; 23(13)2022 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-35806163

RESUMO

We previously reported the design and synthesis of a small-molecule drug conjugate (SMDC) platform that demonstrated several advantages over antibody-drug conjugates (ADCs) in terms of in vivo pharmacokinetics, solid tumor penetration, definitive chemical structure, and adaptability for modular synthesis. Constructed on a tri-modal SMDC platform derived from 1,3,5-triazine (TZ) that consists of a targeting moiety (Lys-Urea-Glu) for prostate-specific membrane antigen (PSMA), here we report a novel class of chemically identical theranostic small-molecule prodrug conjugates (T-SMPDCs), [18/19F]F-TZ(PSMA)-LEGU-TLR7, for PSMA-targeted delivery and controlled release of toll-like receptor 7 (TLR7) agonists to elicit de novo immune response for cancer immunotherapy. In vitro competitive binding assay of [19F]F-TZ(PSMA)-LEGU-TLR7 showed that the chemical modification of Lys-Urea-Glu did not compromise its binding affinity to PSMA. Receptor-mediated cell internalization upon the PSMA binding of [18F]F-TZ(PSMA)-LEGU-TLR7 showed a time-dependent increase, indicative of targeted intracellular delivery of the theranostic prodrug conjugate. The designed controlled release of gardiquimod, a TLR7 agonist, was realized by a legumain cleavable linker. We further performed an in vivo PET/CT imaging study that showed significantly higher uptake of [18F]F-TZ(PSMA)-LEGU-TLR7 in PSMA+ PC3-PIP tumors (1.9 ± 0.4% ID/g) than in PSMA- PC3-Flu tumors (0.8 ± 0.3% ID/g) at 1 h post-injection. In addition, the conjugate showed a one-compartment kinetic profile and in vivo stability. Taken together, our proof-of-concept biological evaluation demonstrated the potential of our T-SMPDCs for cancer immunomodulatory therapies.


Assuntos
Pró-Fármacos , Neoplasias da Próstata , Antígenos de Superfície/metabolismo , Linhagem Celular Tumoral , Preparações de Ação Retardada , Glutamato Carboxipeptidase II/metabolismo , Humanos , Masculino , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Medicina de Precisão , Pró-Fármacos/farmacologia , Neoplasias da Próstata/metabolismo , Receptor 7 Toll-Like , Ureia
2.
Int J Mol Sci ; 23(9)2022 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-35563272

RESUMO

Obesity is a leading cause of preventable death and morbidity. To elucidate the mechanisms connecting metabolically active brown adipose tissue (BAT) and metabolic health may provide insights into methods of treatment for obesity-related conditions. 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18FDG-PET/CT) is traditionally used to image human BAT activity. However, the primary energy source of BAT is derived from intracellular fatty acids and not glucose. Beta-methyl-p-iodophenylpentadecanoic acid (BMIPP) is a fatty acid analogue amenable to in vivo imaging by single photon emission computed tomography/CT (SPECT/CT) when radiolabeled with iodine isotopes. In this study, we compare the use of 18FDG-PET/CT and 125I-BMIPP-SPECT/CT for fat imaging to ascertain whether BMIPP is a more robust candidate for the non-invasive evaluation of metabolically active adipose depots. Interscapular BAT, inguinal white adipose tissue (iWAT), and gonadal white adipose tissue (gWAT) uptake of 18FDG and 125I-BMIPP was quantified in mice following treatment with the BAT-stimulating drug CL-316,243 or saline vehicle control. After CL-316,243 treatment, uptake of both radiotracers increased in BAT and iWAT. The standard uptake value (SUVmean) for 18FDG and 125I-BMIPP significantly correlated in these depots, although uptake of 125I-BMIPP in BAT and iWAT more closely mimicked the fold-change in metabolic rate as measured by an extracellular flux analyzer. Herein, we find that imaging BAT with the radioiodinated fatty acid analogue BMIPP yields more physiologically relevant data than 18FDG-PET/CT, and its conventional use may be a pivotal tool for evaluating BAT in both mice and humans.


Assuntos
Tecido Adiposo Marrom , Fluordesoxiglucose F18 , Tecido Adiposo Marrom/diagnóstico por imagem , Tecido Adiposo Marrom/metabolismo , Animais , Ácidos Graxos/metabolismo , Fluordesoxiglucose F18/metabolismo , Iodobenzenos , Camundongos , Obesidade/metabolismo , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/metabolismo , Tomografia Computadorizada de Emissão de Fóton Único/métodos
3.
J Org Chem ; 85(14): 9096-9105, 2020 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-32569467

RESUMO

Biomimetic flavin organocatalysts oxidize nitromethane to formaldehyde and NOx-providing a relatively nontoxic, noncaustic, and inexpensive source for catalytic NO2 for aerobic TEMPO oxidations of alcohols, diols, and ethers. Alcohols were oxidized to aldehydes or ketones, cyclic ethers to esters, and terminal diols to lactones. In situ trapping of NOx and formaldehyde suggest an oxidative Nef process reminiscent of flavoprotein nitroalkane oxidase reactivity, which is achieved by relatively stable 1,10-bridged flavins. The metal-free flavin/NOx/TEMPO catalytic cycles are uniquely compatible, especially compared to other Nef and NOx-generating processes, and reveal selectivity over flavin-catalyzed sulfoxide formation. Aliphatic ethers were oxidized by this method, as demonstrated by the conversion of (-)-ambroxide to (+)-sclareolide.

4.
J Org Chem ; 85(4): 1991-2009, 2020 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-31928002

RESUMO

Benzimidazoles are common in nature, medicines, and materials. Numerous strategies for preparing 2-arylbenzimidazoles exist. In this work, 1,2-disubstituted benzimidazoles were prepared from various mono- and disubstituted ortho-phenylenediamines (OPD) by iron-catalyzed oxidative coupling. Specifically, O2 and FeCl3·6H2O catalyzed the cross-dehydrogenative coupling and aromatization of diarylmethyl and dialkyl benzimidazole precursors. N,N'-Disubstituted-OPD substrates were significantly more reactive than their N,N-disubstituted isomers, which appears to be relative to their propensity for complexation and charge transfer with Fe3+. The reaction also converted N-monosubstituted OPD substrates to 2-substituted benzimidazoles; however, electron-poor substrates produce 1,2-disubstituted benzimidazoles by intermolecular imino-transfer. Kinetic, reagent, and spectroscopic (UV-vis and EPR) studies suggest a mechanism involving metal-substrate complexation, charge transfer, and aerobic turnover, involving high-valent Fe(IV) intermediates. Overall, comparative strategies for the relatively sustainable and efficient synthesis of 1,2-disubstituted benzimidazoles are demonstrated.

5.
J Org Chem ; 84(2): 1025-1034, 2019 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-30571120

RESUMO

N-Alkyl and N-aryl-isoindolinones were prepared by a dioxane-mediated oxidation of isoindoline precursors. The transformation exhibits unique chemoselectivity for isoindonlines. A chiral tertiary (3°)-benzylic position was not racemized during oxidation, and methyl indoprofen was prepared by late stage oxidation. Mechanistic studies suggest a selective H atom transfer, which avoids many known oxidation (by-)products of isoindolinones.

6.
Arch Biochem Biophys ; 631: 66-74, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28826737

RESUMO

Thiol dioxygenases are non-heme mononuclear iron enzymes that catalyze the O2-dependent oxidation of free thiols (-SH) to produce the corresponding sulfinic acid (-SO2-). Previous chemical rescue studies identified a putative FeIII-O2- intermediate that precedes substrate oxidation in Mus musculus cysteine dioxygenase (Mm CDO). Given that a similar reactive intermediate has been identified in the extradiol dioxygenase 2, 3-HCPD, it is conceivable that these enzymes share other mechanistic features with regard to substrate oxidation. To explore this possibility, enzymatic reactions with Mm CDO (as well as the bacterial 3-mercaptopropionic acid dioxygenase, Av MDO) were performed using a substrate analogue (2-mercaptoaniline, 2ma). This aromatic thiol closely approximates the catecholic substrate of homoprotocatechuate of 2, 3-HPCD while maintaining the 2-carbon thiol-amine separation preferred by Mm CDO. Remarkably, both enzymes exhibit 2ma-gated O2-consumption; however, none of the expected products for thiol dioxygenase or intra/extradiol dioxygenase reactions were observed. Instead, benzothiazoles are produced by the condensation of 2ma with aldehydes formed by an off-pathway oxidation of primary alcohols added to aqueous reactions to solubilize the substrate. The observed oxidation of 1º-alcohols in 2ma-reactions is consistent with the formation of a high-valent intermediate similar to what has been reported for cytochrome P450 and mononuclear iron model complexes.


Assuntos
Ácido 3-Mercaptopropiônico/metabolismo , Álcoois/metabolismo , Compostos de Anilina/metabolismo , Azotobacter vinelandii/enzimologia , Benzotiazóis/metabolismo , Cisteína Dioxigenase/metabolismo , Dioxigenases/metabolismo , Animais , Azotobacter vinelandii/metabolismo , Camundongos , Modelos Moleculares , Oxirredução , Oxigênio/metabolismo , Especificidade por Substrato
7.
J Am Soc Mass Spectrom ; 33(1): 189-197, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34928623

RESUMO

Proteolysis is one of the most important protein post-translational modifications (PTMs) that influences the functions, activities, and structures of nearly all proteins during their lifetime. To facilitate the targeted identification of low-abundant proteolytic products, we devised a strategy incorporating a novel biotinylated reagent PFP (pentafluorophenyl)-Rink-biotin to specifically target, enrich and identify proteolytic N-termini. Within the PFP-Rink-biotin reagent, a mass spectrometry (MS)-cleavable feature was designed to assist in the unambiguous confirmation of the enriched proteolytic N-termini. The proof-of-concept study was performed with multiple standard proteins whose N-termini were successfully modified, enriched and identified by a signature ion (SI) in the MS/MS fragmentation, along with the determination of N-terminal peptide sequences by multistage tandem MS of the complementary fragment generated after the cleavage of MS-cleavable bond. For large-scale application, the enrichment and identification of protein N-termini from Escherichia coli cells were demonstrated, facilitated by an in-house developed NTermFinder bioinformatics workflow. We believe this approach will be beneficial in improving the confidence of identifying proteolytic substrates in a native cellular environment.


Assuntos
Peptídeo Hidrolases , Processamento de Proteína Pós-Traducional/fisiologia , Proteínas , Espectrometria de Massas em Tandem/métodos , Biotina/química , Biologia Computacional/métodos , Fluorbenzenos/química , Fluorocarbonos/química , Peptídeo Hidrolases/análise , Peptídeo Hidrolases/metabolismo , Fenóis/química , Proteínas/química , Proteínas/metabolismo , Proteólise
8.
ACS Sens ; 6(1): 192-202, 2021 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-33400506

RESUMO

Single-molecule fluorescence imaging (SMFI) of gas-phase ions has been proposed for "barium tagging," a burgeoning area of research in particle physics to detect individual barium daughter ions. This has potential to significantly enhance the sensitivity of searches for neutrinoless double-beta decay (0νßß) that is obscured by background radiation events. The chemistry required to make such sensitive detection of Ba2+ by SMFI in dry Xe gas at solid interfaces has implications for solid-phase detection methods but has not been demonstrated. Here, we synthesized simple, robust, and effective Ba2+-selective chemosensors capable of function within ultrapure high-pressure 136Xe gas. Turn-on fluorescent naphthalimide-(di)azacrown ether chemosensors were Ba2+-selective and achieved SMFI in a polyacrylamide matrix. Fluorescence and NMR experiments supported a photoinduced electron transfer mechanism for turn-on sensing. Ba2+ selectivity was achieved with computational calculations correctly predicting the fluorescence responses of sensors to barium, mercury, and potassium ions. With these molecules, dry-phase single-Ba2+ ion imaging with turn-on fluorescence was realized using an oil-free microscopy technique for the first time-a significant advance toward single-Ba2+ ion detection within large volumes of 136Xe, plausibly enabling a background-independent technique to search for the hypothetical process of 0νßß.


Assuntos
Éter , Naftalimidas , Bário , Éteres , Corantes Fluorescentes , Íons
9.
ACS Omega ; 5(12): 6919-6927, 2020 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-32258928

RESUMO

Photoluminescence of Eu3+ in DMSO is intense and ultrasensitive to water, thereby providing a novel method for water detection. Herein, for the first time, we investigated the effects of Eu3+ concentration on luminescence and developed a multiparameter method for trace water detection based on a single luminescence agent. To further extend its practical applications, we explored its performance for water detection in ethanol and gasoline. Our findings demonstrate that it is a sensitive and reliable probe for the detection of a wide concentration range of water in ethanol (0-24.24%) and gasoline (0-32.43%), making Eu-DMSO a promising candidate to detect water in a wide concentration range. These phenomena not only make Eu-DMSO a sensitive agent for in situ water detection in real time but also provide scientifically interesting mechanisms behind its application as a water sensing probe.

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