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1.
Chem Commun (Camb) ; 59(33): 4974-4977, 2023 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-37016952

RESUMO

Here we report the development of an equimolar conjugate of a metal-organic cage (MOC) and DNA (MOC-DNA). Several MOC-DNA conjugates were assembled into a programmed structure by coordinating with a template DNA having a complementary base sequence. Moreover, conjugation with the MOC drastically enhanced the permeability of DNA through the lipid bilayer, presenting great potential as a drug delivery system.


Assuntos
DNA , Bicamadas Lipídicas , DNA/química , Nanotecnologia , Metais , Sequência de Bases
2.
ChemMedChem ; 16(5): 743-766, 2021 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-33230979

RESUMO

Acquired immunodeficiency syndrome (AIDS) is caused by infection with the human immunodeficiency virus (HIV). Although treatments against HIV infection are available, AIDS remains a serious disease that causes many deaths annually. Although a variety of anti-HIV drugs have been synthesized and marketed to treat HIV-infected patients, nucleoside analogue reverse transcriptase inhibitors (NRTIs), which mimic nucleosides, are used extensively and remain a subject of interest to medicinal chemists. However, HIV has acquired drug resistance against NRTIs, and thus the struggle to find novel therapies continues. In this review, we trace the trajectory of NRTIs, focusing on the synthesis, mechanisms of action and applications of NRTIs that have been developed.


Assuntos
Fármacos Anti-HIV/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Nucleosídeos/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Fármacos Anti-HIV/química , Transcriptase Reversa do HIV/metabolismo , HIV-1/metabolismo , Humanos , Estrutura Molecular , Nucleosídeos/química , Inibidores da Transcriptase Reversa/química
3.
Nucleic Acid Ther ; 30(6): 346-364, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33016851

RESUMO

siRNAs are being developed as a novel therapeutic modality; however, problems impeding their application in extrahepatic tissues persist, including inadequate stability in biological environments and inefficient drug delivery system to target tissues. Thus, technological improvements that enable robust silencing of target messenger RNA (mRNA) in extrahepatic tissues are necessary. We developed prodrug type covalently closed siRNA (circular siRNA) as a novel nucleic acid agent to knockdown target genes in extrahepatic tissues by systemic administration without drug delivery components. Circular siRNA, which is chemically synthesizable, can assume optimal structures for efficient knockdown using its cleavable linker; namely, circular and linear structure in extracellular and intracellular environment, respectively. In this study, we investigated circular siRNA physicochemical properties, knockdown mechanism, and characteristics in vitro, as well as pharmacokinetics, accumulation, knockdown activity, and safety in vivo. Our circular siRNA exhibited higher stability against serum and exonucleases, increased cellular uptake, and stronger knockdown activity without transfection reagent in vitro than linear siRNA. Furthermore, after systemic administration to mice, circular siRNA showed prolonged circulation and improved knockdown activity in the liver, kidney, and muscle, without causing adverse effects. Circular siRNA may represent an additional platform for RNAi therapeutics, providing alternate solutions for disease treatment.


Assuntos
Pró-Fármacos/farmacologia , RNA Circular/farmacologia , RNA Interferente Pequeno/farmacologia , Terapêutica com RNAi , Animais , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Técnicas de Silenciamento de Genes , Humanos , Rim/efeitos dos fármacos , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Camundongos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/patologia , RNA Circular/genética , RNA Interferente Pequeno/genética
4.
J Biomater Sci Polym Ed ; 29(4): 448-459, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29318941

RESUMO

Nucleic acid medicine is the next-generation therapeutic modality for refractory diseases with its unique mode of action as an alternative to traditional therapies. A nucleic acid delivery system targeted to liver was validated clinically; however, the delivery system of nucleic acids targeting solid tumors following systemic administration is not efficient enough for clinical use. In this study, we first utilized an antisense oligonucleotide (ASO) and polyethylene glycol (PEG) in one-to-one conjugation (PEG-ASO) at the endo-position of the ASO (endo-PEG-ASO). The effects of ASO modification position, PEG structure and molecular weight, and PEG-ASO tumor accumulation were evaluated in vivo. The endo-PEG-ASO showed prolonged pharmacokinetics and enhanced tumor accumulation compared with the conventional ASO and the PEG-ASO modified at the ASO exo-position (exo-PEG-ASO), indicating that the modification position of PEG is crucial for targeting tumors. We also observed that the endo-PEG-ASO indicated possibility of enhanced permeability inside the tumor. Further research is needed to optimize the linker in the endo-PEG-ASO for clinical application as a novel and promising therapeutic format for targeting solid tumors.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Experimentais , Oligonucleotídeos Antissenso/uso terapêutico , Polietilenoglicóis , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/química , Humanos , Masculino , Camundongos Endogâmicos BALB C , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/genética , Oligonucleotídeos Antissenso/efeitos adversos , Oligonucleotídeos Antissenso/química
5.
J Am Chem Soc ; 133(50): 20175-85, 2011 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-22050305

RESUMO

Diphenylprolinol silyl ether was found to be an effective organocatalyst for promoting the asymmetric, catalytic, intramolecular [6 + 2] cycloaddition reactions of fulvenes substituted at the exocyclic 6-position with a δ-formylalkyl group to afford synthetically useful linear triquinane derivatives in good yields and excellent enantioselectivities. The cis-fused triquinane derivatives were obtained exclusively; the trans-fused isomers were not detected among the reaction products. The intramolecular [6 + 2] cycloaddition occurs between the fulvene functionality (6π) and the enamine double bond (2π) generated from the formyl group in the substrates and the diphenylprolinol silyl ether. The absolute configuration of the reaction products was determined by vibrational circular dichroism. The reaction mechanism was investigated using molecular orbital calculations, B3LYP and MP2 geometry optimizations, and subsequent single-point energy evaluations on model reaction sequences. These calculations revealed the following: (i) The intermolecular [6 + 2] cycloaddition of a fulvene and an enamine double bond proceeds in a stepwise mechanism via a zwitterionic intermediate. (ii) On the other hand, the intramolecular [6 + 2] cycloaddition leading to the cis-fused triquinane skeleton proceeds in a concerted mechanism via a highly asynchronous transition state. (iii) The fulvene functionality and the enamine double bond adopt the gauche-syn conformation during the C-C bond formation processes in the [6 + 2] cycloaddition. (iv) The energy profiles calculated for the intramolecular reaction explain the observed exclusive formation of the cis-fused triquinane derivatives in the [6 + 2] cycloaddition reactions. The reasons for the enantioselectivity seen in these [6 + 2] cycloaddition reactions are also discussed.

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