Steric and stereoscopic disulfide construction for cross-linkage <i>via N</i>-dithiophthalimides

Gao, Wenchao; Tian, Jinfeng; Shang, Yu-Zhu; Jiang, Xuefeng

doi:10.1039/d0sc01060j

Cited by 78 publications

(33 citation statements)

References 30 publications

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“…For instance, linker-based conjugates, such as antibody drug conjugates (ADCs) and small-molecule theranostic prodrugs, have become promising in drug discovery ( 37 ). Because of the embedded cavity and chiral environment in cellular redox systems, the stability of the disulfide linker mainly relies on the adjacent steric and stereoscopic effects ( 38 , 39 ). However, increasing the stability of the disulfide causes a corresponding decrease in the cleavage and payload release ( 38 ).…”

Section: Discussionmentioning

confidence: 99%

Trisulfide bond–mediated doxorubicin dimeric prodrug nanoassemblies with high drug loading, high self-assembly stability, and high tumor selectivity

et al. 2020

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Rational design of nanoparticulate drug delivery systems (nano-DDS) for efficient cancer therapy is still a challenge, restricted by poor drug loading, poor stability, and poor tumor selectivity. Here, we report that simple insertion of a trisulfide bond can turn doxorubicin homodimeric prodrugs into self-assembled nanoparticles with three benefits: high drug loading (67.24%, w/w), high self-assembly stability, and high tumor selectivity. Compared with disulfide and thioether bonds, the trisulfide bond effectively promotes the self-assembly ability of doxorubicin homodimeric prodrugs, thereby improving the colloidal stability and in vivo fate of prodrug nanoassemblies. The trisulfide bond also shows higher glutathione sensitivity compared to the conventional disulfide bond, and this sensitivity enables efficient tumor-specific drug release. Therefore, trisulfide bond–bridged prodrug nanoassemblies exhibit high selective cytotoxicity on tumor cells compared with normal cells, notably reducing the systemic toxicity of doxorubicin. Our findings provide new insights into the design of advanced redox-sensitive nano-DDS for cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Trisulfide bond–mediated doxorubicin dimeric prodrug nanoassemblies with high drug loading, high self-assembly stability, and high tumor selectivity

et al. 2020

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“…However, the fragile S−S bond poses serious challenges toward this end. There is only one report about catalytic asymmetric disulfuration via C−S formation, [11] though their counterpart enantioselective sulfuration have been extensively reported [12] . In this case, the reaction was limited in terms of scopes and stereoselectvity.…”

Section: Introductionmentioning

confidence: 99%

Catalytic Asymmetric Disulfuration by a Chiral Bulky Three‐Component Lewis Acid‐Base

Luo

Zhang

et al. 2021

Angew Chem Int Ed

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A three‐component Lewis acid–base (Lewis trio) involving a bulky chiral primary amine, B(C6F5)3 and a bulky tertiary amine has been developed as an effective enamine catalyst for enantioselective disulfuration reactions. The bulky tertiary amine was found to activate a bulky primary–tertiary diamine–borane Lewis pair for enamine catalysis via frustrated interaction. The resulted chiral bulky Lewis trio (BLT) allows for the construction of chiral disulfides via direct disulfuration with β‐ketocarbonyls or α‐branched aldehydes in a practical and highly stereocontrolled manner.

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“…Therefore, the direct disulfuration using the disulfurating reagents has become a better choice owing to their straightforward facility for unsymmetrical disulfide and late‐stage modification. A facile and robust strategy for the fabrication of diverse steric and stereoscopic unsymmetrical disulfides was developed by Jiang and coworkers through disulfuration of α‐branched esters with N ‐dithiophthalimides as disulfurating reagents [46] . The reaction exhibited good tolerance towards various substituted β‐ketone esters and silyl ketene acetals ( Scheme 22, Methods A and B ).…”

Section: Synthesis Of Unsymmetrical Organic Disulfidesmentioning

confidence: 99%

An Overview of Recent Advances in the Synthesis of Organic Unsymmetrical Disulfides

Ong

Titinchi

Juan

et al. 2021

Helvetica Chimica Acta

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Organic unsymmetrical disulfides have been extensively applied in various academic and industrial fields including intermediates in organic synthesis, agriculture, and food science, natural materials, biochemistry, pharmaceutical and medicine chemistry, polymers, material engineering, etc. They play a crucial role in the fabrication of various biological active sulfur heterocycles. Due to broad and extensive applications, many methods have been developed for the synthesis of unsymmetrical S−S and efforts have been made to improve some issues such as cost, energy efficiency, green chemistry, avoid or minimizing waste generation. Several outstanding review articles have been previously published highlighting the advances of S−S bond formation, in general, using various reagents under different conditions in the absence or presence of oxidants/catalysts. In 2020, a review paper was published by our group focusing on recent developments since 2014 in the synthesis of organic symmetrical disulfides. However, investigations on new catalytic methods are being regularly reported and new types of unsymmetrical disulfides are synthesized. The present overview has attempted to systematically summarize recent advances in the process of unsymmetrical S−S bond formation with a major focus since 2010, highlighting mechanistic considerations, substrate scope, advantages, and limitations. The patents are not studied in this overview.

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Steric and stereoscopic disulfide construction for cross-linkage via N-dithiophthalimides

Abstract: A series of steric and stereoscopic disulfides are constructed with N-dithiophthalimides, enabling the cross-linkage of biomolecules, drugs and fluorescent molecules.

Cited by 78 publications

References 30 publications

Trisulfide bond–mediated doxorubicin dimeric prodrug nanoassemblies with high drug loading, high self-assembly stability, and high tumor selectivity

Trisulfide bond–mediated doxorubicin dimeric prodrug nanoassemblies with high drug loading, high self-assembly stability, and high tumor selectivity

Catalytic Asymmetric Disulfuration by a Chiral Bulky Three‐Component Lewis Acid‐Base

An Overview of Recent Advances in the Synthesis of Organic Unsymmetrical Disulfides

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