Structural Analysis of a Facile Lactonization System Facilitated by a “Trimethyl Lock”

Wang, Binghe; Nicolaou, Michalis G.; Liu, Siming; Borchardt, Ronald T.

doi:10.1006/bioo.1996.0005

Cited by 29 publications

(20 citation statements)

References 20 publications

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“…It is demonstrated that cells can be selectively captured on the anti-EpCAM-modified silicon surface, even from whole blood, and when desired, photo-electrochemically released from the modified silicon surface. This advance is based on the photo-resolved electrochemical property of a silicon substrate 19 and the attached electrochemically cleavable trimethyl lock 36 . The capture & release surface is compatible with imaging and allows direct visualisation of cell morphology and enables localising the release of any single cell the user desires.…”

Section: Discussionmentioning

confidence: 99%

A photoelectrochemical platform for the capture and release of rare single cells

et al. 2018

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For many normal and aberrant cell behaviours, it is important to understand the origin of cellular heterogeneity. Although powerful methods for studying cell heterogeneity have emerged, they are more suitable for common rather than rare cells. Exploring the heterogeneity of rare single cells is challenging because these rare cells must be first pre-concentrated and undergo analysis prior to classification and expansion. Here, a versatile capture & release platform consisting of an antibody-modified and electrochemically cleavable semiconducting silicon surface for release of individual cells of interest is presented. The captured cells can be interrogated microscopically and tested for drug responsiveness prior to release and recovery. The capture & release strategy was applied to identify rare tumour cells from whole blood, monitor the uptake of, and response to, doxorubicin and subsequently select cells for single-cell gene expression based on their response to the doxorubicin.

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Section: Discussionmentioning

confidence: 99%

A photoelectrochemical platform for the capture and release of rare single cells

et al. 2018

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“…The rate of lactonizationd ecreases by 10 %i fa ll six hydrogen atoms in the geminal dimethyl moiety of trimethyl lock 1 are replaced by deuterium. [19] All of theseo bservations lead to the conclusion that the relief of steric compression is the dominant enthalpic factor for the rate enhancement. The authors surmise that the steric hindranceo ft he interacting methyl groups in 1 is relieved upon cyclization.…”

Section: Trimethyl Lock:s Tructure Reactivityand Kineticsmentioning

confidence: 99%

“…Although the crystal structures indicate no change in the distance of the methyl group between the open and closed structures, the uncaged oxygen atom is forced out of the plane of the quinone ring system in theses tructures, whereas the strain is reduced in closed structure 3. [19] All of theseo bservations lead to the conclusion that the relief of steric compression is the dominant enthalpic factor for the rate enhancement. However,t he relief of strain cannotb et he only factor influencing the rate of lactonization,a nd presumably,o ther factors, havingb oth enthalpic and entropic components,p lay ac rucial role in rapid lactonization.…”

Section: Trimethyl Lock:s Tructure Reactivityand Kineticsmentioning

confidence: 99%

“…An early model system for the use of esterase-sensitive TML systemsf or prodrug development of amine-containing drugs is reported by Borchardta nd co-workers. [19,21,22] TML acetyl ester 12 (Scheme3)h as ah alf-life of t 1/2 = 4039min in phosphate-buffered saline. The addition of porcine liver esterase leads to cleavage of the acetate and release of p-methoxyaniline within af ew minutes.…”

Section: Esterase-sensitive Tmls Ystemsmentioning

confidence: 99%

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Trimethyl Lock: A Multifunctional Molecular Tool for Drug Delivery, Cellular Imaging, and Stimuli‐Responsive Materials

Okoh

Klahn

2018

ChemBioChem

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Trimethyl lock (TML) systems are based on ortho-hydroxydihydrocinnamic acid derivatives displaying increased lactonization reactivity owing to unfavorable steric interactions of three pendant methyl groups, and this leads to the formation of hydrocoumarins. Protection of the phenolic hydroxy function or masking of the reactivity as benzoquinone derivatives prevents lactonization and provides a trigger for controlled release of molecules attached to the carboxylic acid function through amides, esters, or thioesters. Their easy synthesis and possible chemical adaption to several different triggers make TML a highly versatile module for the development of drug-delivery systems, prodrug approaches, cell-imaging tools, molecular tools for supramolecular chemistry, as well as smart stimuliresponsive materials.

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“…4) showed that the methyl group distances did not change between the open and closed forms; however, the open forms 8 – 11 had the unmasked oxygen forced out of the plane of the quinone ring system. 8 Some of this strain was relieved in the closed form, 12 .…”

Section: Introductionmentioning

confidence: 99%

Trimethyl lock: a trigger for molecular release in chemistry, biology, and pharmacology

2012

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The trimethyl lock is an o-hydroxydihydrocinnamic acid derivative in which unfavorable steric interactions between three pendant methyl groups encourage lactonization to form a hydrocoumarin. This reaction is extremely rapid, even when the electrophile is an amide and the leaving group is an amino group of a small-molecule drug, fluorophore, peptide, or nucleic acid. O-Acylation of the phenolic hydroxyl group prevents reaction, providing a trigger for the reaction. Thus, the release of an amino group from an amide can be coupled to the hydrolysis of a designated ester (or to another chemical reaction that regenerates the hydroxyl group). Trimethyl lock conjugates are easy to synthesize, making the trimethyl lock a highly versatile module for chemical biology and related fields.

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Structural Analysis of a Facile Lactonization System Facilitated by a “Trimethyl Lock”

Cited by 29 publications

References 20 publications

A photoelectrochemical platform for the capture and release of rare single cells

A photoelectrochemical platform for the capture and release of rare single cells

Trimethyl Lock: A Multifunctional Molecular Tool for Drug Delivery, Cellular Imaging, and Stimuli‐Responsive Materials

Trimethyl lock: a trigger for molecular release in chemistry, biology, and pharmacology

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