Ester Bonds in Prodrugs

Lavis, Luke D.

doi:10.1021/cb800065s

Cited by 137 publications

(108 citation statements)

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“…We exploited these differences and identified a selective esterase-ester pair capable of the targeted delivery of small molecules in complex environments with cellular specificity. The described α-cyclopropyl ester moiety has low molecular mass, is synthetically accessible, and is easily incorporated into existing strategies to mask polar functionalities using ester groups, such as the widely used, but cell-type-unselective, acetoxymethyl ether/ester system (10,11). The complementary exogenous enzyme, PLE, efficiently catalyzes the hydrolysis of this ester bond and does not show obvious effects on cellular properties, even in highly sensitive neuronal tissue.…”

Section: Resultsmentioning

confidence: 99%

“…Esters have many advantages as masking moieties: they are simple to synthesize, can mask a variety of functional groups, and render molecules cell permeable. Indeed, chemical derivatization with esters reactive to endogenous esterases is an established and effective strategy to deliver compounds to cells in many contexts (10,11). Moreover, exogenous esterases can be expressed heterologously; carboxylesterases from different species have been used to enrich an anticancer agent (7) or a calcium indicator (12) in specific cells and subcellular locales.…”

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confidence: 99%

“…The aforementioned expression of exogenous esterases can improve small molecule targeting (7,12), but current systems use ester masking groups that are also reactive to endogenous esterases, leading to incomplete cellular selectivity. To overcome these stability and selectivity problems, we explored synthetic branched esters, as substitutions on the α-carbon can increase chemical stability (15) and cellular esterases can exhibit surprising selectivity toward complex esters (11,16). To quickly identify a selective esterase-ester pair, we prepared a series of unique, chemically stable fluorogenic esterase substrates bearing different ester functionalities.…”

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confidence: 99%

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Selective esterase–ester pair for targeting small molecules with cellular specificity

Tian

Yang

Wysocki

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Small molecules are important tools to measure and modulate intracellular signaling pathways. A longstanding limitation for using chemical compounds in complex tissues has been the inability to target bioactive small molecules to a specific cell class. Here, we describe a generalizable esterase-ester pair capable of targeted delivery of small molecules to living cells and tissue with cellular specificity. We used fluorogenic molecules to rapidly identify a small ester masking motif that is stable to endogenous esterases, but is efficiently removed by an exogenous esterase. This strategy allows facile targeting of dyes and drugs in complex biological environments to label specific cell types, illuminate gap junction connectivity, and pharmacologically perturb distinct subsets of cells. We expect this approach to have general utility for the specific delivery of many small molecules to defined cellular populations. cellular imaging | microscopy | enzyme substrates | fluorophores | pharmacological agents C hemical probes are essential tools in biology for measuring and manipulating cellular properties. Optimization of the structural and electronic features of small molecules allows the fine-tuning of molecular recognition specificity for a particular cellular target. Even with high molecular specificity, however, the application of small molecules in complex biological environments is frequently limited by poor cellular specificity. The inability to target small molecules, such as imaging or pharmacological agents, to defined cellular populations can confound the evaluation and control of discrete subsets of cells within a multicellular environment. A general and efficient strategy for cell-specific targeting, combining the molecular specificity of small molecules with the cellular specificity of genetics, would allow intracellular pathways in defined cell types to be selectively probed in complex tissues.An attractive approach for general cell-specific delivery of small molecules employs selective enzyme-substrate pairs. In this strategy, compounds are masked by attachment of a standard, disposable blocking group that is stable to native cellular enzymes, but labile to a specific exogenous enzyme. Expression of such a protein in a genetically defined cell population permits unmasking of the small molecule with cellular specificity. To be useful across experimental paradigms, such a system should utilize an enzyme that unmasks molecules with high efficiency, expresses in different cell types, and exhibits low cellular toxicity. The cognate masking group must be modular, synthetically efficient, and allow molecules to diffuse passively across the cellular membrane, while also exhibiting favorable solubility and stability in aqueous solution.To date only a few enzyme-substrate pairs have been used as targeted delivery systems for small molecules, and none meet all the criteria outlined above. Strategies employing enzymes encoded by common reporter genes (1) have found some success in targeting small molecules (2-4), ...

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Selective esterase–ester pair for targeting small molecules with cellular specificity

Tian

Yang

Wysocki

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

165

212

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“…40–44 One strategy commonly implemented in eukaryotic cells is to temporarily mask polar groups such as carboxylates via esterification, which promotes passage through the cell membrane. 45, 46 Upon reaching the cell’s interior the polar group can be unmasked by esterases, thereby generating the active small molecule. 47–49 This strategy relies on the presence of highly promiscuous esterases within the cell that can process the compound of interest.…”

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confidence: 99%

Carboxylate Surrogates Enhance the Antimycobacterial Activity of UDP-Galactopyranose Mutase Probes

2016

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Uridine diphosphate galactopyranose mutase (UGM also known as Glf) is a biosynthetic enzyme required for construction of the galactan, an essential mycobacterial cell envelope polysaccharide. Our group previously identified two distinct classes of UGM inhibitors; each possesses a carboxylate moiety that is crucial for potency yet likely detrimental for cell permeability. To enhance antimycobacterial potency, we sought to replace the carboxylate with a functional group mimic–an N-acylsulfonamide group. We therefore synthesized a series of N-acylsulfonamide analogs and tested their ability to inhibit UGM. For each inhibitor scaffold tested, the N-acylsulfonamide group functions as an effective carboxylate surrogate. While the carboxylates and their surrogates show similar activity against UGM in a test tube, several N-acylsulfonamide derivatives more effectively block the growth of Mycobacterium smegmatis. These data suggest the replacement of a carboxylate with an N-acylsulfonamide group could serve as a general strategy to augment antimycobacterial activity.

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“…10 -5). This strategy is based on the ancient design principle-exemplified by aspirin-where prodrugs are rendered more lipophilic and cell permeable by masking their hydrophilic moieties with a SCFA, which is usually acetate [64]. In the context of sugars, peracetylation of ManNAc increases cellular uptake by about 600-fold compared to the perhydroxylated monosaccharide [65], presumably because of the increased lipophilicity and resulting membrane permeability of the prodrug.…”

Section: Metabolic Flux Considerations For Development Of Moe-based Tmentioning

confidence: 99%

Chemical Biology of Cell Surface Oligosaccharides

Atukorale

Choi

Aich

et al. 2009

Protein Targeting With Small Molecules

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Ester Bonds in Prodrugs

Cited by 137 publications

References 25 publications

Selective esterase–ester pair for targeting small molecules with cellular specificity

Selective esterase–ester pair for targeting small molecules with cellular specificity

Carboxylate Surrogates Enhance the Antimycobacterial Activity of UDP-Galactopyranose Mutase Probes

Chemical Biology of Cell Surface Oligosaccharides

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