The pyridinone-methide elimination

Perry-Feigenbaum, Rotem; Baran, Phil S.; Shabat, Doron

doi:10.1039/b915265b

Cited by 26 publications

(31 citation statements)

References 18 publications

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“…150 kJ mol À1 ), [123] so should be favorable to build fast self-immolative spacers.This was observed in as pacer containing the pyridinic core (formula 31;F igure 6). [108] After enzymatic activation, its self-immolation was complete after 30 min, compared to more than 4hfor the benzenic analogue. [108] In contrast, other results (see Table 2S) relying on photochemical activation and detailed kinetic analysis demonstrated that the pyridine ring decreases the rate of disassembly relative to the benzene core (see formulas 34 and 37 relatively to others) and that the position of its nitrogen atom is significant (see formulas 31 and 32).…”

Section: Aromatic Corementioning

confidence: 98%

“…[108] After enzymatic activation, its self-immolation was complete after 30 min, compared to more than 4hfor the benzenic analogue. [108] In contrast, other results (see Table 2S) relying on photochemical activation and detailed kinetic analysis demonstrated that the pyridine ring decreases the rate of disassembly relative to the benzene core (see formulas 34 and 37 relatively to others) and that the position of its nitrogen atom is significant (see formulas 31 and 32). Moreover,i th as even been shown that the introduction of two nitrogen atoms in the aromatic core (pyrimidines;f ormulas 33 and 35)p revents release of the leaving group under acidic conditions.T hus,m ore than the drop of the resonance energy,i ts eems that disassembly kinetics of the heterocyclic self-immolative spacer is controlled by the electron density at the benzylic carbon atom bearing the leaving group.This electron density is lowered by the presence of nitrogen atoms exerting electron-withdrawing effects.…”

Section: Aromatic Corementioning

confidence: 98%

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Self‐Immolative Spacers: Kinetic Aspects, Structure–Property Relationships, and Applications

et al. 2015

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Self-immolative spacers are covalent assemblies tailored to correlate the cleavage of two chemical bonds after activation of a protective part in a precursor: Upon stimulation, the protective moiety is removed, which generates a cascade of disassembling reactions leading to the temporally sequential release of smaller molecules. Originally introduced to overcome limitations for drug delivery, self-immolative spacers have gained wide interest in medicinal chemistry, analytical chemistry, and material science. For most applications, the kinetics of the disassembly of the activated self-immolative spacer governs functional properties. This Review addresses kinetic aspects of self-immolation. It provides information for selecting a particular self-immolative motif for a specific demand. Moreover, it should help researchers design kinetic experiments and fully exploit the rich perspectives of self-immolative spacers.

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Section: Aromatic Corementioning

confidence: 98%

Section: Aromatic Corementioning

confidence: 98%

Self‐Immolative Spacers: Kinetic Aspects, Structure–Property Relationships, and Applications

et al. 2015

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“…We have shown that the pyridinone-methide elimination can take place in a pyridine-based linker in a manner analogous to that from a benzene-based system. 33 Dendron 8 was composed with two reporter units attached to a pyridine core and phenylacetamide group as a triggering substrate (Figure 9). The dendron releases phenolate 8a upon reaction with the enzyme PGA.…”

Section: ■ the Pyridinone-methide Eliminationmentioning

confidence: 99%

Quinone-Methide Species, A Gateway to Functional Molecular Systems: From Self-Immolative Dendrimers to Long-Wavelength Fluorescent Dyes

2014

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Over the last 30 years, the quinone-methide elimination has served as a valuable tool for achieving various important molecular functions. Molecular adaptors based on quinone-methide or aza-quinone-methide reactivity have been designed, synthesized, and used in diagnostic probes, molecular amplifiers, drug delivery systems, and self-immolative dendritic/polymeric molecular systems. These unique adaptors function as stable spacers between an enzyme- or reagent-responsive group and a reporter moiety and can undergo 1,4-, 1,6-, or 1,8-type elimination reactions upon cleavage of the triggering group. Such reactivity results in the release of the reporter group through formation of a quinone-methide species. This type of elimination was applied to design distinct molecular adaptors capable of multiple quinone-methide eliminations. Using this chemistry, we have developed unique molecular structures that are known today as self-immolative dendrimers. These dendrimers disassemble upon a single triggering event in a domino-like manner from the focal point to their periphery with the consequent release of multiple end-groups. Such molecular structures are used in self-immolative dendritic prodrugs and in diagnostic probes to obtain a significant amplification effect. To further enhance amplification, we have developed the dendritic chain reaction, which uses simple molecules to achieve functionality of high-generation virtual self-immolative dendrimers. In addition, we harnessed the quinone-methide elimination reactivity to design polymers that disassemble from head-to-tail initiated by an analyte-responsive event. Following this example, other chemical reactivities were demonstrated by scientists to design such polymeric molecules. In a manner analogous to the quinone-methide elimination, electron rearrangement can lead to formation of conjugated quinone-methide-type dyes with long-wavelength emission of fluorescence. We have recently applied an intramolecular charge transfer to form a unique kind of quinone-methide type derivative based on a donor-two-acceptors molecular structure. This intramolecular charge transfer produces a new fluorochrome with an extended conjugation of π-electron system that is used for the design of long-wavelength fluorogenic probes with a turn-ON option. The rapidly expanding use of quinone-methide species, reflected in the increased number of examples reported in the literature, indicates the importance of this tool in chemistry. These species provide a useful gateway to functional molecular structures with distinct reactivities and spectroscopic characteristics.

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“…Apart from PABA, some analogs, such as ortho ‐aminobenzyl alcohol (OABA), (5‐aminopyridin‐2‐yl)methanol, and (3‐aminopyridin‐2‐yl)methanol, are also acceptable self‐immolative linkers. Because of the lightweight structural variation among these linkers, the spontaneous decomposition rate are varied: (5‐aminopyridin‐2‐yl)methanol > PABA, (3‐aminopyridin‐2‐yl)methanol > OABA, and PABA > OABA . There are other linkers that combine the function of PABA and OABA, the self‐immolative dendrimers .…”

Section: Activable Probesmentioning

confidence: 99%

“…Because of the lightweight structural variation among these linkers, the spontaneous decomposition rate are varied: (5-aminopyridin-2-yl)methanol > PABA, (3-aminopyridin-2-yl)methanol > OABA, and PABA > OABA. 54,57 There are other linkers that combine the function of PABA and OABA, the self-immolative dendrimers. 65,66 This type of probe can usually connect one substrate with two or three reporters.…”

Section: B Substrate-self-immolative Linker-fluorophore Probesmentioning

confidence: 99%

Strategies in the Design of Small‐Molecule Fluorescent Probes for Peptidases

Chen

et al. 2014

Medicinal Research Reviews

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Peptidases, which can cleave specific peptide bonds in innumerable categories of substrates, usually present pivotal positions in protein activation, cell signaling and regulation as well as in the origination of amino acids for protein generation or application in other metabolic pathways. They are also involved in many pathological conditions, such as cancer, atherosclerosis, arthritis, and neurodegenerative disorders. This review article aims to conduct a wide-ranging survey on the development of small-molecule fluorescent probes for peptidases, as well as to realize the state of the art in the tailor-made probes for diverse types of peptidases.

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The pyridinone-methide elimination

Cited by 26 publications

References 18 publications

Self‐Immolative Spacers: Kinetic Aspects, Structure–Property Relationships, and Applications

Self‐Immolative Spacers: Kinetic Aspects, Structure–Property Relationships, and Applications

Quinone-Methide Species, A Gateway to Functional Molecular Systems: From Self-Immolative Dendrimers to Long-Wavelength Fluorescent Dyes

Strategies in the Design of Small‐Molecule Fluorescent Probes for Peptidases

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