Aqueous-Phase Deactivation and Intramolecular [2 + 2 + 2] Cycloaddition of Oxanorbornadiene Esters

Kislukhin, Alexander A.; Higginson, Cody J.; Finn, M. G.

doi:10.1021/ol103153f

Cited by 15 publications

(20 citation statements)

References 25 publications

(52 reference statements)

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“…This is consistent with the known rapid nature of cycloreversion of similar adducts, particularly under mass spectrometry conditions. 12,33 Conversely, intact RSA- 1b conjugates at Cys-34 were observed in abundance, highlighting the greater stability of these adducts. 11 Adducts of 3 with Cys-34 were identified as the hydrolyzed succinimide (Supporting Information).…”

Section: Resultsmentioning

confidence: 99%

Albumin-Oxanorbornadiene Conjugates Formed ex Vivo for the Extended Circulation of Hydrophilic Cargo

et al. 2016

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Oxanorbornadiene dicarboxylate (OND) reagents were explored for the purpose of binding and releasing chemical cargos from endogenous circulating serum albumins. ONDs bearing gadolinium chelates as model cargos exhibited variable conjugation efficiencies with albumin in rat subjects that are consistent with the observed reactivity of each linker and their observed stability toward serum hydrolases in vitro. The terminal elimination rate from circulation was dependent on the identity of the OND used, and increased circulation time of gadolinium cargo was achieved for linkers bearing electrophilic fragments designed to react with cysteine-34 of circulating serum albumin. This binding of and release from endogenous albumin highlights the potential of OND linkers in the context of optimizing the pharmacokinetic parameters of drugs or diagnostic agents.

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Section: Resultsmentioning

confidence: 99%

Albumin-Oxanorbornadiene Conjugates Formed ex Vivo for the Extended Circulation of Hydrophilic Cargo

et al. 2016

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“…Despite their strongly electrophilic nature, dialkyl OND esters were found to be very stable in aqueous solutions, with the exception of dipropargyl esters that undergo intramolecular [2+2+2] cycloaddition. 9 …”

Section: Resultsmentioning

confidence: 99%

“…10–100 M -1 s -1 with glutathione, pH 7), while their aqueous stability generally exceeds that of the maleimides. 8-9 OND–thiol adducts 2 were found to undergo retro-Diels–Alder (rDA) fragmentation, giving furans 3 and thiomaleates 4 , whereas the rDA cleavage of the starting OND fragment is completely absent under the same conditions. 9 Thus, thiol addition constitutes a trigger for cleavage if the OND moiety bridges the carrier and the cargo.…”

Section: Introductionmentioning

confidence: 99%

“…8-9 OND–thiol adducts 2 were found to undergo retro-Diels–Alder (rDA) fragmentation, giving furans 3 and thiomaleates 4 , whereas the rDA cleavage of the starting OND fragment is completely absent under the same conditions. 9 Thus, thiol addition constitutes a trigger for cleavage if the OND moiety bridges the carrier and the cargo. In our initial report, we noted a wide range of stabilities of different versions of 2 with changes in substitution pattern.…”

Section: Introductionmentioning

confidence: 99%

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Degradable Conjugates from Oxanorbornadiene Reagents

et al. 2012

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Oxanorbornadienedicarboxylate (OND) reagents were explored for purposes of binding and releasing drugs from serum albumins as representative macromolecular carriers. Being highly reactive Michael acceptors, ONDs form adducts with thiols and amines, which then undergo retro-Diels–Alder fragmentation. The study of more than 30 model adducts revealed a number of modifications that can be used to influence adduct stability. For the most reactive OND linkers, the labeling of the single available bovine serum albumin (BSA) cysteine residue was complete within minutes at mid-micromolar concentration of reactants. While a selectivity of greater than 1000-fold for thiol over amine was observed with model amino acids, the labeling of protein amines with ONDs is fast enough to be practical, as demonstrated by reaction with thiol-depleted BSA. The OND–amine adducts were found to be up to 15 times more stable than OND–thiol adducts, and to be sensitive to acid by virtue of a stereochemically-dependent acceleration of cycloreversion. The release rate of fluorescent cargo from serum albumins was tuned by selecting the coupling partners: the available half-lives ranged from 40 minutes to 7 days at 37 °C. Such versatility of release profiles from protein carriers, controlled by the nature of the OND linkage, is a useful addition to the drug delivery toolbox.

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“…Another alternative to maleimides are electron-deficient oxanorbornadienes (entry 10), which display thiol addition rates similar to those of maleimides, but have greater aqueous stability (Hong et al, 2009a; Kislukhin et al, 2011; Kislukhin et al, 2012). An additional fragmentation feature of this linkage is discussed at the end of this article.…”

Section: B Bioorthogonal Conjugation Strategies and Applicationsmentioning

confidence: 99%

Click Chemistry in Complex Mixtures: Bioorthogonal Bioconjugation

McKay

Finn

2014

Chemistry & Biology

643

555

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The selective chemical modification of biological molecules drives a good portion of modern drug development and fundamental biological research. While a few early examples of reactions that engage amine and thiol groups on proteins helped establish the value of such processes, the development of reactions that avoid most biological molecules so as to achieve selectivity in desired bond-forming events has revolutionized the field. We provide an update on recent developments in bioorthogonal chemistry that highlights key advances in reaction rates, biocompatibility, and applications. While not exhaustive, we hope this summary allows the reader to appreciate the rich continuing development of good chemistry that operates in the biological setting.

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Aqueous-Phase Deactivation and Intramolecular [2 + 2 + 2] Cycloaddition of Oxanorbornadiene Esters

Abstract: Both inter- and intramolecular degradation pathways were identified for the aqueous phase deactivation of oxanorbornadiene (OND) electrophiles, and propargylic OND esters were found to undergo facile intramolecular [2+2+2] homo-Diels–Alder cycloaddition in polar media.

Cited by 15 publications

References 25 publications

Albumin-Oxanorbornadiene Conjugates Formed ex Vivo for the Extended Circulation of Hydrophilic Cargo

Albumin-Oxanorbornadiene Conjugates Formed ex Vivo for the Extended Circulation of Hydrophilic Cargo

Degradable Conjugates from Oxanorbornadiene Reagents

Click Chemistry in Complex Mixtures: Bioorthogonal Bioconjugation

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