13717-93-6

Upstream product

• 1448811-54-8 3,6-diisopropyl-1,4-ditosyl-1,4-dihydro-1,2,4,5-tetrazine 
• 78-82-0 Isobutyronitrile 
• 56873-77-9 3,6-diisopropyl-1,2⁽⁴⁾-dihydro-[1,2,4,5]tetrazine 

Relevant academic research and scientific papers

Bio-orthogonal click-and-release donation of caged carbonyl sulfide (COS) and hydrogen sulfide (H2S)

Hydrogen sulfide (H2S) is an important biomolecule with high therapeutic potential. Here we leverage the inverse-electron demand Diels-Alder (IEDDA) click reaction between a thiocarbamate-functionalized trans-cyclooctene and a tetrazine to deliver carbonyl sulfide (COS), which is quickly converted to H2S by the uniquitous enzyme carbonic anhydrase (CA), thus providing a new strategy for bio-orthogonal COS/H2S donation.

Switchable Fluorescence of Doxorubicin for Label-Free Imaging of Bioorthogonal Drug Release

Monitoring the release and activation of prodrug formulations provides essential information about the outcome of a therapy. While the prodrug delivery can be confirmed by using different imaging techniques, confirming the release of active payload by using imaging is a challenge. Here, we have discovered that the switchable fluorescence of doxorubicin can validate drug release upon its uncaging reaction with a highly specific chemical partner. We have observed that the conjugation of doxorubicin with a trans-cyclooctene (TCO) diminishes its fluorescence at 595 nm. This quenched fluorescence of the doxorubicin prodrug is recovered upon its bond-cleaving reaction with tetrazine. Clinically assessed iron oxide nanoparticles were used to formulate a doxorubicin nanodrug. The release of doxorubicin from the nanodrug was studied under various experimental conditions. A fivefold increase in doxorubicin fluorescence is observed after complete release. The studies were carried out in vitro in MDA-MB-231 breast cancer cells. An increase in Dox signal was observed upon tetrazine administration. This switchable fluorescence mechanism of Dox could be employed for fundamental studies, that is, the reactivity of various tetrazine and TCO linker types under different experimental conditions. In addition, the system could be instrumental for translational research where the release and activation of doxorubicin prodrug payloads can be monitored by using optical imaging systems.

Catalyst-free photooxidation reaction from 1,4-dihydropyridazine to pyridazine under air

In the inverse electron-demand Diels–Alder (iEDDA) reactions between tetrazines and strained alkenes, a mixture of 1,4-dihydropyridazine isomers are formed first, and they are then oxidized to pyridazines. Although the products of these related oxidation processes converge as pyridazines, the oxidation rate is quite low with some substrates. In this study, we revealed that 1,4-dihydropyridazines formed in the iEDDA reactions were oxidized to pyridazines by simply irradiating with an ultraviolet light under an air atmosphere. Our experimental results implied that singlet oxygen was formed in the course of the reactions to oxidize the 1,4-dihydropyridazine molecules.

CHANNEL PROTEIN ACTIVATABLE LIPOSOMES

Disclosed is a liposome, comprising a lipid bilayer enclosing a cavity, wherein the bilayer comprises a channel protein releasably linked to an eight-membered non-aromatic cyclic alkenylene group, preferably a cyclooctene group, and more preferably a trans-cyclooctene group. The liposomes are used in a kit comprising the liposome, the liposomal membrane of which comprises a channel protein linked to a Trigger, and an Activator for the Trigger, wherein the Trigger comprises the eight- membered non-aromatic cyclic alkenylene group, and the Activator comprises a diene.

CHEMICALLY CLEAVABLE GROUP

Disclosed is the use of the reactive components of the inverse electron-demand Diels Alder reaction for chemical masking and unmasking in vitro. This can be applied in complex chemical reactions and, particularly in the synthesis of biomolecules, e.g. on solid supports. The reactice components are a dienophile, particularly a trans-cyclooctene, and a diene, particularly a tetrazine.

ACTIVATABLE LIPOSOMES

Disclosed are reactive liposome, comprising a lipid bilayer enclosing a cavity, wherein the bilayer comprises a linkage to an eight-membered non-aromatic cyclic alkenylene group, preferably a cyclooctene group, and more preferably a trans-cyclooctene group. The liposomes are use in a kit comprising the liposome linked, directly or indirectly, to a Trigger, and an Activator for the Trigger, wherein the Trigger comprises an eight-membered non-aromatic cyclic alkenylene group, and the Activator comprises a diene.

BIO-ORTHOGONAL DRUG ACTIVATION

Disclosed is a kit for the administration and activation of a Prodrug. The kit comprises a Masking Moiety linked, directly or indirectly, to a Trigger moiety, which in turn is linked to a Drug, and an Activator for the Trigger moiety. The Trigger moiety comprises a dienophile and the Activator comprises a diene, whereby the dienophile is an eight-membered non- aromatic cyclic alkenylene group, preferably a cyclooctene group, and more preferably a trans-cyclooctene group. The Trigger and the Activator undergo a fast, bio-orthogonal reaction resulting in the release of the Masking Moiety, and activation of the drug.

Novel synthesis of 3,6-disubstituted-1,2,4,5-tetrazine derivatives from hydrazones by using [hydroxyl(tosyloxy)iodo]benzene

A mild and efficient protocol for the construction of 1,4-dihydro-3,6- disubstituted-1,4-bis(p-toluenesulfonyl)-1,2,4,5-tetrazines from p-toluenesulfonyl hydrazones mediated by [hydroxyl(tosyloxy)iodo]benzene in the presence of pyridine has been developed. This protocol affords the products in good to excellent yields. The corresponding 3,6-disubstituted-1,2,4,5-tetrazines can be easily obtained through one-step N-deprotection of p-toluensulfonyl groups and aromatization by tetrabutyl ammonium fluoride in THF. A mechanism has been proposed.