The Emerging Role of Tetrazines in Drug-Activation Chemistries

Traditionally, prodrug activation has been limited to enzymatic triggers or gross physiological aberrations, such as pH, that offer low selectivity and control over dosage. In recent years, the field of prodrug activation chemistry has been transformed by the use of bioorthogonal reactions that can be carried out under biological conditions at sub-millimolar concentrations, with the tetrazine-mediated inverse electron demand Diels–Alder reaction amongst the most recognised. Their high reaction rates, chemoselectivity and excellent biocompatibility make tetrazines ideal small molecules for activating prodrugs. Recently the tetrazine moiety has been used as a prodrug for a pyridazine thus broadening the scope of prodrug systems. This article discusses the concept of using tetrazines as small-molecule activators for prodrugs, and provides an overview of tetrazine-based prodrug systems, with a particular focus on the recently reported prodrug–prodrug activation strategy.     

四嗪类高氮分子及离子含能化合物的研究进展

详细论述了近年来国内外报道的四嗪类高氮分子及离子含能化合物的合成与性能研究,指出部分化合物由于其生成焓高、热稳定性好以及感度低等特点在含能材料领域具有广泛的应用前景.同时还总结了目前四嗪类含能化合物普遍存在的问题及以后的发展方向.     

3,6-二肼基-1,2,4,5-四嗪及其盐的合成与表征

以三氨基胍盐酸盐和2,4-戊二酮为原材料,通过成环反应,氧化脱氢,肼基取代,三步合成了3,6-二肼基-1,2,4,5-四嗪,同时,对3,6-二肼基-1,2,4,5-四嗪的含能盐的合成进行了研究。对文献报道的反应路线进行了适当的放大研究。通过红外光谱分析、元素分析、质谱分析和1HNMR等方法对产物的结构特征进行了鉴定。     

Coordination‐Assisted Bioorthogonal Chemistry: Orthogonal Tetrazine Ligation with Vinylboronic Acid and a Strained Alkene

Bioorthogonal chemistry can be used for the selective modification of biomolecules without interfering with any other functionality that might be present. Recent developments in the field include orthogonal bioorthogonal reactions to modify multiple biomolecules simultaneously. During our research, we observed that the reaction rates for the bioorthogonal inverse‐electron‐demand Diels–Alder (iEDDA) reactions between nonstrained vinylboronic acids (VBAs) and dipyridyl‐s‐tetrazines were exceptionally higher than those between VBAs and tetrazines bearing a methyl or phenyl substituent. As VBAs are mild Lewis acids, we hypothesised that coordination of the pyridyl nitrogen atom to the boronic acid promoted tetrazine ligation. Herein, we explore the molecular basis and scope of VBA–tetrazine ligation in more detail and benefit from its unique reactivity in the simultaneous orthogonal tetrazine labelling of two proteins modified with VBA and norbornene, a widely used strained alkene. We further show that the two orthogonal iEDDA reactions can be performed in living cells by labelling the proteasome by using a nonselective probe equipped with a VBA and a subunit‐selective VBA bearing a norbornene moiety.     

国外四嗪四唑类高氮含能材料研究进展

对国外正在研究的四嗪、四唑类高氮含能材料进行了综述,介绍了部分四嗪、四唑类高氮化合物及其衍生物的合成、理化性质和应用前景,对国外研究的3,6-二肼基-1,2,4,5-四嗪(DHT)、3,3′-偶氮(6-氨基-1,2,4,5-四嗪)(DAAT)、3,6-双(1氢-1,2,3,4-四唑-5-氨基)-1,2,4,5-四嗪(BTATz)、联四唑(BHT)等进行了重点描述。     

Synthesis of high metal‐complexation linear elastomers containing sym‐1,2,4,5‐tetrazine rings

We report the synthesis of polyurethane‐urea elastomers containing 1,2,4,5‐tetrazine covalently reacted within the main chains of the polymers. Our study investigates the synthesis of 3,6‐diamino‐1,2,4,5‐tetrazine (DAT), the polymerization reaction conditions for reacting DAT into the backbone of segmented polyurethane elastomers, and the metal‐complexation capabilities of tetrazine‐containing elastomers with cobalt (II) chloride. Tetrazines are highly colored and electro‐active heterocyclic moieties, which have a very high electron affinity which make them reducible at high to very high potentials. Upon complexation with metals, we observed a strong color shift of the polymers from deep red to blue indicating the binding efficacy for the polymers. We quantified the metal‐complexation capability of the tetrazine elastomers and determined a molar ratio of approximately two metal atoms per tetrazine allowing us to provide a plausible complexation mechanism for the active polymers. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Two-component,one-pot synthesis of pyrimido[1,2-b] [1,2,4,5]tetrazines

Derivatives containing the cyclohepta4′,5′thieno[2′,3′:4,5]pyrimido[1,2-b][1,2,4,5]-tetrazin-6-one system were prepared from the reaction of 3-amino-2-thioxo-1,2,3,5,6,7,8,9-octahydro-4H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-one (5) or its 2-methylthio derivative 6 with hydrazonoyl chlorides 9. The mechanism of the studied reactions has been discussed and the biological activity of the isolated products has been evaluated.     

Are DTTO and iso‐DTTO Worthwhile Targets for Synthesis?

Theoretical calculations were carried out for the isomeric di‐1,2,3,4‐tetrazine tetraoxides (DTTO and iso‐DTTO). The most important explosion performance parameters, the detonation pressure and detonation velocity, are dominated by the densities and not by the heats of formation of these compounds. Since DTTO and iso‐DTTO are unknown, reliable predictions of their crystal densities are crucial for an evaluation of the potential of these materials as explosives. In this study, the crystal densities were predicted using both Ammon’s Atom/Functional Group and Atom Code Volume Additivity Parameters and Quantum Mechanical molecular Volume methods, resulting in similar densities and explosion parameters. Although the likely uncertainties in our predicted density values are difficult to assess due to a lack of experimental data for closely related known compounds, our results demonstrate that Shechter’s originally proposed densities and performance parameters were grossly overestimated. Furthermore, it is shown that, based on our predicted density value ranges, DTTO and iso‐DTTO could match or substantially outperform the best state of the art explosives, such as CL‐20. Therefore, the synthesis of DTTO and iso‐DTTO should be further pursued.     

四嗪衍生物的合成及其抗癌性能的研究Ⅱ.钯/碳催化氧化合成3,6-二甲基-1,6-二氢-1,2,4,5-四嗪

研究了合成标题化合物时各种因素对产率的影响,发现用三聚乙醛解聚制备的新鲜乙醛为原料,是至关重要的。乙醛与水合肼反应温度为５～１０℃,六氢四嗪氧化脱氢时间７２ｈ,并以３％Ｐｄ／Ｃ取代ＰｔＯ２作催化剂,产率４０％。     

Tetrazine‐Responsive Self‐immolative Linkers

Molecules that undergo activation or modulation following the addition of benign external small‐molecule chemical stimuli have numerous applications. Here, we report the highly efficient “decaging” of a variety of moieties by activation of a “self‐immolative” linker, by application of water‐soluble and stable tetrazine, including the controlled delivery of doxorubicin in a cellular context.