Reaktivität einfacher offenkettiger und cyclischer dienophile bei Diels-Alder-reaktionen mit inversem elektronenbedarf

Thalhammer, Franz; Wallfahrer, Uwe; Sauer, Jürgen

doi:10.1016/s0040-4039(00)97188-0

Cited by 181 publications

(177 citation statements)

References 8 publications

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“…As expected, dienophiles with different structures and steric deand phenylacetylenes [ Table 6: 43 (ρ ϭ Ϫ0.67), 7 (ρ ϭ Ϫ0.58)] are used as dienophiles. For styrene and phenyl-mands have poorer correlation coefficients, while the comparison of dienophiles with similar steric properties leads acetylene the highly negative values for the activation entropy ∆S ϭ Ϫ42 and ∆S ϭ Ϫ31 (cal mol Ϫ1 K Ϫ1 ) are to quite satisfying r values: (a) Figure 2 presents a comparison of all dienophiles included in this study for dimethyl also in agreement with a highly ordered rate-determining 1,2,4,5-tetrazine-3,6-dicarboxylate (1, R ϭ CO 2 CH 3 ) and studies [1,13,16] . Predictions can thus be made for the reactivity of systems not yet studied kinetically, which may be of 1,2,4,5-tetrazine (2).…”

Section: Preparative Resultssupporting

confidence: 59%

1,2,4,5-Tetrazine: Synthesis and Reactivity in [4+2] Cycloadditions

Sauer¹,

et al. 1998

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Full details on the reactivity of the title compound as 4π component in inverse‐type Diels–Alder reactions, including kinetic data, are reported. Donor‐substituted alkynes, alkenes, donor‐substituted and unsubstituted cycloalkenes, ketene acetals and aminals, as well as several cyclic enol ethers were used as dienophiles in these investigations. A number of 4‐mono‐ and 4,5‐disubstituted pyridazines can easily be obtained by this method.

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Section: Preparative Resultssupporting

confidence: 59%

1,2,4,5-Tetrazine: Synthesis and Reactivity in [4+2] Cycloadditions

Sauer¹,

et al. 1998

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“…11 These IEDDA reactions have second-order rate constants ranging from k 2 = 10 3 –10 6 M −1 s −1 , which are primarily driven by expulsion of N 2 and TCO strain relief following the cycloaddition 12,13 Furthermore, electron withdrawing substituents attached to the tetrazine confer increased reaction rates between the dienophile and diene. 14,15 Successful pretargeted in vivo nuclear imaging has been demonstrated in preclinical models using PET isotopes, including 11 C (t 1/2 20.3 minutes), 16,17 18 F (t 1/2 110 minutes) 18–20 and 64 Cu (t 1/2 12.7 hours), 4,21–24 as well as SPECT isotopes including 99m Tc (t 1/2 6 hours), 25–27 111 In (t 1/2 2.8 days) 28–30 and 177 Lu (t 1/2 6.7 days).…”

Section: Introductionmentioning

confidence: 99%

Site-specific conjugation allows modulation of click reaction stoichiometry for pretargeted SPECT imaging

Mandikian¹,

Rafidi²,

Adhikari³

et al. 2018

mAbs

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Antibody pretargeting is a promising strategy for improving molecular imaging, wherein the separation in time of antibody targeting and radiolabeling can lead to rapid attainment of high contrast, potentially increased sensitivity, and reduced patient radiation exposure. The inverse electron demand Diels-Alder ‘click’ reaction between trans-cyclooctene (TCO) conjugated antibodies and radiolabeled tetrazines presents an ideal platform for pretargeted imaging due to rapid reaction kinetics, bioorthogonality, and potential for optimization of both slow and fast clearing components. Herein, we evaluated a series of anti-human epidermal growth factor receptor 2 (HER2) pretargeting antibodies containing distinct molar ratios of site-specifically incorporated TCO. The effect of stoichiometry on tissue distribution was assessed for pretargeting TCO-modified antibodies (monitored by 125I) and subsequent accumulation of an 111In-labeled tetrazine in a therapeutically relevant HER2+tumor-bearing mouse model. Single photon emission computed tomography (SPECT) imaging was also employed to assess tumor imaging at various TCO-to-monoclonal antibody (mAb) ratios. Increasing TCO-to-mAb molar ratios correlated with increased in vivo click reaction efficiency evident by increased tumor distribution and systemic exposure of 111In-labeled tetrazines. The pharmacokinetics of TCO-modified antibodies did not vary with stoichiometry. Pretargeted SPECT imaging of HER2-expressing tumors using 111In-labeled tetrazine demonstrated robust click reaction with circulating antibody at ~2 hours and good tumor delineation for both the 2 and 6 TCO-to-mAb ratio variants at 24 hours, consistent with a limited cell-surface pool of pretargeted antibody and benefit from further distribution and internalization. To our knowledge, this represents the first reported systematic analysis of how pretargeted imaging is affected solely by variation in click reaction stoichiometry through site-specific conjugation chemistry.

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“…环 DOI: 10.6023/A13121206 戊二烯或 1,3-丁二烯与烯烃的反应是理论上研究 Diels-Alder 反应机理的典型例子, 此类反应一般只有一个过渡态, 即协同反应机理 [9 ～ 16] . 而对于四嗪参与的 Diels-Alder 反应研究不多 [9,17] , 文献中有关生物分子结合自由能的计算多采用分子动力学模拟方法得到…”

Section: 引言unclassified

“…a The reaction numbering system given in Figure 1; b Output from Gaussian program, 101 kPa, 293 K; c Calculated from free volume for 1 M and 293 K [24] ; d Calculated from experimental rate constants [17] . au), 并且 M062x 计算得到的稳定化焓在 293 K 下为 -5.9 kcal/mol, 溶液中稳定化自由能为-2.4 kcal/mol, 这就意味着这种络合物是稳定的, 很显然这种结果是很难令人信服的.…”

Section: Reaction Bmentioning

confidence: 99%