Novel valdecoxib derivatives by ruthenium(ii)-promoted 1,3-dipolar cycloaddition of nitrile oxides with alkynes – synthesis and COX-2 inhibition activity†,RSC Medicinal Chemistry

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Novel valdecoxib derivatives by ruthenium(ii)-promoted 1,3-dipolar cycloaddition of nitrile oxides with alkynes – synthesis and COX-2 inhibition activity†
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2018-02-13 00:00:00 , DOI: 10.1039/c7md00575j
Silvia Roscales _{1,

2,

3,

4,

5} , Nicole Bechmann _{1,

2,

3,

4,

5} , Daniel Holger Weiss _{5,

6,

7,

8,

9} , Martin Köckerling _{5,

6,

7,

8,

9} , Jens Pietzsch _{1,

2,

3,

4,

5} , Torsten Kniess _{1,

2,

3,

4,

5}

Affiliation

Novel valdecoxib-based cyclooxygenase-2 inhibitors were synthesized in one step via 1,3-dipolar cycloaddition of nitrile oxides with a series of eleven aryl alkynes, six of them described for the first time. Application of Ru(II)-catalysis leads preferably to the formation of the 3,4-diaryl-substituted isoxazoles, while under thermal heating with base the 3,5-diaryl substitution pattern is favoured. The new the 3,4-diaryl-substituted isoxazoles possessing a small substituent (H and Me) displayed high COX-2 inhibition affinity (IC₅₀ = 0.042–0.073 μM) and excellent selectivity (COX-2 SI > 2000). In contrast, the 3,5-diaryl substituted compounds displayed almost no COX activity. The introduction of a 4-fluorophenyl substituent resulted in retained high COX-2 affinity, making these compounds together with the feasible one step reaction promising candidates for the development of fluorine-18 labelled radiotracers.

中文翻译：

钌（ii）促进的带有炔烃的腈类氧化物的新型瓦尔德考昔衍生物的合成（1,3-偶极环加成反应）–合成和COX-2抑制活性†

通过将腈与一系列十一个芳基炔烃进行1,3-偶极环加成反应，一步合成了一种新的基于valdecoxib的环氧合酶-2抑制剂，其中六个首次被描述。Ru（II）催化的应用优选导致3，4-二芳基取代的异恶唑的形成，而在与碱一起热加热下，有利于3，5-二芳基取代的模式。具有小的取代基（H和Me）的新的3,4-二芳基取代的异恶唑显示出高的COX-2抑制亲和力（IC ₅₀= 0.042–0.073μM）和优异的选择性（COX-2 SI> 2000）。相反，3，5-二芳基取代的化合物几乎没有表现出COX活性。4-氟苯基取代基的引入导致保留了较高的COX-2亲和力，使这些化合物与可行的一步反应一起有望成为开发氟18标记的放射性示踪剂的候选物。

更新日期：2018-02-13

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