Alkoxypsoralens, Novel Nonpeptide Blockers of Shaker-Type K⁺ Channels:  Synthesis and Photoreactivity

Abstract

A series of psoralens and structurally related 5,7-disubstituted coumarins was synthesized and investigated for their K+ channel blocking activity as well as for their phototoxicity to Artemia salina and their ability to generate singlet oxygen and to photomodify DNA. After screening the compounds on Ranvier nodes of the toad Xenopus laevis, the affinities of the most promising compounds, which proved to be psoralens bearing alkoxy substituents in the 5-position or alkoxymethyl substituents in the neighboring 4- or 4'-position, to a number of homomeric K+ channels were characterized. All compounds exhibited the highest affinity to Kv1.2. 5,8-Diethoxypsoralen (10d) was found to be an equally potent inhibitor of Kv1.2 and Kv1.3, while lacking the phototoxicity normally inherent in psoralens. The reported compounds represent a novel series of nonpeptide blockers of Shaker-type K+ channels that could be further developed into selective inhibitors of Kv1.2 or Kv1. 3.

Synthesis and biological evaluation of fused oxepinocoumarins as free radicals scavengers

“…From the RCM of 5b with the catalyst 6 (0.9 mol%, added at once) in dichloromethane solution under stirring at room temperature, the dihydrooxepin derivative 7b was obtained in 90% yield. The same reaction was performed in refluxing dichloromethane (10 mol% of catalyst), and the product 7b was received in 33% yield along with a pyrano [7,8]coumarin derivative (24%) 27 . The 6-allyl-7-hydroxycoumarin (4) (isolated 45 also from the mixture of the Claisen rearrangement reaction of 2a) allylated with allyl bromide and gave the 6-allyl-7-(allyloxy) coumarin (8) (91%).…”

“…In particular, coumarins fused with a ring containing an O-atom such as furocoumarins and pyranocoumarins are important as photochemotherapeutic [4][5][6][7][8][9][10] agents and exhibit antitumorial 11 , antifungal 12 , insecticidal 12 , anticancer 12 , anti-HIV 6,13 , anti-inflammatory 3,14 , and antioxidant 3,14 activities. The synthesis of those coumarins has been achieved mainly by formation of furan or pyran ring starting from hydroxycoumarins and using the tandem Claisen rearrangement-cyclization reaction 15,16 of the intermediate propargyloxy-or allyloxycoumarins [17][18][19][20][21] .…”

“…With this method, oxepines 25,27,[31][32][33][34] , oxocines 25,27,34,35 , or larger O-containing rings 25,[36][37][38] have also been prepared. In the course of our interest on the synthesis 21,39 of coumarin derivatives and the study 3,14,40,41 of their biological activities and in continuation to our previous work on RCM 37,42 , we wish to report here the synthesis of [6,5]-, [7,6]-, [7,8]-and [8,7]-fused oxepinocoumarins through the combination of Claisen rearrangement, allylation, and RCM starting from allyloxycoumarins.…”

Trichlorotriazine as a Simple and Efficient Catalyst Promoter for the Synthesis of New Generation of Coumarins

“…Coumarins are well known natural products for their diverse biological activity such as photosensitizes 1 …”

Isoquinoline-catalyzed reaction between 4-hydroxycoumarin or 4-hydroxy-6-methylpyran-1-one and dialkyl acetylene dicarboxylates: synthesis of coumarin and pyranopyrane derivatives

“…Given the development of coumarins as photosensitizers, 1 anti-HIV agents, 2 antibiotics, 3 rodenticides, and oral anticoagulants, 4 there is continuing interest in the synthesis of these materials.…”