Synthesis and anticancer activity novel dimeric azatriperoxides

Abstract

An efficient method was developed for the synthesis of tetra(spirocycloalkane)-substituted a,udi (1,2,4,5,7,8-hexaoxa-10-azacycloundecan-10-yl)alkanes by a ring transformation reaction of 3,6di(spirocycloalkane)-substituted 1,2,4,5,7,8,10-heptaoxacycloundecanes with a,u-alkanediamines (1,4butane-, 1,5-pentane-, 1,7-heptane-, 1,8-octane-and 1,10-decanediamines) catalyzed by Sm(NO 3 ) 3 /g-Al 2 O 3 . Using flow cytometry, it was shown for the first time that synthesized dimeric azatriperoxides are efficient apoptosis inducers with Jurkat, K562, U937, and Hek296.Scheme 1 Synthesis of a,u-bis-(1,2,4,5,7,8-hexaoxa-10-azacycloundecan-10-yl)alkanes.

First Example of Catalytic Synthesis of Cyclic S-Containing Di- and Triperoxides

“…We assumed that cyclic thia-diperoxides may be synthesized by a reaction of pentaoxacanes with hydrogen sulfide in a similar manner to what we reported previously for the synthesis of cyclic aza-diperoxides via the reaction of pentaoxacanes with primary amines [46,47,50]. Preliminary experiments demonstrated that 7,8,10,12,13-pentaoxaspiro [5.7]tridecane [51] (1) reacts with H2S in the presence of the catalyst Sm(NO3)3·6H2O [46][47][48][49][50] for 6 h at room temperature in tetrahydrofuran (THF) solvent to produce 7,8,12,13-tetraoxa-10-thiaspiro [5.7]tridecane (8) in 98% yield. The reaction does not proceed in the absence of a catalyst (Scheme 1).…”

“…We developed a method for the preparation of thioperoxycarbocycles through the recyclization of pentaoxacanes and heptaoxadispiroalkanes with hydrogen sulfide under the action of lanthanide catalysts. We chose lanthanide catalysts due to their high activity in recyclization reactions involving primary amines, leading to cyclic N-containing diand triperoxides [46][47][48][49][50].…”

“…These signals reflect the process of cyclic interconversion in solution; therefore, we observed a set of signals with close chemical shifts for each of the individual compounds. The effect of the splitting of the NMR signals of the ring atoms is due to the presence of a multicomponent conformational equilibrium at room temperature, which can be assumed on the basis of published data on the identification of known heteroatom-containing peroxides, in particular azadi-and triperoxides [46][47][48][49][50]. The presence of one conformation was observed only in the case of 3-(adamantyl-2-yl)-1,2,4,5,7-tetraaoxatiocane (14), probably due to the rigidity of the structure of the spiroadamantane substituent.…”

Catalyzed ring transformation of cyclic N-aryl-azadiperoxides with participation of α,ω-dithiols

“…Recently, [5][6][7][8][9][10] nitrogen-and sulfur-containing cyclic di-and triperoxides with antitumor activity have been synthesized. [5][6][7][8][9] The development of efficient methods for the preparation of new cyclic hetero-di(tri)peroxides [5][6][7][8][9][10] promotes active investigation of their transformations. It was shown that the reduction of silatriperoxycycloalkanes with PPh 3 affords siladiperoxycycloalkanes; 11 the reaction of spiro{adamantane-[2,3 0 ]-(pentaoxacane)} with o-phenylenediamine results in the synthesis of benzodioxazocine.…”

“…5 The implemented conversion of pentaoxacane with o-phenylenediamine to benzodioxazocine 5 suggests that cyclic N-containing peroxides can be involved in reactions with binucleophilic reagents, in particular a,u-dithiols, to give new heterocycles. In contrast to the previously described methods of synthesis [5][6][7][8][9][10] and transformation of the peroxide ring, 5,11 this work for the rst time discusses the method of catalytic conversion of tetraoxazaspirotridecane to dithiazacycloalkanes.…”