Chemical Stability of the Peroxide Bond Enables Diversified Synthesis of Potent Tetraoxane Antimalarials

Abstract

Of 17 prepared 1,2,4,5-tetraoxacyclohexanes stable to reductive and acidic conditions, 3 of them were more active than artemisinin against CQ and MFQ resistant strain TM91C235 and all compounds were more active in vitro against W2 than against D6 strain. In vivo, amines 10 and 11a cured all mice at higher doses with MCD < or = 37.5 (mg/kg)/day. Triol 13 was exceptionally active against melanoma (LOX IMVI) and ovarian cancer (IGROV1), both with LC 50 = 60 nM.

Redox-Directed Cancer Therapeutics: Molecular Mechanisms and Opportunities

“…3A-8), a compound that displays potent antiproliferative effects in the nanomolar concentration range as determined in the NIH 60 cancer cell line screen without displaying significant antimalarial effects (268,337).…”

Synthesis, antimalarial activity evaluation and molecular docking studies of some novel dispiro-1,2,4,5-tetraoxanes

“…The reaction mixture was stirred for 2 hours at room temperature and quenched with saturated NaHCO3 and CH2Cl2. The organic layer was separated, and the water layer was filtered and dried Opsenica et al, 2008;Terent'ev et al, 2012).…”

“…After an additional 50 min of stirring, the reaction was quenched with saturated NaHCO3 and CH2Cl2. The organic layer was separated, and the water layer was filtered and dried Opsenica et al, 2008;Terent'ev et al, 2012 24.96, 25.29 (2xC, cyclohexyl), 27.52, 27.61, 27.79, 27.85, 28.46, 29.26 (2xC, cyclopentyl), 30.38, 30.84, 32.08, 33.01, 33.11, 33.68, 33.49 (2xC, cyclohexyl), 38.92 (1xC, cyclohexyl), 39.12, 39.33, 39.54, 39.75, 39.96, 40.17 (2xC, cyclopentyl), 53.93, 60.59, 63.16, 63.38, 63.43, 78.42, 78.75, 79.08 (1xC, tetraoxane), 172.41, 172.54, 174.09, 174.24 (1xC, tetraoxane) 25.62 (2xC, cyclopentyl), 28.01, 28.10 (2xC, cycloheptyl), 29.71, 40.40 (2xC, cyclopentyl), 76.72, 77.04, 77.36 (2xC, cycloheptyl), 125.50, 125.64 (2xC, cycloheptyl), 127.65 (1xC, tetraoxane), 127.97 (1xC, tetraoxane).…”

Synthesis of pentaoxaspiroalkanes and pentaoxocanes catalyzed by lanthanide compounds

“…5 The nitrogen-containing cyclic peroxides are promising compounds with antimalarial activity. 2,6 The best known methods for the synthesis of pentaoxocanes are the acid-catalyzed reaction of α-alkoxyhydroperoxides with aliphatic aldehydes, [7][8][9] the acidolysis of aryl/alkyl cycloalkene ozonides with chlorosulfonic acid, 4,[10][11][12] and the reaction of bissilylisochromane with aromatic aldehydes. 12 Drawbacks of the known methods of pentaoxocane synthesis include the low (5%) or moderate (34%) yields and the several steps needed to obtain the desired products.…”